Pancreatitis - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

PANCREATITIS A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES J AMES ...

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PANCREATITIS A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES

J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS

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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright 2004 by ICON Group International, Inc. Copyright 2004 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Pancreatitis: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-597-84149-7 1. Pancreatitis-Popular works. I. Title.

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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.

Copyright Notice If a physician wishes to copy limited passages from this book for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications have copyrights. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs, or other materials, please contact us to request permission (E-mail: [email protected]). ICON Group often grants permission for very limited reproduction of our publications for internal use, press releases, and academic research. Such reproduction requires confirmed permission from ICON Group International, Inc. The disclaimer above must accompany all reproductions, in whole or in part, of this book.

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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on pancreatitis. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.

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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.

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About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes&Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health

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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON PANCREATITIS........................................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Pancreatitis ................................................................................. 26 E-Journals: PubMed Central ....................................................................................................... 79 The National Library of Medicine: PubMed ................................................................................ 80 CHAPTER 2. NUTRITION AND PANCREATITIS ............................................................................... 125 Overview.................................................................................................................................... 125 Finding Nutrition Studies on Pancreatitis ................................................................................ 125 Federal Resources on Nutrition ................................................................................................. 133 Additional Web Resources ......................................................................................................... 134 CHAPTER 3. ALTERNATIVE MEDICINE AND PANCREATITIS ........................................................ 135 Overview.................................................................................................................................... 135 National Center for Complementary and Alternative Medicine................................................ 135 Additional Web Resources ......................................................................................................... 148 General References ..................................................................................................................... 149 CHAPTER 4. DISSERTATIONS ON PANCREATITIS .......................................................................... 151 Overview.................................................................................................................................... 151 Dissertations on Pancreatitis..................................................................................................... 151 Keeping Current ........................................................................................................................ 152 CHAPTER 5. CLINICAL TRIALS AND PANCREATITIS ..................................................................... 153 Overview.................................................................................................................................... 153 Recent Trials on Pancreatitis ..................................................................................................... 153 Keeping Current on Clinical Trials ........................................................................................... 155 CHAPTER 6. PATENTS ON PANCREATITIS ..................................................................................... 157 Overview.................................................................................................................................... 157 Patents on Pancreatitis .............................................................................................................. 157 Patent Applications on Pancreatitis .......................................................................................... 175 Keeping Current ........................................................................................................................ 196 CHAPTER 7. BOOKS ON PANCREATITIS ......................................................................................... 197 Overview.................................................................................................................................... 197 Book Summaries: Federal Agencies............................................................................................ 197 Book Summaries: Online Booksellers......................................................................................... 204 The National Library of Medicine Book Index ........................................................................... 206 Chapters on Pancreatitis ............................................................................................................ 207 CHAPTER 8. MULTIMEDIA ON PANCREATITIS .............................................................................. 211 Overview.................................................................................................................................... 211 Video Recordings ....................................................................................................................... 211 Audio Recordings....................................................................................................................... 213 Bibliography: Multimedia on Pancreatitis................................................................................. 213 CHAPTER 9. PERIODICALS AND NEWS ON PANCREATITIS ........................................................... 217 Overview.................................................................................................................................... 217 News Services and Press Releases.............................................................................................. 217 Newsletter Articles .................................................................................................................... 221 Academic Periodicals covering Pancreatitis .............................................................................. 223 CHAPTER 10. RESEARCHING MEDICATIONS................................................................................. 225 Overview.................................................................................................................................... 225 U.S. Pharmacopeia..................................................................................................................... 225 Commercial Databases ............................................................................................................... 227 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 231

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Overview.................................................................................................................................... 231 NIH Guidelines.......................................................................................................................... 231 NIH Databases........................................................................................................................... 233 Other Commercial Databases..................................................................................................... 235 The Genome Project and Pancreatitis ........................................................................................ 235 APPENDIX B. PATIENT RESOURCES ............................................................................................... 241 Overview.................................................................................................................................... 241 Patient Guideline Sources.......................................................................................................... 241 Finding Associations.................................................................................................................. 245 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 249 Overview.................................................................................................................................... 249 Preparation................................................................................................................................. 249 Finding a Local Medical Library................................................................................................ 249 Medical Libraries in the U.S. and Canada ................................................................................. 249 ONLINE GLOSSARIES................................................................................................................ 255 Online Dictionary Directories ................................................................................................... 257 PANCREATITIS DICTIONARY ................................................................................................ 259 INDEX .............................................................................................................................................. 361

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FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with pancreatitis is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about pancreatitis, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to pancreatitis, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on pancreatitis. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to pancreatitis, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on pancreatitis. The Editors

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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.

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CHAPTER 1. STUDIES ON PANCREATITIS Overview In this chapter, we will show you how to locate peer-reviewed references and studies on pancreatitis.

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and pancreatitis, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type “pancreatitis” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is what you can expect from this type of search: •

Understanding Pancreatitis and Pancreatic Cancer Source: Digestive Health and Nutrition. 3(3): 17-20. May-June 2001. Contact: Available from American Gastroenterological Association. 7910 Woodmont Avenue, 7th Floor, Bethesda, MD 20814. (877) DHN-4YOU or (301) 654-2055, ext. 650. Email: [email protected]. Summary: Acute pancreatitis (inflammation of the pancreas) can happen to anyone, anytime. However, repeated episodes put the patient at risk for chronic pancreatitis and pancreatic cancer, so it is important to learn about the risk factors and symptoms of these diseases. This article reviews the presenting symptoms of pancreatitis, the anatomy and physiology of the healthy pancreas, treatment options, and the risk factors for pancreatic cancer. The most common cause of acute pancreatitis is gallstones that get

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caught at the opening into the small intestine. Excessive alcohol use is another common cause of the disease. Diagnosis can include blood tests, an abdominal CT (computed tomography) scan, and endoscopic ultrasound. Treatment for acute pancreatitis is usually relatively low tech, featuring hydration (adequate fluids), pain management, and nutrition support (intravenous). During an episode of acute pancreatitis, which can last days or even a week, patients usually do not eat any food at all initially. Clear liquids and then low fat foods are added gradually as symptoms improve. When gallstones cause pancreatitis, surgery to remove them is usually necessary. For those who already have chronic pancreatitis or are at risk for developing it, a healthy lifestyle and positive attitude are essential. Many people with pancreatitis find that a low fat diet helps reduce the severity of acute episodes and also slows the progression of the chronic disease. One sidebar offers a description of hereditary pancreatitis, which is a rare condition. The final section of the article discusses pancreatic cancer, noting that both chronic and hereditary pancreatitis put people at higher risk for developing pancreatic cancer. Appended to the article is a list of websites for readers who want to locate additional information about pancreatitis. 2 figures. •

Identification of Pancreatitis in the Ambulatory Setting Source: Gastroenterology Nursing. 24(1): 20-22. January-February 2001. Contact: Available from Williams and Wilkins. 351 West Camden Street, Baltimore, MD 21201-2436. (410) 528-8555. Summary: Acute pancreatitis can be life threatening and nurse practitioners must know the signs, symptoms, and risk factors for pancreatitis. This article reviews the identification of pancreatitis in the ambulatory setting. The author uses a case study of a 59 year old white woman who presents to the clinic with vague complaints of abdominal pain. Her symptoms began the evening before presentation and are progressively worsening. The author uses this case to illustrate the differential diagnostic process. The most common differential diagnoses for this patient's symptoms include appendicitis, acute pancreatitis, mesenteric ischemia or infarction, perforated gastric or duodenal ulcer, intestinal obstruction, biliary colic, and perhaps even inferior wall myocardial infarction. Making a diagnosis of acute pancreatitis depends on clinical history, physical examination, serum enzyme assays, and radiologic tests. The main goal of treatment for pancreatitis is supportive care, limitation of complications, and prevention of necrosis (tissue death) of the pancreas. In the case example, the patient's pancreatitis was thought to be caused by a mixture of estrogen and an ACE inhibitor. Although alcohol consumption and gallstones are the most frequent causes of pancreatitis in the general population, mediations are now being recognized as important causative agents that are often overlooked. The author reiterates that early recognition and treatment of acute pancreatitis can reduce suffering and serious complications for the patient. 3 tables. 7 references.

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Fungal Infection in Acute Necrotizing Pancreatitis Source: Journal of the American College of Surgeons. 188(4): 408-414. April 1999. Summary: Anecdotal reports suggest that patients with fungal infection of necrotizing pancreatitis (NP) have worse outcomes than those with bacterial infections. This article reports on a study undertaken to compare the clinical course and outcomes of patients with NP infected with fungal versus nonfungal organisms. Data collected prospectively from 1983 through 1995 on 57 patients with infected NP (1983 through 1995) were reviewed. Seven patients (12 percent) developed fungal infection, and 50 (88 percent)

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developed bacterial infection. Groups had similar mean ages (60 versus 63 years) and APACHE II scores on admission. The cause of NP was ERCP (endoscopic retrograde cholangiopancreatography) induced in 3 of 7 with fungal infection versus 3 of 50 with bacterial infection. Patients with fungal infection had been treated with a mean of 4 different antibiotics for a mean of 23 days, and 4 of 7 (57 percent) required preoperative mechanical ventilation. In addition, postoperative intensive care unit stays were longer (20 versus 10 days), as were total hospital stays (59 versus 41 days). Mortality was higher with fungal infections; 3 of 7 patients (43 percent) died, versus 10 of 50 patients with bacterial infection (20 percent). The authors conclude that although NP presents with similar initial severity, patients with fungal infection tend to have a more complicated course and worse outcomes than those with bacterial infection. They recommend that low dose antifungal prophylaxis should be added to the early management of NP. 1 figure. 1 table. 33 references. (AA-M). •

Biliary Tract Disease and Pancreatitis in Pregnancy Source: Practical Gastroenterology. 15(2): 46-48, 51. February 1991. Summary: Biliary colic, acute cholecystitis, and acute pancreatitis occasionally complicate pregnancy and can result in difficult diagnostic and therapeutic challenges. Pregnancy seems to predispose women to gallstone formation. However, since cholelithiasis is common in women of childbearing age, the biliary tract disease that sometimes occurs in pregnant women may be coincidental rather than the result of pregnancy. Initial treatment of both biliary tract disease and pancreatitis in pregnancy is almost always medical, especially in the first and third trimesters. Elective surgery, when indicated, may be safely carried out during the second trimester or after delivery. In the vast majority of cases, acute biliary and pancreatic disorders, if properly managed, do not adversely affect the pregnancy. 18 references. (AA-M).

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Regression of Liver Fibrosis After Biliary Drainage in Patients with Chronic Pancreatitis and Stenosis of the Common Bile Duct Source: New England Journal of Medicine. 344(6): 418-423. February 8, 2001. Summary: Chronic obstruction of the common bile duct may cause hepatic (liver) fibrosis and secondary biliary cirrhosis (scarring). This article reports on a study of liver biopsy specimens from 11 patients with chronic stenosis (narrowing) of the common bile duct due to chronic pancreatitis (inflammation of the pancreas). All the patients had undergone liver biopsy before or at the time of surgical biliary decompression and all underwent a subsequent liver biopsy for various clinical reasons. The patients were followed as part of a prospective study of 501 patients who had been treated for chronic pancreatitis. Two pathologists, who were unaware of the sequence of specimens, graded fibrosis on a scale of 0 (none) to 3 (cirrhosis). The 11 patients were all men. Chronic pancreatitis was due to alcohol abuse in 10 of the men; 1 had idiopathic disease. The median age at diagnosis was 38 years. The median interval between the first and second liver biopsies was 2.5 years (range of 0.3 to 9.0 years). The two patients who had restenosis of the biliary anastomosis were excluded from the analysis. In the remaining group of nine patients, the second specimen showed significant improvement in fibrosis. The fibrosis improved by two grades in two patients and by one grade in four patients; in three patients, the grade did not change. The pathologists agreed on the grading of specimens from 10 of the 11 patients. The authors conclude that, in patients with chronic pancreatitis and stenosis of the common bile duct, liver fibrosis may regress after biliary drainage. 1 figure. 2 tables. 24 references.

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Chronic Pancreatitis: Complications and Management Source: Journal of Clinical Gastroenterology. 29(3): 225-240. October 1999. Contact: Available from Lippincott Williams and Wilkins, Inc. 12107 Insurance Way, Hagerstown, MD 21740. (800) 638-3030 or (301) 714-2300. Summary: Chronic pancreatitis is characterized by progressive and irreversible loss of pancreatic exocrine and endocrine function. In the majority of cases, particularly in Western populations, the disease is associated with alcohol abuse. This article reviews recent research and prevailing concepts regarding the three major complications of chronic pancreatitis: abdominal pain, malabsorption, and diabetes. Of these, pain is the most difficult to treat and is therefore the most frustrating symptom for both the patient and the physician. While analgesics form the cornerstone of pain therapy, a number of other treatment modalities (inhibition of pancreatic secretion, antioxidants, and surgery) have also been described. Unfortunately, the efficacy of these treatments is hard to assess, primarily because of the lack of properly controlled clinical trials. Replacement of pancreatic enzymes (particularly lipase) in the gut is the mainstay of treatment for malabsorption. Diabetes secondary to chronic pancreatitis is difficult to control and its course is often complicated by hypoglycemic attacks. Therefore, it is essential that caution is exercised when treating this condition with insulin. The authors also present a discussion of current opinion on clinical issues relating to the other known complications of chronic pancreatitis, including pseudocysts, venous thromboses, biliary and duodenal obstruction, biliary cirrhosis, and pancreatic cancer. 2 figures. 2 tables. 170 references.

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Serial Computed Tomography Is Rarely Necessary in Patients with Acute Pancreatitis: A Prospective Study in 102 Patients Source: Journal of the American College of Surgeons. 193(2): 146-152. August 2001. Contact: Available from Journal of the American College of Surgeons. P.O. Box 2127, Marion, OH 43306-8227. (800) 214-8489 or (740) 382-3322. Fax (740) 382-5866. Summary: Computed tomography (CT) has proved to be helpful in patients with acute pancreatitis for differentiating between mild and severe forms. Follow up of acute pancreatitis with CT has been advocated but rarely studied. This article reports on a study undertaken to determine if late CT performed at day 7 might be helpful in establishing the prognosis or the type of complications, and to select a subgroup of patients with pancreatitis in whom CT could be beneficial. Contrast enhanced CT was performed at the admission day and 7 days after admission in 102 patients admitted for acute pancreatitis. The extent of pancreatic inflammation was classified according to Balthazar grade, and intrapancreatic necrosis (tissue death) on these examinations was prospectively assessed and compared with clinical and biologic data and with patient outcomes. Among 102 patients, complications developed in 24 (23 percent). Complications developed in only 8 percent of patients with Ranson score less than 2, making routine early CT unnecessary. For the patients with Ranson score less than 2 and Balthazar grades A and B at day 1 CT, late CT seemed to be useless. Complication was suspected by clinical and biologic tests before day 7 in 22 of 24 complicated patients (94 percent), suggesting that CT could be proposed only in cases of clinical or biologic deterioration. Late CT was correlated with a complicated course in patients with Balthazar grades D and E or intrapancreatic necrosis greater than 50 percent. Late CT was predictive of complications in cases of intrapancreatic necrosis enlarging since the first examination. The authors conclude that in cases of acute pancreatitis, there is little justification for systematic early CT, especially in patients with Ranson score less than 2,

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and late CT does not need to be performed routinely, but only in cases of clinical or biologic worsening. 2 figures. 4 tables. 26 references. •

Better Test for Pancreatitis? Source: Emergency Medicine. 22(16): 109. September 30, 1990. Summary: Elevated serum amylase and the clinical picture usually identify acute pancreatitis within 24 hours after the onset of an attack. This brief article discusses the use of a serum lipase test followed, if necessary, by computed tomography (CAT Scan), to reliably confirm the diagnosis. CAT scanning can reveal the presence and extent of pancreatic necrosis and, therefore, the risk of local or systemic complications. The author concludes that initial management of patients thought to have acute pancreatitis, even before the results of the blood tests are available, should include immediate hydration with intravenously-delivered fluids, decompression of the stomach, and the cessation of any oral intake.

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Non-Surgical Treatment for Gallstone Pancreatitis Source: Current Topics in Gastroenterology. March 1992. p. 4. Summary: Gallstone pancreatitis is a painful and potentially serious condition caused by gallstones passing from the gallbladder and causing inflammation of the pancreas. This article reports on the use of a non-surgical treatment for gallstone pancreatitis: endoscopic retrograde cholangiopancreatography (ERCP), with sphincterotomy. The article discusses patient selection, indications for the procedure, the techniques used, and the results obtained in a group of 15 patients who were treated with this technique. The researchers conclude that ERCP with sphincterotomy is a safe alternative to gallbladder surgery in high risk patients with gallstone pancreatitis.

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Experimental Pancreatitis Source: Current Opinion in Gastroenterology. 7(5): 702-708. October 1991. Summary: Given the practical limitations of clinical research in acute pancreatitis, experimental animal models represent the primary means for investigating the pathophysiology of pancreatitis and of initially testing potential therapeutic modalities. This review article describes recent studies of pathophysiology mechanisms that have evaluated a number of factors, including possible injurious effects of nicotine on the pancreas, alterations in normal exocrine secretory processes, the role of oxygen-derived free radicals, effects of acute pancreatitis on other organs and physiologic functions, and the contribution of stress to the severity of pancreatitis. Investigations of potential therapies have included cholecystokinin-receptor antagonists, peritoneal lavage with protease inhibitors, prostaglandin analogues, and drugs that alter pancreatic blood flow and microvascular permeability. In addition, experimental models of pancreatitis are providing insights into mechanisms of pancreatic growth, differentiation, and repair. 35 annotated references. (AA).

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Refractory Pancreatitis Secondary to Ruptured Hepatocellular Carcinoma into the Common Bile Duct Source: Digestive Diseases and Sciences. 46(5): 1029-1033. May 2001. Contact: Available from Kluwer Academic Publishers. Customer Service Department, P.O. Box 358, Accord Station, Hingham, MA 02018-0358. (781) 871-6600. Fax (781) 6819045. E-mail: [email protected]. Website: www.wkap.nl. Distribution Centre, P.O. Box

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322, 3300 AH Dordrecht, The Netherlands. 31 78 6392392. Fax: 31 78 6546474. E-mail: [email protected]. Summary: Hepatocellular carcinoma (HCC, liver cancer) is a common disease worldwide and continues to be the leading cause of death of males in Taiwan (from where this article originates). Jaundice is present in 19 to 44 percent of cases of HCC at the time of diagnosis and is usually attributed to the preexisting liver cirrhosis (scarring) or extensive hepatic parenchymal (the liver body) destruction by tumor. Icteric hepatoma (a type of liver tumor) is characterized by intermittent obstructive jaundice with associated complications, such as cholangitis (inflammation of the bile ducts) and hemobilia. In this article, the authors report the first case of icteric hepatoma that initially presented as pancreatitis in addition to obstructive jaundice. The 59 year old man was admitted with a 2 week history of tea colored urine, intermittent tarry stool, vomiting, and postprandial epigastralgia (pain in the stomach after meals) with radiation to his back. He denied alcohol abuse and drugs consumption and he had never experienced pancreatitis. After 8 days of hospital treatment, the patient was released and able to eat a normal diet at an outpatient visit one month later. However, he was rehospitalized 8 weeks later with another episode of pain; surgical treatment was implemented. The patient died of multisystem organ failure on the 32nd postoperative day. For this case, the treatment was focused on two goals. First, the consequences of the biliary obstruction including the pancreatitis should be resolved by nonoperative methods, if available. Second, the origin of the migrating tumor should be eradicated either by transarterial chemoembolization or hepatic (liver) resection. The present case was not suitable for hepatic resection or hepatic artery ligation because of intrahepatic metastasis of both lobes and portal vein thrombosis (clotting) seen at exploration. Although palliation could be satisfactorily given, the prognosis continues to be dismal. 4 figures. 11 references. •

Managing Acute Pancreatitis: New ACG Recommendations Source: Journal of Critical Illness. 12(8): 508-510, 511. August 1997. Summary: In early 1997, the American College of Gastroenterology (ACG) issued guidelines for the diagnosis and treatment of acute pancreatitis. The guidelines included the clinical terminology for acute pancreatitis and its complications, the appropriate criteria for determining the severity of the disorder, and the indications for medical and surgical treatment. This article provides summaries of these guidelines and includes recommendations for practical patient care. Topics include diagnostic guidelines, symptoms, laboratory findings, severity criteria, supportive care, and additional interventions. The goals of medical therapy for acute pancreatitis are to provide supportive care and to prevent systemic complications, pancreatic necrosis, and pancreatic infection. In a patient with mild pancreatitis, supportive care and monitoring for complications often are all that is required. However, when severe pancreatitis is present, ICU admission is indicated for the management of systemic complications, and additional diagnostic tests are needed to rule out pancreatic necrosis. A detailed patient care algorithm is provided. 1 figure. 1 table. 1 reference. (AA-M).

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Acute Pancreatitis: Diagnosis and Management Source: American Family Physician. 52(2): 435-443. August 1995. Summary: In this article, the authors outline the steps in the diagnosis and management of acute pancreatitis, a clinical syndrome characterized by midepigastric pain, nausea, and vomiting. Topics include definitions; etiology; medications associated with acute

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pancreatitis; pathophysiology; clinical presentation; laboratory tests; diagnostic tests, including serum amylase level, lipase, abdominal radiographs, ultrasonography, and computed tomography; prognostic criteria for acute pancreatitis; treatment; and the role of surgery. The authors note that, once a diagnosis of pancreatitis is confirmed, supportive therapy with intravenous hydration and close observation is effective in the majority of patients. Lack of improvement may indicate the need to search for a local complication such as pseudocyst or abscess. They stress that evidence of the systemic complications of pancreatitis mandates intensive care monitoring. 4 figures. 4 tables. 41 references. (AA-M). •

Acute Pancreatitis in Peritoneal Dialysis and Haemodialysis: Risk, Clinical Course, Outcome, and Possible Aetiology Source: Gut. 46(3): 385-389. March 2000. Contact: Available from BMJ Publishing Group. P.O. Box 590A, Kennebunkport, ME 04046. (800) 236-6265. Summary: It has been suggested that the incidence of acute pancreatitis (pancreas infection) in patients with end stage renal disease (ESRD, kidney failure) is increased. This article reports on a study undertaken to assess the risk of acute pancreatitis in patients on long term peritoneal dialysis (PD) and long term hemodialysis (HD) compared with the general population, to evaluate its clinical course and outcome, and to identify possible etiological factors. All patients from a large general hospital in The Netherlands who were maintained on long term PD or HD (total dialysis time more than six weeks) from January 1989 to March 1998 were included. In 269 patients on HD (total of 614 person years), one patient developed an attack of acute pancreatitis. Patients on hemodialysis did not show an increased risk for acute pancreatitis compared with the general population. In 128 patients on PD (total of 241 person years), seven patients had nine attacks of acute pancreatitis. Patients on PD had a significantly and highly increased risk for acute pancreatitis. Mortality in this series of nine attacks was 11 percent. No single etiological risk factor could be identified. The authors conclude that the risk of acute pancreatitis in patients on long term PD is significantly and highly increased compared with the general population. 3 tables. 22 references.

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Nutrition Support in Pancreatitis Source: Nutrition in Clinical Practice (NCP). 10(2): 45-53. April 1995. Contact: Available from Nutrition in Clinical Practice (NCP). American Society for Parenteral and Enteral Nutrition. 8630 Fenton Street, Suite 412, Silver Spring, MD 209103805. (301) 587-6315. Summary: Nutrition support in patients with pancreatitis has created a challenge for clinicians. Because the pancreas is normally stimulated by the ingestion of food, particularly fat, patients are often denied oral nutrition. This review article summarizes the etiologies and methods for staging pancreatitis; the physiology of pancreatic exocrine secretion; and the response of the pancreas to different methods of nutrition support. The authors review the results of clinical trials, which examine both parenteral and enteral nutrition in animals and humans with this disease. They also discuss recommendations for nutrition management of patients with acute and chronic pancreatitis, and areas for future research. 2 tables. 81 references. (AA-M).

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Acute Pancreatitis: Systemic Complications and Prognostic Assessment Source: Practical Gastroenterology. 15(8): 22, 27-30, 32. Summary: Once a diagnosis of acute pancreatitis (AP) has been made, its severity may range from mild, with abdominal pain, nausea and vomiting, to severe, with multisystem involvement. This article reviews the systemic complications and prognostic assessment of acute pancreatitis. The authors note that the management of AP has paralleled the understanding of the effects of the pancreatic gland's capacity to release hormones, enzymes, and peptides and their clinical manifestations. Advances in critical care permit survival of patients with severe fulminating pancreatitis. Death is primarily due to multisystem failure early on, or sepsis later, as secondary infection sets in. The authors discuss system complications (cardiac, renal, respiratory, and metabolic), infrequent system complications, measuring the severity of AP, peritoneal lavage, computed tomography, and the value of prognostic assessment. 5 tables. 27 references. (AA-M).

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Pain and Chronic Pancreatitis Source: European Journal of Gastroenterology and Hepatology. 3(6): 425-433. June 1991. Summary: Pain is the principal symptom of chronic pancreatitis, and relief of pain the principal aim of treatment. The mechanism of pain production has been a matter of considerable speculation, but remains unclear. This review article collates the available evidence regarding the cause of pain in chronic pancreatitis in an attempt to explain the variable results of treatment. Topics include pancreatic ductal pressure, biliary tract obstruction, pseudocyst formation, perineural inflammation and infiltration, interruption of pain pathways, significance of calcification, and the interplay of abstinence from alcohol, pancreatic function, and pain. 73 references.

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Pancreatic Enzyme Therapy and Nutritional Status of Outpatients with Chronic Pancreatitis Source: Gastroenterology Nursing. 24(2): 84-87. March-April 2001. Contact: Available from Williams and Wilkins. 351 West Camden Street, Baltimore, MD 21201-2436. (410) 528-8555. Summary: Patients with chronic pancreatitis are at risk for poor nutritional status. The two major clinical features of chronic pancreatitis are abdominal pain and maldigestion, both resulting in malnutrition. Abdominal pain often results in decreased oral intake, and decreased enzyme production results in maldigestion. Enzyme therapy often is included in treating chronic pancreatitis. There is limited data on the nutritional assessment of outpatients with chronic pancreatitis, and the efficacy of the use of enzyme therapy remains controversial. Serum albumin (levels of protein in the blood) level and measurement of ideal body weight are two simple measures of nutritional status that can be obtained by gastroenterology nurses. This article reports on a retrospective chart review that was done on patients seen in the authors' outpatient clinic for management of chronic pancreatitis. Serum albumin levels, and indicator of protein caloric malnutrition, were reviewed for 34 patients. Thirty-three percent of these patients were found to have mild to moderate protein calorie malnutrition as evidence by low serum albumin levels. Enzyme therapy information was reviewed for 33 patients. Patients receiving enzyme therapy had better nutritional status based on both serum albumin levels and percent of ideal body weight. The authors conclude that

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gastroenterology nurses can be instrumental in the recognition and treatment of nutritional deficiencies in chronic pancreatitis. 3 figures. 3 tables. 4 references. •

Recurrent Acute Pancreatitis: An Algorithmic Approach to Identification and Elimination of Inciting Factors Source: Gastroenterology. 120(3): 708-717. February 2001. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 32887-4800. (800) 654-2452. Website: www.gastrojournal.org. Summary: Recurrent acute pancreatitis represents a challenging clinical problem associated with significant morbidity, impairment in quality of life, and expense. The evaluation of patients with recurrent acute pancreatitis requires systematic identification or elimination of correctable inciting factors. This article provides a comprehensive yet concise overview of the causes of recurrent acute pancreatitis; a detailed review of data relevant to implicated medications, the controversial issues of pancreas divisum and sphincter of Oddi dysfunction, and the role of genetic testing; a guideline for the evaluation of patients during the initial episode of acute pancreatitis; and a consensus algorithm within which putative inciting factors may be identified and eliminated. The guidelines offered pertain only to patients with recurrent acute pancreatitis in the absence of obvious evidence of chronic pancreatitis. Future advances in the treatment of these patients will almost certainly depend on improved imaging modalities, prospective clinical trials assessing the efficacy of endoscopic and surgical intervention, a better understanding of mutations and pathophysiologic mechanisms responsible for recurrent acute pancreatitis, and the development of novel, effective preventive and therapeutic strategies. 2 figures. 6 tables. 96 references.

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Acute Pancreatitis After Abdominal Vascular Surgery Source: Journal of the American College of Surgeons. 191(4): 373-380. October 2000. Contact: Available from Journal of the American College of Surgeons. P.O. Box 2127, Marion, OH 43306-8227. (800) 214-8489 or (740) 382-3322. Fax (740) 382-5866. Summary: Retroperitoneal dissection and ischemia (lack of blood to a body part) have been proposed as risk factors for postoperative pancreatitis. This study was undertaken to determine the incidence and outcomes of pancreatitis after abdominal vascular surgery. The authors collected data on 21 patients who developed pancreatitis after abdominal vascular operations; 21 controls undergoing identical operations were also randomly identified from the authors' operative log. The incidence of pancreatitis among all patients undergoing abdominal vascular operations during the 6 year study period was 1.8 percent. Pancreatitis was diagnosed a mean of 9.8 days (plus or minus 8 days) after operation and was associated with 3 or less Ranson signs in all 21 study subjects. Although there was a trend towards longer hospitalization in the subjects, there was no difference in complication rates between the two groups. Sixteen subjects (76 percent) had no complications. Three developed severe complications, two of whom died of causes unrelated to pancreatitis. One developed a pseudocyst that resolved spontaneously. Cholelithiasis (gallstones) was a causative factor in two subjects; no cause was established in the remaining 19. There was no difference in operative details between the two groups. The authors conclude that pancreatitis is a rare and self limited complication of abdominal vascular surgery. Pancreatitis is costly and inconvenient but rarely serious after abdominal vascular operations. 3 tables. 26 references.

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Chronic Pancreatitis: Asia-Pacific Consensus Report Source: Journal of Gastroenterology and Hepatology. 17(4): 508-518. April 2002. Contact: Available from Blackwell Science. 54 University Street, Carlton South 3053, Victoria, Australia. +61393470300. Fax +61393475001. E-mail: [email protected]. Website: www.blackwell-science.com. Summary: The current knowledge about chronic pancreatitis (CP) is limited and there is a particular lack of information about the entity known as tropical pancreatitis. A consensus working party was convened by the Trustees of the Journal of Gastroenterology and Hepatology Foundation to conduct a systematic investigation into available evidence about the epidemiology, etiopathogenesis, diagnosis and management of CP. A literature search and formal survey of international experts in the field were used to assemble reliable evidence about these issues. This review article summarizes the results of the working party's findings and presents a series of practice guidelines to improve diagnosis, investigation and treatment of patients with CP, particularly those in the Asia-Pacific region. The authors also identify areas for further research. 98 references.

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Pancreatic and Biliary Disease: Laboratory Diagnostic Tests in Acute Pancreatitis Source: Journal of Clinical Gastroenterology. 34(4): 459-462. April 2002. Contact: Available from Lippincott Williams and Wilkins, Inc. 12107 Insurance Way, Hagerstown, MD 21740. (800) 638-3030 or (301) 714-2300. Summary: The diagnosis of acute pancreatitis (inflammation of the pancreas) depends on a combination of clinical assessment and laboratory testing. This article reviews the laboratory diagnostic tests in acute pancreatitis. Although the serum amylase is the cornerstone laboratory test used in establishing the diagnosis of acute pancreatitis, there are limitations in the sensitivity and specificity that may be important for the clinician to recognize. The serum lipase level may be especially useful in patients with alcoholinduced acute pancreatitis. A new urinary test strip that uses trypsinogen-2 may have a role in establishing the diagnosis of acute pancreatitis. In addition, several new laboratory tests and new interpretations of old laboratory tests may assist in establishing the etiology (cause) and severity of acute pancreatitis. The authors summarize important aspects of standard laboratory tests and new laboratory approaches in establishing the diagnosis, etiology, and severity of acute pancreatitis. 1 table. 36 references.

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Risk Factors for Diabetes Mellitus in Chronic Pancreatitis Source: Gastroenterology. 119(5): 1324-1332. November 2000. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 19106-3399. (800) 654-2452 or (407) 345-4000. Summary: The influence of disease progression and pancreatic surgery on the appearance of diabetes mellitus in patients with chronic pancreatitis is unknown. This article reports on a prospective cohort study of 500 consecutive patients with chronic pancreatitis (alcoholics, 85 percent); patients were followed over a mean period of 7.0 years (plus or minus 6.8 years) in a medical surgical institution between 1973 and 1996. Analysis of risk factors for diabetes mellitus was performed after the exclusion of 47 patients. Patients who underwent elective pancreatic surgery (n = 231; 51 percent) were compared with patients who never underwent surgery (n = 222; 49 percent). The cumulative rate of diabetes mellitus was 83 percent (plus or minus 4 percent) 25 years

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after the clinical onset of chronic pancreatitis (insulin requirement, 54 percent). The prevalence of diabetes mellitus did not increase in the surgical group overall but was higher 5 years after distal pancreatectomy (a surgical procedure that removes 50 to 70 percent of the distal pancreas; 57 percent of the patients) than after pancreaticoduodenectomy (36 percent), pancreatic drainage (36 percent), or cystic, biliary, or digestive drainage (24 percent), without difference in the latter ones. Pancreatic drainage did not prevent the onset of diabetes mellitus. Distal pancreatectomy and early onset of pancreatic calcifications were the only independent risk factors for diabetes mellitus. The authors conclude that the risk of diabetes mellitus is not influenced by elective pancreatic surgical procedures other than distal pancreatectomy in patients with chronic pancreatitis. This risk seems to be largely caused by progression of the disease because it increased by more than 3 fold after the onset of pancreatic calcifications. 4 figures. 4 tables. 55 references. •

Evaluation of Factors That Have Reduced Mortality from Acute Pancreatitis Over the Past 20 Years Source: Journal of Clinical Gastroenterology. 35(1): 50-60. July 2002. Contact: Available from Lippincott Williams and Wilkins, Inc. 12107 Insurance Way, Hagerstown, MD 21740. (800) 638-3030 or (301) 714-2300. Summary: The mortality (death) associated with acute pancreatitis varies markedly in different studies, with most frequently reported mortality rates of 10 to 15 percent for all cases and 15 to 90 percent for attacks regarded as 'severe.' This article reports on a study undertaken to investigate whether there has been a reduction in mortality associated with acute pancreatitis over the past 20 years and the reasons for this reduction. The study featured the authors' 20 year prospective assessment of mortality as it relates to the severity of the disease, complications, and current therapy. The results showed that the initial reduction in mortality related to acute pancreatitis coincided with the recognition and application of the signs of severity. These signs dictated admission to intensive care unit (ICU) therapy, the intensity of ICU monitoring, and the importance of organ specific emergency therapy. Further mortality reduction in the 1990s could be attributed to either a more select study sample or earlier and more selective endoscopic or surgical debridement of infected tissue, endoscopic cyst drainage, and angiographic control of gastrointestinal bleeding. Improved nutritional support by jejunal feeding, earlier use of antibiotic therapy, gut sterilization, early endoscopic retrograde cholangiopancreatography (ERCP) for common bile duct stones, and necrosectomy (removal of dead tissue) for noninfected necrosis have reduced the overall mortality associated with acute pancreatitis to a mean of 5 percent for all cases and 20 percent for severe cases. 1 figure. 7 tables. 44 references.

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Prevalence and Pathogenesis of Duodenal Ulcer in Chronic Alcoholic Pancreatitis Source: Journal of Clinical Gastroenterology. 35(1): 71-74. July 2002. Contact: Available from Lippincott Williams and Wilkins, Inc. 12107 Insurance Way, Hagerstown, MD 21740. (800) 638-3030 or (301) 714-2300. Summary: The prevalence of duodenal ulcer (DU) has been considered high in patients with chronic pancreatitis; however, its pathogenesis is unclear. This article reports on a study that investigated the role of Helicobacter pylori infection in the pathogenesis of DU in this population. The study included 107 cases (97 men, 10 women) of chronic alcoholic pancreatitis (CAP) who were investigated between 1997 and 2001. Two control groups included 137 patients with DU only and 59 nonulcer dyspepsia patients. The

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results showed 15 of the 107 patients (14 percent) with CAP had active DU. There was a trend toward an association between the presence of diabetes mellitus and or steatorrhea and the occurrence of DU in patients with CAP. The rate of H. pylori infection was significantly higher in patients with CAP and DU than in those with only CAP but the rate was similar to that in patients with simple DU. There was no significant difference in prevalence of H. pylori between CAP patients without DU and dyspeptic patients. These data demonstrate that the prevalence of DU in CAP is relatively high. H. pylori infection seems to play the major pathogenic role in DU associated with CAP. 2 tables. 29 references. •

Acute and Chronic Pancreatitis Source: Practical Gastroenterology. 25(12): 47-54. December 2001. Contact: Available from Shugar Publishing. 12 Moniebogue Lane, Westhampton Beach, NY 11978. (516) 288-4404. Fax (516) 288-4435. Summary: There are over 100,000 hospital admissions for pancreatitis in the United States per year. Pancreatitis has numerous causes, obscure pathogenesis, and few effective treatments. This continuing education article reviews the diagnosis and management of patients with acute and chronic pancreatitis. Topics include anatomy and physiology, pathophysiology, etiology (cause), clinical presentation (symptoms), diagnosis, prognosis, treatment options, and complications, first for acute pancreatitis, then for chronic pancreatitis. The management of acute pancreatitis depends on the recognition of severity and the diagnosis and management of pancreatic necrosis (tissue death). The majority of patients will do well with conservative and supportive treatment, but necrotizing pancreatitis requires intervention due to the mortality associated with this local complication. Steatorrhea (excessive amounts of fats in the feces) in chronic pancreatitis responds to enzyme supplementation. Chronic pancreatic pain is very difficult to treat and a multidisciplinary approach is recommended. The characterization of the pain syndrome with diagnostic nerve blocks may prove to be very important at directing medical or surgical therapy. 10 figures. 4 tables. 30 references.

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Surgical Management of Chronic Pancreatitis Source: Practical Gastroenterology. 16(3): 11-13, 17-18. March 1992. Summary: This article addresses the surgical management of chronic pancreatitis. The authors discuss the indications for surgical intervention, surgical alternatives, large-duct pancreatitis, biliary obstruction, duodenal obstruction, and ascites. They note that surgery, like medical treatment, will not repair the damaged pancreas, nor will it halt the progression of the disease. However, surgery can play a very important role in management of the disease, and can significantly improve the quality of life of those affected. 6 figures. 1 table. 6 references.

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Clinical Highlights: Medical Treatment of Acute Pancreatitis Source: Hospital Medicine. 28(1): 63. January 1992. Summary: This article consists of a chart that summarizes the medical treatment of acute pancreatitis. Grouped into supportive and specific nonoperative techniques, the chart covers intravascular volume, indications for pain relief and nutrition, nasogastric suction, percutaneous peritoneal lavage, and the use of antibiotics. 1 figure.

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Diagnostic Tests in Chronic Pancreatitis Source: Practical Gastroenterology. 16(1): 23-27, 30. January 1992. Summary: This article describes the diagnostic tests used to determine chronic pancreatitis. The authors note that pancreatic calcifications and histology are the only two findings that definitively establish the diagnosis of chronic pancreatitis. Since radiologic calcification is demonstrable in only some 20 to 40 percent of patients in most series, and histology is available in only a small number of patients, the majority of patients require ancillary investigation to assist in the diagnosis. Topics include tests of pancreatic function in common use, morphologic tests, tests of endocrine function, tests of exocrine function, and etiologic tests. 4 tables. 8 references. (AA-M).

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Childhood Pancreatitis Source: American Family Physician. 59(9): 2507-2512. May 1, 1999. Contact: Available from American Academy of Family Physicians. 11400 Tomahawk Creek Parkway, Leawood, KS 66211-2672. (800) 274-2237. Website: www.aafp.org. Summary: This article discusses acute pancreatitis in children, a rare finding but one that is probably more common than is generally realized. This condition should be considered in evaluating children with vomiting and abdominal pain, because it can cause significant morbidity and mortality. Clinical suspicion is required to make the diagnosis, especially when the serum amylase concentration is normal. The most common cause of pancreatitis in childhood and adolescence is blunt trauma; child abuse should not be overlooked as a possible cause of the trauma. Other causes include metabolic and nutritional factors, alcohol abuse (particularly in older adolescents), drug effects, obstructive causes, infectious causes, and systemic causes (such as hypotension and ischemia). Recurrent pancreatitis may be familial and result from inherited biochemical or anatomic abnormalities. The mainstays of supportive treatment are fluid resuscitation, pain medication, and attention to nutritional needs. The authors note that patients with hereditary pancreatitis are at high risk for pancreatic cancer. The article includes the case of a 10 year old boy with chronic pancreatitis. 3 figures. 1 table. 15 references.

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Acute Pancreatitis in the Elderly Source: Practical Gastroenterology. 19(1): 10-12, 14-16, 21-22. January 1995. Contact: Available from Shugar Publishing, Inc. 99B Main Street, Westhampton Beach, NY 11978. (631) 288-4404. Fax (631) 288-4435. E-Mail: [email protected]. Summary: This article focuses on acute pancreatitis (AP) in the elderly. The authors note that the initial considerations in managing patients with acute pancreatitis are etiology and severity of the underlying inflammatory process. Drugs and biliary causes are the primary etiologies among elderly patients. Topics include the clinical presentation of AP in the elderly; etiological considerations; prognostic indicators, including single biochemical factors and multiple prognostic criteria; peritoneal lavage; computed tomography; therapy; development of systemic complications; pancreatic necrosis; and biliary pancreatitis. The authors conclude that laparoscopic cholecystectomy with intraoperative cholangiography and common bile duct exploration is the treatment of choice in the presence of cholelithiasis; preoperative endoscopic retrograde cholangiopancreatography (ECRP) reserved for severe cases. 5 tables. (AA-M).

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Pancreatitis: Managing a Flare-Up Source: Nursing96. 26(4): 33-40. April 1996. Summary: This article guides nurses in the care of managing patients experiencing a flare-up of pancreatitis. Topics include the degrees of inflammation of the pancreas (acute versus chronic), the anatomy and physiology of the pancreas, the causes of pancreatitis, assessing pain, symptoms, diagnostic tests and understanding laboratory findings, diagnosis and prognostic issues, setting nursing goals, managing drug therapy, managing abscesses and other complications of pancreatitis, and planning for discharge. A posttest is included with which readers can qualify for continuing education credits. 1 figure. 1 table. 3 references.

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Acute Pancreatitis: Which Route Is Better for Nutritional Support? Source: Journal of Critical Illness. 15(1): 10-11. January 2000. Contact: Available from Cliggott Publishing Company. 55 Holly Hill Lane, Greenwich, CT 06831-0010. (203) 661-0600. Summary: This article is an entry from a regular column in which physicians answer specific clinical problems. In this column, the question concerned the nutritional management of patients with acute pancreatitis and the preferred method of nutritional support (enteral or parenteral route). The author answers by noting that the optimal route and timing of nutritional support in patients with acute pancreatitis is controversial. Deciding when to start nutritional support depends on the patient's nutritional history and severity of pancreatitis. If a patient has adequate nutritional reserve and has mild or moderate pancreatitis, it is appropriate to wait 7 to 10 days before starting either enteral or parenteral nutrition and to give intravenous fluids only. There is insufficient evidence that shows nutrition alone positively affects the outcome of acute pancreatitis. Nutritional support simply supplies fluid, macronutrients (proteins, carbohydrates, and fats) and micronutrients (electrolytes, trace elements, and vitamins) while the patient takes nothing by mouth to minimize pancreatic stimulation. After 7 to 10 days without nutrition, negative nitrogen balance occurs, increasing a patient's risk of infection. At this point, nutritional support should be started if the patient is unable to take adequate oral nutrition. The author briefly summarizes two studies that support enteral over parenteral nutrition in the management of acute pancreatitis. The author cautions that in clinical practice, however, the choice is not always that easy. Patients frequently refuse nasal tubes and often do not tolerate the feedings. The author stresses that each case needs an individualized approach and that enteral nutrition should be used whenever possible. 5 references.

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Should Elective Endoscopic Sphincterotomy Replace Cholecystectomy for the Treatment of High-Risk Patients with Gallstone Pancreatitis? (editorial) Source: Journal of Clinical Gastroenterology. 13(2): 125-128. April 1991. Summary: This article notes that endoscopic sphincterotomy is currently the procedure of choice for management of retained common bile duct stones following cholecystectomy. It also is used more frequently for choledocholithiasis with an intact gallbladder in high-risk patients and in some patients with acute gallstone pancreatitis. To avoid surgery in high-risk patients, the authors propose that an elective endoscopic sphincterotomy may be a reasonable therapeutic option regardless of whether common bile duct stones are present. A prospective trial is needed to examine this issue, since, to date, there is no literature on endoscopic sphincterotomy in the absence of

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choledolithiasis for gallstone pancreatitis in patients with intact gallbladders. 1 table. 30 references. (AA-M). •

Current Concepts in the Management of Pancreatitis Source: Drugs. 41(3): 358-366. March 1991. Contact: Available from ADIS International. Suite B-30, Oxford Court Business Center, 582 Middletown Boulevard, Langhorne, PA 19047. (215) 752-4500. ISSN: 0012-6667. Summary: This article presents current concepts in the management of pancreatitis. Topics include establishing a diagnosis, determining severity, the treating and preventing complications, and preventing recurrence. The authors note that early endoscopic sphincterotomy for patients with severe gallstone pancreatitis and ductal calculi has been reported to reduce mortality and morbidity and may prove to be an important advance. 4 tables. 42 references.

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Octreotide Treatment in Patients with Severe Acute Pancreatitis Source: Digestive Dieseases and Sciences. 45(11): 2247-2251. November 2000. Contact: Available from Kluwer Academic/Plenum Publishers. 233 Spring Street, New York, NY 10013-1578. (212) 620-8000. Fax (212) 807-1047. Summary: This article reports on a study that investigated the effect of octreotide (Sandostatin) in the treatment of severe acute pancreatitis in a case control study. Experimental and clinical studies on the effect of octreotide in the treatment of acute pancreatitis have shown controversial results. The authors report on their prospective randomized study (begun in 1992) on the effect of octreotide in severe acute pancreatitis, undertaken in three hospitals in Israel. Patients were randomly assigned to conservative treatment either with or without octreotide (0.1 mg subcutaneously three times a day). Of 50 patients, 25 were assigned to octreotide (treatment group) and 25 to conservative treatment only (control group). The two groups were matched with regard to age, sex, etiology, and severity of the disease. The complication rate was lower in the treatment group with regard to sepsis and adult respiratory distress syndrome (ARDS). These decreases could be explained by the immunomodulatory effects of octreotide. The hospital stay was shorter in the treatment group. Two patients died in the treatment group and eight in the control group. These results suggest that octreotide may have a beneficial effect in the treatment of severe acute pancreatitis. 4 tables. 36 references.

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Acute Pancreatitis in Chronic Renal Failure Source: American Journal of Gastroenterology. 91(12): 2477-2482. December 1996. Summary: This article reports on a study to estimate the frequency and severity of acute pancreatitis (AP) associated with chronic renal failure (CRF) and to find out whether CRF causes AP. The authors studied 532 patients with a first episode of AP during the period of 1982 to 1994. Twenty-one patients had CRF; 511 patients without CRF served as controls. AP was diagnosed clinically and by elevation of amylase and lipase. CT or sonographic confirmation of diagnosis was made in all CRF patients. The cause of AP in the non-CRF group was significantly different from that seen in the CRF group. Incidence of severe AP in the two groups was 47.6 percent in the CRF group versus 21 percent in the non-CRF group. By simplified prognostic criteria, it was 38 versus 10.3 percent, respectively. Overall, CRF patients had more complications compared with non-CRF. CRF patients with severe AP had high mortality when stratified by either Ranson's or simplified prognostic criteria. The authors conclude that AP in CRF is

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frequently of unknown cause, suggesting the role of either CRF or other factors. Irrespective of cause, AP in CRF is a serious disease, associated with a high morbidity and mortality. 1 figure. 3 tables. 38 references. (AA-M). •

Pancreatitis in the Elderly Source: Journal of Clinical Gastroenterology. 19(1): 64-68. July 1994. Summary: This article reviews pancreatitis in older adults. The authors note that although acute and chronic pancreatitis in this age group are essentially the same diseases as in younger patients, some features are unique to the aged patient. Topics include incidence and etiology, clinical presentation, mortality, diagnosis, and treatment of acute pancreatitis; and the incidence and etiology, clinical presentation, diagnosis and treatment of chronic pancreatitis, including early or adult-onset chronic pancreatitis and senile chronic pancreatitis. The authors stress that complications of pancreatitis in older adults must be adequately treated to avoid malnutrition, which may seriously affect well-being and quality of life. 3 tables. 19 references. (AA-M).

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Diagnosis and Management of Acute Pancreatitis Source: American Family Physician. 62(1): 164-174. July 1, 2000. Contact: Available from American Academy of Family Physicians. 11400 Tomahawk Creek Parkway, Leawood, KS 66211-2672. (800) 274-2237. Website: www.aafp.org. Summary: This article reviews the diagnosis and management of acute pancreatitis, which usually occurs as a result of alcohol abuse or bile duct obstruction. A careful review of the patient's history and appropriate laboratory studies can help the physician identify the etiology (cause) of the condition and thus guide management. Serum (blood) amylase and lipase levels are still used to confirm the diagnosis of acute pancreatitis. Although not routinely available, the serum trypsin level is the most accurate laboratory indicator for pancreatitis. Ultrasonography, computed tomography, and endoscopic retrograde cholangiopancreatography (ERCP) are additional modalities that can help the family physician choose the best treatment approach. Prompt identification of patients who need intensive care referral or subspecialty consultation is crucial. The APACHE II and the multiple organ system failure scales provide prognostic information at the time of admission and may be repeated daily to monitor disease progression. Therapies such as nasogastric suctioning, anticholinergics, and histamine H2 receptor blockers have not been shown to decrease symptoms or hospital stays in patients with acute pancreatitis. Systemic antibiotics have been found to improve outcome in patients with severe disease. With supportive care, most patients have a good clinical outcome. 4 figures. 8 tables. 39 references.

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Etiology and Pathogenesis of Acute Pancreatitis: Current Concepts Source: Journal of Clinical Gastroenterology. 30(4): 343-356. June 2000. Contact: Available from Lippincott Williams and Wilkins, Inc. 12107 Insurance Way, Hagerstown, MD 21740. (800) 638-3030 or (301) 714-2300. Summary: This article reviews the etiology and pathogenesis of acute pancreatitis, a disorder that has numerous causes and an obscure pathogenesis. Bile duct stones and alcohol abuse together account for about 80 percent of acute pancreatitis. Most episodes of biliary pancreatitis are associated with transient impaction of the stone in the ampulla (that causes obstruction of the pancreatic duct, with ductal hypertension) or passage of the stone through and into the duodenum. Other causes of acute pancreatitis are various

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toxins, drugs, other obstructive causes (such as malignancy [cancer] or fibrotic sphincter of Oddi), metabolic abnormalities, trauma, ischemia, infection, and autoimmune diseases. In 10 percent of cases of acute pancreatitis, no underlying cause can be identified; this condition is known as idiopathic acute pancreatitis. Intra acinar activation of trypsinogen plays a central role in the pathogenesis of acute pancreatitis, resulting in subsequent activation of other proteases, causing the subsequent cell damage. Ischemia (fluid) or reperfusion injury is increasingly recognized as a common and important mechanism is the pathogenesis of acute pancreatitis and especially in the progression from mild edematous to severe necrotizing form of the disease. Increased intracellular calcium concentration also mediates acinar cell damage. Oxygen derived free radicals and may cytokines (e.g., interleukin 1, tumor necrosis factor alpha, platelet activating factor) are considered to be principal mediators in the transformation of acute pancreatitis from a local inflammatory process into a multiorgan illness. The damage to pancreatic cells and blood vessels that the different enzymes and inflammatory substances cause can result in tissue hypoxia (lack of oxygen) and further cellular necrosis (cell death), resulting in a vicious circle in which more pancreatic enzymes are released and more pancreatic injury occurs. 4 figures. 2 tables. 155 references. •

Nutritional Management in Acute and Chronic Pancreatitis Source: Gastroenterology Clinics of North America. 27(2): 421-434. June 1998. Contact: Available from W.B. Saunders. 6277 Sea Harbor Drive, Orlando, FL 32887-4800. (800) 654-2452 or (407) 345-4000. Summary: This article reviews the nutritional management of patients with acute or chronic pancreatitis. Topics include determining the need and route for nutritional support, factors that affect caloric requirements, enteral access, formulas, complications of pancreatitis and how they affect nutritional therapy, outpatient therapy, and evidence that nutritional therapy makes a difference. The authors note that not all patients with acute or chronic pancreatitis require nutritional alimentation. For those whose disease is more severe, however, failure to provide nutritional support can contribute to reduced defenses, an increased rate of complications, and a prolonged hospital course. Nutritional therapy in the past was governed by the principle that the gut should rest, and stimulation of pancreatic exocrine secretion should be avoided. These concepts have been replaced by the principle that pancreatic stimulation should be reduced to subclinical levels; that gut integrity should be maintained; and that the stress response should be contained to reduce the likelihood of multiple organ failure, nosocomial infection, and mortality. 70 references.

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Role of Imaging in Acute Pancreatitis Source: European Journal of Gastroenterology and Hepatology. 9(2): 106-116. February 1997. Contact: Available from Rapid Science Publishers. 400 Market Street, Suite 750, Philadelphia, PA 19106. (800) 552-5866 or (215) 574-2210. Summary: This article reviews the roles of ultrasound, computed tomography, and magnetic resonance imaging (MRI) in the evaluation and management of acute pancreatitis. The author notes that pancreatitis can remain localized to the pancreas and immediate peripancreatic tissues or can affect structures remote from the pancreatic bed. Thus, the imaging techniques chosen need to cover all organs and pathways likely to be affected. The author reviews the importance of imaging in the diagnosis of pancreatic necrosis, acute fluid collections, pancreatic abscess, pseudocysts, and vascular

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complications. Ultrasound is useful in the detection of gallstones and any associated compromise to the biliary tree; and in the detection of pancreatic and peripancreatic fluid collections. The role of MRI in the imaging of acute pancreatitis remains uncertain, with supporters of the technique suggesting that MRI is complementary to CT with definite advantages in certain situations. Other authors contend that the role of MRI has not been fully evaluated and currently offers no advantage over CT. The use of interventional techniques as opposed to surgical intervention is also discussed. 8 figures. 35 references (32 annotated). •

Tropical Pancreatitis Source: Journal of Clinical Gastroenterology. 35(1): 61-66. July 2002. Contact: Available from Lippincott Williams and Wilkins, Inc. 12107 Insurance Way, Hagerstown, MD 21740. (800) 638-3030 or (301) 714-2300. Summary: This article reviews tropical pancreatitis, an uncommon cause of acute, and often chronic, relapsing pancreatitis. Patients present with abdominal pain, weight loss, pancreatic calcifications, and glucose intolerance or diabetes mellitus. Etiologies (causes) include a protein-calorie malnourished state, a variety of exogenous food toxins, pancreatic duct anomalies, and a possible genetic predisposition. Chronic cyanide exposure from the diet may contribute to this disease, seen often in India, Asia, and Africa. The pancreatic duct of these patients often is markedly dilated, and may contain stones, with or without strictures. The risk of ductal carcinoma (cancer) with this disease is accentuated. Treatment may be frustrating, and may include pancreatic enzymes, duct manipulations at endoscopic retrograde cholangiopancreatography (ERCP), octreotide (drug therapy), celiac axis blocks for pain control, or surgery via drainage or resection. The article includes a representative example case study. 1 figure. 32 references.

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Chronic Pancreatitis Source: Lancet. 350(9088): 1379-1385. November 8, 1997. Summary: This article updates physicians on the diagnosis and treatment of chronic pancreatitis. Chronic pancreatitis is an inflammatory disease in which progressive and irreversible structural changes to the pancreas result in a permanent impairment of both the exocrine and endocrine functions. The authors cover classification; etiology, including alcohol-related (70 to 80 percent of all cases of chronic pancreatitis), idiopathic, hereditary, tropical, obstructive, hyperparathyroidism, trauma, pancreas divisum, and alfa-1-antitrypsin deficiency; clinical features, including pain, pancreatic insufficiency, glucose intolerance, diabetes mellitus, and classical physical appearance; diagnostic tests, including dynamic tests and pancreatic imaging; differential diagnosis; treatment options, including for pain management, relief of obstruction, maldigestion, and malabsorption; and complications, including duodenal and bile duct obstruction, pancreatic pseudocyst, pancreatic fistula, splenic-vein thrombosis, and pseudoaneurysm formation. The authors conclude with a brief section considering when patients with chronic pancreatitis should be referred to a specialist. 4 figures. 50 references. (AA-M).

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Chronic Pancreatitis: Surgical Treatment and Procedures Source: Practical Gastroenterology. 20(9): 40, 43-44, 46, 51-52, 54-56, 59-60, 62-63. August 1996. Contact: Available from Shugar Publishing, Inc. 99B Main Street, Westhampton Beach, NY 11978. (631) 288-4404. Fax (631) 288-4435. E-Mail: [email protected].

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Summary: This article, the eighth in a series on pancreatic disease, considers the use of surgical treatment for patients with chronic pancreatitis (CP). Surgery for chronic pancreatitis is performed for complications of the disease, for intractable pain, or when cancer cannot be excluded. The authors lament that the ideal operation, which should be simple to perform, provide longlasting pain relief, rectify the complications, avoid further endocrine and exocrine insufficiency, and have low mortality and morbidity, does not exist. Partington Rochelle decompression of the major pancreatic duct can be performed with low morbidity and mortality. Disenchantment with the operation has resulted from repeated failure to achieve sustained pain relief in half the patients who undergo it. The surgical procedures of 95 percent distal pancreatectomy was abandoned because of the high incidence of exocrine and endocrine insufficiency. From 50 to 60 percent distal pancreatectomy is applicable to a small percentage of patients with chronic pancreatitis who have ducts measuring 3 mm or less and disease limited to the body and tail of the pancreas. Pancreaticoduodenectomy, with or without pylorus preservation, is associated with sustained pain relief in 80 percent of patients, but it has not been embraced by many surgeons as their primary operation for pain relief because simpler procedures give promise of providing equivalent degrees of relief. These newer procedures, local resection of the head of the pancreas combined with longitudinal pancreaticojejunostomy, and duodenum preserving resection of the head of the pancreas, have been reported to provide sustained pain relief in about 80 percent of patients followed for an average of 37 months and 46 months, respectively. Further followup will be required to determine whether this degree of pain relief is maintained for 5 years or longer. 8 figures. 2 tables. 17 references. (AA-M). •

Acute Pancreatitis: Principles of Management Source: Practical Gastroenterology. 20(6): 26, 28, 33-36, 38-39. June 1996. Contact: Available from Shugar Publishing, Inc. 99B Main Street, Westhampton Beach, NY 11978. (631) 288-4404. Fax (631) 288-4435. E-Mail: [email protected]. Summary: This article, the fourth in a series on pancreatic disease, presents principles of management for the care of patients with acute pancreatitis. The authors note that the treatment of these patients depends primarily on the etiology and severity of the disease. The goals of therapy are to control the inflammatory process and manage any complications that arise. The finding of complications such as respiratory impairment, sepsis, and renal failure importantly influences treatment planning. Intravascular volume repletion and maintenance is vital in acute pancreatitis because it prevents further extension of the inflammatory process. A new treatment modality that involves the use of dextran seems to provide additional benefits in this regard. Patients with acute pancreatitis should be kept fasting until the inflammatory process is deemed to be controlled. Nutritional support with parenteral feeding is indicated for patients with severe pancreatitis and those expected to fast for a prolonged period. Pain, a cardinal symptom in acute pancreatitis, can be treated with parenteral meperidine. Octreotide seems to decrease the exocrine secretory activity of the pancreas. Prophylaxis with antibiotics may be considered for patients with severe forms of the disease. A new specific cytokine antagonist, lexipafant, has been shown to be effective in decreasing complications in severe acute pancreatitis. Endoscopic treatment of severe gallstone pancreatitis in its early stages decreases the frequency of biliary sepsis. Surgical treatment is indicated in cases of infected necrotizing pancreatitis. The optimal treatment for noninfected necrotizing pancreatitis remains to be defined. Intensive medical treatment should be provided initially, with failure to respond requiring a surgical approach. 1 figure. 57 references. (AA-M).

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Surgery for Acute and Chronic Pancreatitis Source: Practical Gastroenterology. 21(1): 30-34, 37-40, 42-43. January 1997. Contact: Available from Shugar Publishing, Inc. 99B Main Street, Westhampton Beach, NY 11978. (631) 288-4404. Fax (631) 288-4435. E-Mail: [email protected]. Summary: This article, the ninth in a series on surgery of the gastrointestinal (GI) tract, describes surgery for acute and chronic pancreatitis. The authors note that the clinical management of acute pancreatitis has been evolving during the last decade because of advances in critical care and better understanding of the natural history of the disease. Bacterial infection of pancreatic necrosis now plays a crucial role in the outcome of severe acute pancreatitis. Surgical intervention is concentrated in dealing with infection of the necrosed pancreas during the acute phase. In the late phase, the indications for surgery include prolonged ventilator dependency, intractable pain, biliary disease, and complications related to the gastrointestinal tract or the pancreatic ductal system. For chronic pancreatitis, major advances include better diagnostic modalities (endoscopy, computed tomography, and magnetic resonance imaging) and newer surgical procedures (the Beger and Frey procedures). Although there is no single operation that can deal with all the complications associated with chronic pancreatitis, surgical intervention, when appropriately chosen and properly performed, can be effective in relieving pain and potentially preserving organ function. 1 figure. 1 table. 33 references. (AA-M).

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Acute Pancreatitis: Clinical Classification and Terminology Source: Practical Gastroenterology. 20(5): 8, 9-10, 12, 14, 16, 21-22, 24. May 1996. Contact: Available from Shugar Publishing, Inc. 99B Main Street, Westhampton Beach, NY 11978. (631) 288-4404. Fax (631) 288-4435. E-Mail: [email protected]. Summary: This article, the second in a series on pancreatic disease, considers the clinical classification and terminology of acute pancreatitis. The author contends that the management of acute pancreatitis and its complications has been hampered by imprecise terminology and idiosyncratic definitions. Since optimal therapy requires accuracy in diagnosis, and since accurate diagnosis depends in turn on precise terminology, the need for an international consensus was apparent. Accordingly, a multidisciplinary group of 40 internationally recognized experts in acute pancreatitis was assembled in Atlanta, GA, in 1992 for the stated purposes of constructing a clinically based classification system for acute pancreatitis and creating a plan of management based on the new definitions. This article describes the deliberations and resulting recommendations of this symposium. The author concludes that the Atlanta Symposium's suggested classification and resulting therapeutic approach has been in prospective use for the past 5 years by authorities on acute pancreatitis all over the world and may now be recommended without reservation. One chart outlines the flow diagram for the initial management of patients with acute pancreatitis. 3 figures. 7 references. (AA-M).

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Chronic Pancreatitis: Medical Management Source: Practical Gastroenterology. 20(8): 6-8, 14-16, 18, 20-21. August 1996. Contact: Available from Shugar Publishing, Inc. 99B Main Street, Westhampton Beach, NY 11978. (631) 288-4404. Fax (631) 288-4435. E-Mail: [email protected].

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Summary: This article, the seventh in a series on pancreatic disease, considers the medical management of patients with chronic pancreatitis. The authors classify patients with chronic pancreatitis into two categories: those with big duct disease and those with small duct disease. The diagnostic approach to and medical management of the patient with chronic pancreatitis are greatly influenced by the degree of damage to the exocrine pancreas (i.e., the size of the involved ducts). Patients with chronic pancreatitis come to medical attention primarily because of abdominal pain and or maldigestion. The cornerstone of medical management for either of these complaints is the employment of pancreatic enzyme formulations. If severe damage to the pancreas is present (big duct disease), surgical decompression of the main duct or experimental suppression of pancreatic secretion with octreotide may afford pain relief. The authors conclude by reiterating the need for the clinician to consider duct size when designing appropriate management plans for patients with chronic pancreatitis. 4 figures. 4 tables. 30 references. (AA-M). •

Chronic Pancreatitis: Selective Use of Diagnostic Laboratory Procedures Source: Practical Gastroenterology. 20(7): 54-59. July 1996. Contact: Available from Shugar Publishing, Inc. 99B Main Street, Westhampton Beach, NY 11978. (631) 288-4404. Fax (631) 288-4435. E-Mail: [email protected]. Summary: This article, the sixth in a series on pancreatic disease, considers the selective use of diagnostic laboratory procedures in chronic pancreatitis (CP). The authors stress that the ease of diagnosing CP depends on the etiology, severity, and duration of the disease. In patients with severe CP due to alcohol, the diagnosis can be achieved through the characteristic history, plain abdominal xrays, and measurement of serum enzymes. Difficulties arise when, as in early idiopathic CP, the suspicion of CP is high but routine tests are negative. The use of more complex tests may not yield the diagnosis of CP because imaging tests (ultrasonography, computed tomography, and endoscopic retrograde pancreatography) and exocrine pancreative function tests may not yield abnormal findings until the disease is far advanced. The authors focus on providing practical points regarding the currently available tests that may be required to diagnose CP. 5 tables. 15 references. (AA-M).

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Acute Pancreatitis: Diagnosis and Evaluation Source: Practical Gastroenterology. 20(6): 8, 13-14, 16, 18, 20, 25. June 1996. Contact: Available from Shugar Publishing, Inc. 99B Main Street, Westhampton Beach, NY 11978. (631) 288-4404. Fax (631) 288-4435. E-Mail: [email protected]. Summary: This article, the third in a series on pancreatic disease, considers the diagnosis and evaluation of acute pancreatitis. The authors note that acute pancreatitis can be diagnosed in the vast majority of patients on the basis of the history and the finding of hyperamylasemia (raised amylase level in the blood). In about 5 to 30 percent of patients, the hyperamylasemia arises from causes other than pancreatitis, thus necessitating additional investigations. If differentiation from other catastrophic surgically correctable disease is problematic, an immediate computed tomography (CT) scan or, if CT is not available, laparotomy should be performed. Once the diagnosis of pancreatitis is established, the severity of the attack should be assessed in accord with some grading schema. Severity grading derives importance because it governs prognosis, mortality, and the intensity of therapy. The scoring systems currently in use correctly predict a severe or fulminating attack with an accuracy of about 80 to 90 percent in the 20 percent of patients who present with such attacks. A CT scan should

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not be used for the sole purpose of assessing severity, as the effect of the contrast material on renal and pancreatic microcirculation is still uncertain. However, CT is essential to uncover and delineate intra abdominal complications if the attack persists. Early etiologic assessment is also important because the detection of potential causes for acute pancreatitis will influence the treatment approach, both immediately and after subsidence of the acute process. 4 tables. 6 references. (AA-M). •

Acute Pancreatitis: Another Piece of the Puzzle? Source: New England Journal of Medicine. 325(6): 423-424. August 8, 1991. Summary: This brief article describes two forms of experimental pancreatitis and hypothesizes a connection between the occurrence of pancreatic cellular injury and calcium levels. The author briefly reviews the history of research work searching for the mechanisms that trigger acute pancreatitis. The author concludes that the observation of a relation between pancreatitis and calcium administration may provide yet another clue to the still puzzling story of the pathogenesis of pancreatitis. Reference is made to another article in the same journal issue that presents research in this area. 10 references.

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Acute Pancreatitis-A Historical Update Source: Practical Gastroenterology. 16(1): 18-19. January 1992. Summary: This brief article, serving as an introduction to a series of articles on pancreatitis, presents an historical update of the condition. Topics include early references to chronic pancreatitis secondary to alcoholism, the Marseille symposium of 1963, and the non-alcohol-related forms of chronic pancreatitis (senile, hereditary, and idiopathic). 2 figures. 1 table. 14 references.

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Antibiotics Prove No Match for Necrotizing Pancreatitis Source: Gastroenterology and Endoscopy News. p. 1, 10. January 2000. Contact: Available from McMahon Publishing Group. 545 West 45th Street, 8th Floor, New York, NY 10036. (212) 957-5300. Website: www.gastroendonews.com. Summary: This news article, from a monthly newspaper for gastroenterologists, describes the use of antibiotic prophylaxis in patients undergoing surgery for acute necrotizing pancreatitis (ANP). The author notes that the data demonstrate no net benefit for this antibiotic prophylaxis. Moreover, the widespread use of imipenem (Primaxin, Merck) alters the prevalence of various microorganisms in the pancreas and results in the emergence of antibiotic resistant flora. The author briefly reports on a new study that supports this contention; 46 patients were enrolled in the study, 20 of whom received imipenem, 16 received other antibiotics, and 10 received no prophylaxis. Drug resistant organisms were found in 12 (39 percent) of the 31 infected patients. The prevalence of the pancreatic organisms in infected patients differed from the researchers' expectations. Prior studies have tended to support the use of prophylactic antibiotics to reduce the rate of pancreatic infection in patients undergoing operative procedures for ANP. 2 tables.

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Practice Guidelines in Acute Pancreatitis Source: American Journal of Gastroenterology. 92(3): 377-386. March 1997. Summary: This practice guideline reviews the basis of decisions in the management of patients with acute pancreatitis. The author notes that there are a number of important

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issues pertaining to these decisions, including the need for a consensus on terminology, the most appropriate criteria for determining severity of acute pancreatitis, choices of medical versus surgical therapy, and options for treating complications, including pancreatic pseudocysts. After a section of definitions, the author provides goals and recommendations for each category. The goals of medical therapy include supportive care, limitation of systemic complications, prevention of pancreatic necrosis, and prevention of pancreatic infection once necrosis takes place. In mild pancreatitis, fluid resuscitation and careful monitoring are the two most important components of treatment. Dynamic contrast-enhanced CT scan is recommended at some point beyond the first 3 days in severe acute pancreatitis to distinguish interstitial from necrotizing disease. In the absence of clinical improvement, guided percutaneous aspiration should be performed to distinguish infected necrosis from severe sterile necrosis. Infected necrosis requires surgical debridement; severe sterile necrosis can usually be treated medically. Asymptomatic pseudocysts require no specific treatment. Symptomatic pseudocysts can be decompressed by surgical, radiologic, or endoscopic methods. 1 figure. 6 tables. 38 references. (AA-M). •

Management of Acute Pancreatitis: A Critical Assessment as Dr. Bockus Would Have Wished Source: American Journal of Gastroenterology. 90(5): 696-703. May 1995. Summary: This presentation, from the 1994 World Congress of Gastroenterology, reviews the management of acute pancreatitis. Topics covered include etiology and pathogenesis; terminology; severity grading; initial management of acute pancreatitis; peritoneal lavage; necrosis and infection; and biliary pancreatitis. The author focuses on some selected features and certain collateral factors that subtly or overtly influence the nature, breadth, and intensity of the therapeutic measures. 6 figures. 67 references. (AAM).

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Clinical Update: Management of Acute Pancreatitis Source: Journal of Gastroenterology and Hepatology. 12(3): 189-197. March 1997. Contact: Available from Blackwell Science Pty Ltd. P.O. Box 378, Carlton, Victoria 3053, Australia. Phone: 61 3 9347 0300; Fax: 61 3 9347 5001; E-mail: [email protected]. Web site: http://www.blacksci.co.uk. Summary: This review article considers the management of acute pancreatitis. The authors follow the clinically based classification system adapted at an international symposium in Atlanta in 1992. Acute pancreatitis refers to an acute inflammatory process of the pancreas, with variable involvement of other regional tissues or remote organ systems. The authors emphasize the importance of confirming the diagnosis and establishing the etiology. Improved methods of assessing the biliary tree may reduce the number of patients regarded as having idiopathic pancreatitis. Detailed clinical and laboratory protocols, designed to assess severity, have no major advantage over clinical assessment. The contrast-enhanced computed tomography (CT) scan is important to assess the degree of pancreatic necrosis and to detect local complications. The treatment of pancreatitis continues to be largely supportive. However, controlled studies support the use of antibiotics in severe acute pancreatitis and indicate a possible role for the use of octreotide and antioxidants. The place of endoscopic and surgical intervention is becoming better defined. Once an attack has passed, further investigation is often required in an attempt to prevent further episodes of inflammation. 1 figure. 2 tables. 99 references. (AA-M).

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Chronic Pancreatitis: Diagnosis, Classification, and New Genetic Developments Source: Gastroenterology. 120(3): 682-707. February 2001. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 32887-4800. (800) 654-2452. Website: www.gastrojournal.org. Summary: This review article focuses on the definitions and classification of chronic pancreatitis, on structural and genetic analysis, and on risk factors. Recent advances in molecular and genomic technologies and progress in pancreatic imaging techniques provided remarkable insight into genetic, environmental, immunologic, and pathobiological factors leading to chronic pancreatitis. Translation of these advances into clinical practice demands a reassessment of current approaches to diagnosis, classification, and staging. The authors maintain that an adequate pancreatic biopsy must be the gold standard against which all diagnostic approaches are judged. Although computed tomography (CT) remains the initial test of choice for the diagnosis of chronic pancreatitis, the roles of endoscopic retrograde pancreatography, endoscopic ultrasonography, and magnetic resonance imaging (MRI) are considered. Once chronic pancreatitis is diagnosed, proper classification become important. Major predisposing risk factors to chronic pancreatitis may be categorized as either toxic metabolic, idiopathic (unknown), genetic, autoimmune, recurrent and severe acute pancreatitis, or obstructive (TIGAR O system). After classification, staging of pancreatic function, injury, and fibrosis becomes the next major concern. Further research is needed to determine the clinical and natural history of chronic pancreatitis developing in the context of various risk factors. New methods are needed for early diagnosis of chronic pancreatitis, and new therapies are needed to determine whether interventions will delay or prevent the progression of the irreversible damage characterizing end stage chronic pancreatitis. 8 figures. 5 tables. 242 references.

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Gallstone Pancreatitis: Choosing and Timing Treatment Source: Postgraduate Medicine. 89(2): 123-129. February 1, 1991. Summary: Why the passage of small gallstones sometimes causes pancreatitis is still unclear, but the condition leads to life-threatening multisystem dysfunction in some people. This article notes that surgical removal of stones or the gallbladder is often necessary to prevent complications and recurrence. The timing of surgery is dictated by serum enzyme levels and liver function test results as well as by the patient's condition. Whether surgery or endoscopic sphincterotomy is preferable as primary therapy for gallstone pancreatitis remains unresolved. The authors illustrate diagnosis of the disorder with two representative case reports and also address treatment issues. 2 figures. 3 tables. 24 references.

Federally Funded Research on Pancreatitis The U.S. Government supports a variety of research studies relating to pancreatitis. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable

2 Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).

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database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to pancreatitis. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore pancreatitis. The following is typical of the type of information found when searching the CRISP database for pancreatitis: •

Project Title: 13CHIOLEIN BREATH TEST--NONINVASIVE MEASUREMENT OF PANCREATIC EXOCRINE FUNCTION Principal Investigator & Institution: Toskes, Phillip; University of Florida Gainesville, Fl 32611 Timing: Fiscal Year 2001 Summary: The purpose of this study is to show that the Hiolein breath test is a simple, safe and reliable test to diagnosis patients with chronic pancreatitis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: A PHYSICAL ACTIVITY & NUTRITION INTERVENTION IN HIV Principal Investigator & Institution: Smith, Barabara A.; None; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 30-JUN-2005 Summary: Although the use of potent antiretrovirals has improved mortality and morbidity associated with HIV-1 infection, new constellations of side effects continue to challenge nurses and other providers. One new syndrome associated with the antiretroviral therapy, lipodystrophy or fat redistribution, includes peripheral wasting, central fat accumulation, elevated blood lipids, glucose and insulin and places patients at risk for cardiovascular disease, diabetes, pancreatitis and may influence adherence to drug therapy; thus, the management of troubling side effects and symptoms such as lipodystrophy has taken on new importance and underscores the need to examine strategies that may attenuate or alleviate these side effects/symptoms. Subsequent work will need to focus on the prevention of the syndrome once strategies for managing the syndrome(s) have been identified. The purpose of the proposed study is to examine the effects of a 16-week integrated intervention designed to improve body composition, blood lipids and metabolic variables in HIV-1 infected individuals who are enrolled in NIH funded clinical trials of highly active antiretroviral therapy (HAART) and who are experiencing lipodystrophy. The intervention consists of three major components: physical activities intended to increase cardiorespiratory endurance, physical activities that will enhance strength, flexibility and increase cross-sectional area of muscle, and a nutrition component. Each component of the intervention is intended to improve some aspect of the lipodystrophy syndrome and is consistent with the Healthy People 2010. This experimental study will use a 2-group design with subjects in the experimental group (n=42) encouraged to accumulate 30 minutes of physical activity most if not all days of the week and set measurable dietary goals with the dietitian. Subjects in the control group (n=42) will maintain usual activity and usual diet for 16 weeks and then enter the intervention phase of the project. Subjects will be recruited from the ALLRT

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protocol or FRAM study at the UAB Outpatient HIV Clinic. A two by two, mixed model ANCOVA will be used to test study hypotheses related to body composition, blood lipids, glucose, insulin and C-peptide. Data from the study will be used to develop evidence-based guidelines for advanced practice nurses, dietitians, physicians and other health care providers to assist patients in managing lipodystrophy associated with HIV1 therapies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ACUTE PANCREATITIS Principal Investigator & Institution: Steer, Michael L.; Professor of Surgery; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2001; Project Start 01-JUL-1982; Project End 31-JUL-2003 Summary: (Adapted from investigator's abstract) Currently available evidence indicates that digestive enzyme zymogens such as trypsinogen become prematurely activated within acinar cells of the pancreas during the early stages of acute pancreatitis. Activated digestive enzymes are believed to cause cell injury leading to acinar cell death and pancreatitis. The proposed project will pursue the following specific aims: 1) to define the mechanisms responsible for premature activation of zymogens within the pancreas and the role of those activated digestive enzymes in the evolution of acute pancreatitis; and 2) to determine if the type of acinar cell death (ie, necrosis or apoptosis) during acute pancreatitis regulates the severity of that acute pancreatitis. The specific aim #1 studies will build on the observation that infusion of a supramaximally stimulating dose of the CCK analog caerulein causes intrapancreatic activation of trypsinogen as well as pancreatitis in rats. Furthermore, cathepsin B mediated activation of trypsinogen occurs when isolated acini are incubated in vitro with supramaximally stimulating concentrations of caerulein. In the proposed studies, the intracellular location of trypsinogen activation, the cellular events involved in trypsinogen activation, and the mechanism by which trypsinogen activation leads to cell injury will be determined. In the specific aim #2 studies, several models of experimental pancreatitis in laboratory animals (mice, rats, opossums) will be utilized to evaluate the possibility that apoptosis minimizes the severity of pancreatitis. The mechanisms underlying this phenomenon will be examined and the potential value of treating established pancreatitis by inducing apoptosis will be evaluated. Successful completion of these proposed studies will provide important new insights into the cellular basis for acute pancreatitis and identify methods of either preventing or minimizing the severity of this frequently lethal disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ADENOSINE IN TRAUMA AND SEPSIS Principal Investigator & Institution: Hasko, Gyorgy; Surgery; Univ of Med/Dent Nj Newark Newark, Nj 07103 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 30-JUN-2006 Summary: Multiple organ failure (MOF) is the cause of 50 percent to 80 percent of all deaths in surgical intensive care units. MOF is documented to occur after a number of diverse clinical conditions, including mechanical and thermal trauma, pancreatitis and shock. In a large subgroup of patients, secondary infections serve to trigger the development of MOF, which is related to the development of an excessive compensatory anti-inflammatory reaction (CARS) and a generalized immunosuppressive state. CARS is characterized by several changes in the patients'

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immune phenotype. Two of the most important of these immune-phenotypic changes are a shift in T helper (Th) cell population from a Th1 to a Th2 response and shift in the macrophage phenotype from a proinflammatory to an anti-inflammatory one. This shift in the macrophage phenotype is characterized by a decrease in the production of IL-12 and an increase in the production of IL-10. Neither the signals nor mechanisms responsible for the development of this altered immune phenotype have been fully elucidated. Recently, it has been proposed that this immunosuppressed state may be secondary to the excessive release of a variety of mediators including catecholamines and glucocorticoids by activation of the stress system. In addition, it appears that adenosine (ADO), another stress mediator released excessively during CARS, could also contribute to the immune paralysis seen in CARS, since ADO appears to potentiate the development of an immune compromised state. Using an anti-CD3- stimulated mouse spleen cell system, we have recently discovered that extracellular ADO augments the production of the Th2 cytokine IL-4, whereas it reduces the production of the Th1 cytokine interferon-gamma. In addition, we have obtained evidence that ADO enhances IL-10 and decreases IL-12 production by immunostimulated macrophages. Thus, we will investigate the hypothesis that high extracellular concentrations of ADO may contribute to the deleterious immune hyporesponsiveness observed in patients with CARS. Because ADO exerts its biological effects by binding to any of 4 specific cell surface receptors, we also hypothesize that ADO shifts the immune response from a proinflammatory to an anti-inflammatory one through the activation of certain ADO receptors present on T cells and macrophages. We will test these hypotheses both in vitro using T cell and macrophage systems as well as in vivo using the mouse cecal ligation and puncture model of MOF. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ALCOHOL REDUCTION IN MEDICAL ILLNESSES:HCV AS PROTOTYPE Principal Investigator & Institution: Dawson, Neal V.; Medicine; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): Alcohol use is discouraged or contraindicated for patients with a variety of medical illnesses. For many diseases directly caused by alcohol, the use of alcohol may be associated with recurrent symptoms shortly after its consumption, e.g., pancreatitis or gastritis, and the prohibition against alcohol is straightforward. However, for many chronic diseases, the use of alcohol is not associated with any short-term symptoms or sequelae. The course of these chronic diseases (or their treatments) among non-abusing/nondependent patients can be adversely affected by even moderate alcohol use, e.g., chronic hepatitis, (nonalcoholic) cirrhosis, severe diabetes, or the use of the 'blood thinner', warfarin. Chronic Hepatitis C virus (HCV) infection is a prototypical example of a disease in which alcohol use tends to cause no symptoms. Even moderate chronic alcohol use can be associated with an increased likelihood of cirrhosis and liver cancer. HCV infection rates and prognosis are related to alcohol use in multiple ways. Alcohol use during HCV treatment is associated with a decreased likelihood of viral clearance. Long-term alcohol use may increase the proliferation of HCV and the associated liver damage even with moderate alcohol consumption. Greatly reducing or eliminating alcohol use may importantly enhance the prognoses of patients, even if they are not candidates for specific HCV treatments. Despite having diagnoses that warrant abstinence from alcohol, many patients continue to drink alcohol. Little is known about why patients continue to consume alcohol in the

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face of diagnoses that warrant a reduction in use or abstinence. The current study is designed to determine factors that lead to continuing alcohol intake among alcohol nonabusing/nondependent patients who are advised to stop drinking by health care providers. In Phase 1, focus groups (patients and providers) will be used to discover issues that may be associated with continued drinking. In Phase 2, questionnaire items will be developed based on the data gleaned from Phase 1. The potential pool of items will be administered to 10 patients per item and factor analyzed. In Phase 3, the items retained from the pool of potential items will be used to create a questionnaire that will be tested for its ability to predict alcohol reduction or cessation. Since alcohol use is common in the U.S. and since most patients who currently have HCV are not candidates for treatment, abstinence from alcohol use represents a major opportunity to prevent a decline in the health and quality of life of patients with HCV and similar diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ALCOHOL SENSITIZES THE PANCREAS FOR CK INDUCED PANCREATITIS Principal Investigator & Institution: Pandol, s; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, Ca 90033 Timing: Fiscal Year 2001 Summary: The broad long-term objective of the work described in this application is to determine the molecular mechanisms responsible for the exocrine pancreatic disorders caused by ethanol. The work proposed is designed to determine the effect of an ethanolcontaining diet on the factors that mediate pancreatitis. Our hypothesis states that a ethanol diet alone or in combination with a low dose of cholecystokinin-octapeptide (CCK-8) infusion results in activation of transcription factors involved in regulating the expression of pro-inflammatory cytokines and chemokines. These cytokines/chemokines, in turn, mediate the inflammatory and cell death responses that are the hallmarks of pancreatitis. Using a rat model of continuous infusion of an ethanol-containing diet, we proposed the following specific aims: 1. Determine the effect of the ethanol diet with and without the CCK-8 infusion on activation of transcription factors (i.e., NF- kappaB and P-1) that regulate cytokine/chemokine production in the pancreas and inflammatory and cell death responses. 2. Determine the mechanism(s) of NF-kappaB and AP-1 activation in the pancreas caused by the ethanol diet in the presence and absence of the CCK-8 infusion. 3. Determine the effect of the ethanol diet with and without the CCK-8 infusion on the expression and regulation of specific cytokines/chemokines and their role in mediating inflammatory and cell death responses in pancreatitis. 4. Determine the effect of the ethanol diet with and without the CCK-8 infusion on intrapancreatic trypsin activation and the mechanism(s) of these effects on intrapancreatic trypsin activation. Measurements. to accomplish these goals will include serum amylase and lipase, pancreatic weight, pancreatic necrosis, apoptosis, vacuolization, neutrophils and macrophages using histologic techniques: pancreatic trypsin activation; transcription factor activation using gel shift assays; and expression of cytokines/chemokines using RT-PCR. Western blot analysis, immunocytochemistry and bioassay. The results of the studies described in this application will be elucidation of the mechanism of ethanol's effects in pancreatitis that can be used to design strategies for therapeutic interventions and clinical trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: AMYLIN AND ITS RELEASING FACTOR IN THE EARLY DIAGNOSIS OF PANCREATIC CANCER Principal Investigator & Institution: Adrian, Thomas E.; Professor; University of Nebraska Medical Center Omaha, Ne 681987835 Timing: Fiscal Year 2001; Project Start 25-MAR-1999; Project End 31-JAN-2003 Summary: Pancreatic cancer is associated with profound insulin resistance, resulting in diabetes in up to 80% of patients. This metabolic abnormality is tumor dependent and disappears after tumor resection, despite the loss of islets. Amylin is a pancreatic hormone that inhibits muscle glycogen synthesis and reduces food intake. In most pancreatic cancer patients, amylin levels are elevated in the fasting state. Even though diabetes may not be a major problem for the management of patients with pancreatic cancer, measurement of amylin may be a valuable marker for the early diagnosis of the disease, at least in a proportion of patients. Furthermore, the increased amylin levels appear to result from stimulation of peri-tumoral islets by a tumor-derived peptide (amylin releasing peptide of ARP). It is likely that, compared with amylin, circulating ARP levels are elevated in an even higher proportion of pancreatic cancer patients. The major goals of this proposal are as follows: 1. To investigate the specificity of elevated circulating amylin in pancreatic cancer, by investigating patients with pancreatitis, biliary obstruction, newly diagnosed diabetes, pancreatic cancer or other malignancies. 2. To purify and sequence ARP and develop a radioimmunoassay to measure this peptide. 3. To establish whether ARP is a better marker for pancreatic cancer than amylin, by measurement in the above groups of patients. 4. To determine the value of amylin and ARP as early indicators of pancreatic cancer, by measuring the peptides in families with a high risk of developing the disease, and by measuring them in samples from pancreatic cancer patient collected several years prior to their cancer diagnosis. This study may aid in the development of an early screening technique for detecting pancreatic cancer at an early, curable stage. In addition, it will improve our understanding of the role played by the islets in this disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ANTI-INFLAMMATORY PAF ACETYLHYDROLASE IN LUNG INJURY Principal Investigator & Institution: Howard, Katherine M.; Assistant Professor; Biochemistry; University of Texas Hlth Sci Ctr San Ant 7703 Floyd Curl Dr San Antonio, Tx 78229 Timing: Fiscal Year 2001; Project Start 01-JUL-2001; Project End 31-MAY-2005 Summary: Plasma-type platelet-activating factor acetylhydrolase is a distinct Ca+2independent phospholipase A2 enzyme specific for the inactivation of platelet-activating factor (PAF) and PAF- like phospholipids. Thus, PAF acetylhydrolase plays a crucial role in inactivating a potent inflammatory mediator implicated in the initiation and propagation of acute lung injury. This anti- inflammatory property of PAF acetylhydrolase has lead to the therapeutic investigation of PAF acetylhydrolase in a wide range of inflammatory diseases including asthma, Adult Respiratory Distress Syndrome, diabetes, pancreatitis, and vascular and heart disease. The objective of the proposed research is to investigate the cellular and molecular mechanisms involved in the expression and regulation of PAF acetylhydrolase in rat models of acute lung injury. Lung tissue PAF acetylhydrolase expression is dramatically increased in response to in vivo inflammatory challenge. Three closely related Specific Aims will lead to the localization and characterization of PAF acetylhydrolase- expressing cells; the

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elucidation of the mechanisms involved in PAF acetylhydrolase up-regulation; and the determination of the physiological consequences of increased PAF acetylhydrolase in resolving and limiting lung injury. First, a detailed localization and characterization of PAF acetylhydrolase in normal lung and in response to lung injury will be performed. These experiments in whole animals will explore the differential expression of PAF acetylhydrolase in resident lung macrophages and granulocytes. Granulocytes, predominately comprised of neutrophils, appear to have the capacity to deliver this potent anti-inflammatory agent to sites of inflammation. Second, the involvement of PAF, the PAF receptor, and STAT transcription factors in PAF acetylhydrolase upregulation will be examined. These experiments will determine the effects on PAF acetylhydrolase expression resulting from the administration of PAF and PAF receptor antagonists and in mice genetically lacking the PAF receptor. Third, the physiological consequences of upregulated PAF acetylhydrolase expression in lung injury will be investigated by assessing the in vivo PAF-degrading capacity of the compromised lung and determining the effects on the lung inflammatory sequelae in response to exogenous PAF acetylhydrolase administration. Through the logical design of the proposed studies, novel and important information will be gained that will significantly advance our understanding of the cell biology of this important anti-inflammatory enzyme. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: APOPTOSIS AND NECROSIS IN PANCREATITIS Principal Investigator & Institution: Gukovskaya, Anna S.; Medicine; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2007 Summary: (provided by applicant): Inflammation and parenchymal tissue damage are hallmarks of pancreatitis. In particular, severe necrosis is a major complication of the disease. Over the past decade, significant progress has been achieved in understanding the mechanisms of the inflammatory response of pancreatitis. In contrast, very little is known about the mechanisms of pancreatic acinar cell death. Mechanisms of necrosis are largely unknown. Key signals mediating apoptosis have been established; however, their roles in disease processes remain obscure, and they have not been investigated in pancreatitis. The role of cell death pathways in pathologic trypsin activation, an important marker of tissue damage in pancreatitis, has not been explored. Our preliminary data indicate that key necrotic and apoptotic mechanisms: poly (ADPribose) polymerase (PARP), mitochondrial dysfunction, caspases (specific cysteine proteases), and the transcription factor NFkappaB are activated in experimental models of pancreatitis and in pancreatic acinar cells stimulated with cholecystokinin (CCK). For the present application, we hypothesize that in pancreatitis, necrotic and apoptotic signaling pathways are interrelated. Activation of PARP and mitochondrial deenergization leads to ATP depletion and necrosis. On the other hand, effector caspases mediate apoptosis and limit necrosis by inactivating PARP and trypsin. NFkappaB negatively regulates effector caspases and, thus plays an anti-apoptotic role in pancreatitis. Thus PARP, mitochondrial dysfunction, caspases, and NFkappaB play central roles in determining the balance between apoptotic versus necrotic type of acinar cell death and the severity of pancreatitis. We propose the following specific objectives for the present application: 1). Determine the role of PARP in necrosis and apoptosis in experimental pancreatitis and in vitro, in pancreatic acini stimulated with CCK. 2). Determine the role of mitochondrial dysfunction in necrosis and apoptosis in experimental pancreatitis and in vitro, in pancreatic acini stimulated with CCK. 3)

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Determine the role of caspases in necrosis, apoptosis, and trypsin activation in experimental pancreatitis and in vitro, in pancreatic acini stimulated with CCK. 4). Determine the role of NFkappaB in necrosis and apoptosis in experimental pancreatitis and in vitro, in pancreatic acini stimulated with CCK. Measurements to achieve these goals will include measures of pancreatitis, morphologic characterization of apoptosis and necrosis, intrapancreatic activation of caspases and trypsin, cytochrome c release, mitochondrial membrane potential, ATP levels, and NFkappaB activation by using Western blot and gel shift analyses, enzymatic and fluorimetric assays. The result of the experiments in the proposed specific objectives will be delineation of key molecular mechanisms regulating necrosis and apoptosis in acute pancreatitis, which will lead to novel therapeutic strategies to treat the disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: APPROACHES TO THE STUDY OF PANCREATIC REGENERATION Principal Investigator & Institution: Raper, Steven E.; Associate Professor; Surgery; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2001; Project Start 01-AUG-1998; Project End 31-JUL-2003 Summary: (Adapted from Applicant's Abstract): This proposal seek to extend the knowledge already accumulated about recombinant adenoviral gene transfer to the pancreas, and to use this knowledge to study two fundamental problems of pancreatic biology-pancreatic regeneration and islet morphogenesis. The experiments outlined below were planned based on four overarching hypotheses which have been developed based on the preliminary work done in the laboratory of the PI, as well as extensive review of the literature: 1.) The transient gene expression seen in pancreatic cells transduced with recombinant adenoviruses can be overcome by further study of the mechanisms involved; 2.) Host immunomodulation is one promising strategy for establishing long-term gene expression; 3.) Recombinant adenoviruses can be engineered to express genes involved in pancreatic growth and used as probes to elucidate the biology of regeneration; 4.) Recombinant adenoviruses will be useful in designing innovative strategies to study islet morphogenesis, and ultimately target the islets for gene therapy in vivo. The following Specific Aims will be undertaken in the conduct of this grant: 1.) To study the interaction of recombinant adenoviral vectors with the pancreas of immunocompetent/immunodeficient mice; 2.) To study the interaction of recombinant adenoviral vectors with the pancreas of immunodeficient mice, and to test innovative approaches to prolonging viral transgene expression in pancreata transduced into immunocompetent mice; 3.) To study the effect of physiologic perturbations (streptozotocin, acute pancreatitis, pancreatic resection) on stability of pancreas directed gene transfer; 4.) To study the effect of recombinant adenoviruses encoding the pancreatic growth genes regA and regB as well as hepatocyte growth factor (HGF) in attempts to stimulate pancreatic regeneration; 5.) To target beta cells of the islets of Langerhans by promoting long-tern gene expression and observing transit of transgene expressing cells from the periphery. The information learned from these studies will be important in understanding the biology of pancreatic regeneration and islet morphogenesis. The work will also allow a deeper understanding of pancreatic immunology and the development of innovative strategies for pancreas and isletdirected gene therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CAR FUNCTION IN VIRUS TROPISM AND CELL-CELL CONTACT Principal Investigator & Institution: Bergelson, Jeffrey M.; Assistant Professor; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 20-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): Coxsackie B viruses (CBV) and Adenoviruses (Ads) are the major causes of viral myocarditis, and CBV are implicated in the pancreatitis and diabetes. All CBV and many Ads initiate infection by attachment to the coxsackievirus and adenovirus receptor (CAR), a cell surface glycoprotein whose physiologic function has not been defined. This proposal concerns both CAR's role in virus tropism and its physiologic function. We recently found that CAR is a functional component of the epithelial cell tight junction, a specialized intercellular contact that serves as a barrier to the paracellular solute movement. On polarized epithelial cells, CAR is sequestered in tight junctions; consequently, epithelial monolayers resist infection by both CBV and Ads. Some CBV also attach to a second receptor, DAF, a molecule whose role in infection has remained poorly understood. Preliminary data indicate that while DAF may alter the route by which virus enters a cell, it does not trigger conformational changes in the virion essential that are essential for infection. However, DAF is targeted to the apical surface of polarized cells, and a DAF-binding CBV variant efficiently infects epithelial monolayers; we propose that interaction with DAF provides a mechanism for virus infection at epithelial and mucosal surfaces. In the first series of proposed experiments, we will determine the functions of CAR and DAF during infection, define the route of virus entry for CAR-binding viruses and DAFbinding variants, and test the hypothesis that attachment to DAF permits CBV to cross epithelial surfaces In a second series of experiments we will define CAR's function in CBV pathogenesis in an in vivo model. In human tissues, CAR mRNA is most highly expressed in the heart and pancreas, the major CBV target organs both in humans and in animal models of infection. We will use a conditional gene targeting strategy to determine whether tissue-specific CAR expression is essential for CBV infection, and for virus-induced pathology in the heart and pancreas. In a final group of experiments we will explore CAR's physiologic functions. We have found that CAR is both a structural and functional component of the tight junction, that CAR interacts with the major junctional protein ZO-1, and that homotypic interactions between CAR extracellular domains mediate cell adhesion and contribute to junctional integrity. We will determine the structures involved in CAR-mediated homotypic adhesion, and define CAR' s interactions with other proteins important for junction formation and function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CENTER FOR ALCOHOLIC LIVER AND PANCREATIC INJURY Principal Investigator & Institution: Tsukamoto, Hidekazu; Professor of Medicine & Pathology; Medicine; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, Ca 90033 Timing: Fiscal Year 2001; Project Start 01-JAN-1999; Project End 31-DEC-2003 Summary: The proposed Alcohol Research Center constitutes the first Los Angeles citywide Center of Excellence devoted to Studies on Alcoholic Liver and Pancreatic Injury. The Center is created through consolidation of existing collaborative and interactive programs among the established investigators at USC and UCLA. These investigators are unified by the Center's theme, "Elucidation of the mechanisms by which ethanol primes and sensitizes the liver and pancreas for injury", which illustrates their shared research philosophy and goal. To pursue this theme, the Center will solidify the

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integration and cross-utilization of the unique and specialized expertise that each participating investigator will contribute to the Center such as animal models, morphology, glutathione homeostasis, oxidative stress, cytoskeletal biology, nonparenchymal liver cell biology, molecular virology, pancreatic acinar cell biology, and signal transduction. The Center will also catalyze cross-utilization of complementary resources by our Center and other existing Centers of Excellence on both campuses (USC Center for Liver Disease, USC Hepatitis C Cooperative Research Center, USC Norris Comprehensive Cancer Center, UCLA CURE Digestive Disease Research Center) to promote technical and academic synergism and to achieve integrated dissemination of educational activities. In addition to the city-wide approach and the unified Center's theme, the Center is unique in that the intragastric ethanol infusion model (IEI model) serves as an integral component which supports most of the enter research activities directed toward the theme. The center will also be the first to offer the animal or tissue sharing program for the IEI model to non-Center investigators. It is our Center's ultimate goal to establish effective preventive and therapeutic modalities for alcoholic liver and pancreatic diseases via mechanistic delineation of ethanol primes and sensitized these organs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHARACTERIZATION AND SORTING OF ZYMOGEN GRANULE PROTEINS Principal Investigator & Institution: Lowe, Anson W.; Medicine; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002; Project Start 01-FEB-1991; Project End 31-JAN-2005 Summary: (provided by applicant): The exocrine pancreas is responsible for the synthesis and secretion of digestive enzymes into the intestine. The acinar cell is responsible for the pancreas' exocrine functions and can be characterized as a polarized secretory epithelia. Digestive enzyme secretion is also regulated and can be stimulated with acetylcholine and cholecystokinin. The key subcellular organelle responsible for regulated secretion in the acinar cell is the zymogen granule; a secretory vesicle that stores and concentrates digestive enzymes until secretion is stimulated. The focus of this project has been the characterization of zymogen granule membrane proteins as a means toward understanding the mechanisms underlying the formation of secretory granules and the targeting of proteins to the regulated secretory pathway. GP2 is the dominant protein in the zymogen granule membrane and accounts for 35 percent of the total granule membrane protein. In vitro studies have demonstrated that GP2 is able to aggregate with other exocrine regulated secretory proteins in acidic conditions designed to mimic the trans-Golgi network and immature secretory granule where sorting occurs. GP2 is initially bound to the membrane through a glycosylphosphotidylinositol linkage, which by itself confers membrane protein sorting to the apical plasma membrane. Because GP2 exhibits binding to the soluble digestive enzymes within the granule and contains a sorting determinant for the apical plasma membrane, it is likely that the protein plays a significant role in sorting digestive enzymes into the zymogen granule and the regulated pathway. The goal of this application for the next funding period is to define GP2's function. Transgenic knockout techniques will be employed to produce a mouse with a GP2 null allele. Because GP2 is specifically expressed in the pancreatic zymogen granule and the exocrine pancreas is not functional until after birth, it is unlikely that an embryonic lethal will result from the mutation. Thus preparations have been made to analyze the resultant mutant mice using biochemical, morphological, and physiological approaches. Electron microscopy will be used to study GP2's role on the

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formation of the zymogen granule. Primary pancreatic cultures will be used to study the integrity of the regulated secretory pathway in the mutants. To establish that any resultant phenotypes are truly secondary to the GP2 null mutant, preparations have been made for the reconstitution of wild-type GP2 in primary pancreatic cultures using adenovirus mediated gene delivery. Adenovirus expression of a variety of mutant GP2 constructs will be used to identify important functional domains in the protein. Last, studies will be performed on the effects of the GP2 mutation in experimentally induced pancreatitis. The model we propose to generate will provide important information on GP2 biology and may also provide potential models for human acute and chronic pancreatic diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--GHC POPULATION AND SURVEILLANCE Principal Investigator & Institution: Chu, Susan; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 98109 Timing: Fiscal Year 2001 Summary: The Overall goal of this Core is to support individual projects and overall objectives by identifying and recruiting patients for participation in Program Project Studies, by collecting gastrointestinal cancer tissues from cases that arise in a population of approximately 400,000 enrollees, and by enhancing the ability of Program Project investigators to conduct longitudinal studies in colon and pancreas cancer. Through the Center for Health Studies, the GHC Population Core will facilitate access to a health care delivery system that has distinct advantages as a setting for translational research that include a large defined patient population and a rich array of information systems; established programs in cancer screening with linkage to risk factors and pathologic outcomes; and experience in the design, conduct, and analysis of intervention and observational studies of cancer prevention, control and treatment. The specific aims of the GHC Population Core are: 1) To identify and collect specimens from patients with chronic pancreatitis, pancreatic cancer, and colon cancer for proposed projects 1 and 4; 2) To recruit patients undergoing colonoscopy and collect risk factor data, fecal and blood samples, and biopsy results, and tissue specimens for longitudinal studies of colon cancer risk and development; and 4) To establish a surveillance system to monitor changes in gastrointestinal cancer incidence, morbidity, and mortality in our defined population. The GHC Population Core will build and maintain a retrospective registry with linked pathology results of more than 9800 patients who underwent colonoscopy between 1991 and 1996 and will add risk factor data for the anticipated 4800 patients who will be colonoscopied during the project period. Group Health Cooperative (GHC) is a staff-model managed care organization that serves over 400,000 enrollees in the western Washington Puget Sound region. The GHC Population Core will operate within the GHC Center for Health Studies, a research organization dedicated to the conduct of studies that contribute to scientific knowledge in the public domain and to the quality of health care at GHC. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORE--PANCREAS TUMOR SPORE TISSUE BANK Principal Investigator & Institution: Bridge, Julia; University of Nebraska Medical Center Omaha, Ne 681987835 Timing: Fiscal Year 2001

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Summary: All projects in this SPORE will use human specimens for translational research directed at reducing the incidence and mortality of pancreatic cancer. In order to provide the necessary specimens, a Pancreas Tumor SPORE Tissue Bank will be developed in cooperation with and under the auspices of the University of Nebraska Medical Center (UNMC) Tumor Bank. The guidelines and protocols for collecting specimens established by the UNMC Tumor Bank and the Institutional Review Board will be followed for the SPORE proposal. This core facility will store normal, benign (i.e. acute and/or chronic fibrosing pancreatitis) and malignant pancreatic tissues (including both primary and metastatic pancreatic carcinomas) and peripheral blood lymphocytes, plasma and serum from patients with pancreatic malignancies. The bank will also coordinate collection and storage of pancreatic ductal secretions and peritoneal washings. Cytogenetic analysis will be performed on all malignant lesions when possible. The core will include a mechanism for database management and specimen distribution. A uniform system of prioritization of requested materials would be defined and used by the Pancreas Tumor SPORE Tissues Bank oversight committee. This core facility is intended to benefit the specific research activities of the SPORE as well as the research activities of other scientists within and outside of UNMC who are concentrating on translational research issues. Additionally, tissues will be available for distribution through NCI supported tissue networks in national prioritization. Only specimens obtained from clinically indicated surgeries after all other diagnostic procedures have been performed will be submitted to the Pancreas Tumor SPORE Tissue Bank for translational research. The specimens would other wise be discarded or disposed of. Eligible patients will have the opportunity to participate by submitting written informed consent. There will be no risk to the patient or compromise to the patient's care, since all of the procedures performed would be performed for diagnostic reasons regardless of the SPORE. Members of the pathology department and the clinical departments are participants in the individual research projects and thus, also contribute to the Core for maximal and effective accumulation of satisfactory specimens. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--PATIENT/BIOSTATISTICS FACILITY Principal Investigator & Institution: Corey, Mary; Associate Professor; Hospital for Sick Chldrn (Toronto) 555 University Ave Toronto, Timing: Fiscal Year 2001 Summary: The Patient/Biostatistics Core provides an overall structure for maintaining and connecting all the available patient data related to mutations in the CFTR gene, generates regular summaries for the design and analysis of experiments and observational studies. Core activities will include: integration of new clinical and scientific data into the Toronto CF Database; support for the database on male infertility patients, who comprise the largest identified group of an expanded spectrum of patients affected by mutations in the CFTR gene; creation of data files and analytic strategies to study other atypical phenotypic groups related to CFTR, such as young patients with pancreatitis and adults with chronic lung disease; provision of clinical profiles for individual patients and patient groups to enhance the planning or interpretation of scientific experiments; statistical analysis of core and project data; and timely statistical consulting for the design and interpretation of experiments. A particular focus in the next period will be the acquisition and support of new and developing software for linkage and association analysis of complex genetic traits. SAS software is used for most data management and statistical analysis, including longitudinal regression and survival regression. Other computer programs used for specific purposes include

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SPLUS (for graphics and sophisticated statistical estimation); Mapmaker/Sibs, SAGE, and GAP (for genetic linkage and association analysis); DBMS/COPY and ConversionsPlus for converting and transferring files between different systems. Increasingly, different types of laboratory data will be retrieved directly from other computer systems within the hospitals, necessitating increased levels of quality control and validity checking to ensure appropriate record linkage and to preserve the confidentiality of identified patient data. Core support will ensure that scientists have access to the most appropriate patient information and material to design experiments, and that research hypotheses and results are related as immediately and precisely as possible to patient data, to define the links between mutations, protein dysfunction, and disease expression. This core encourages collaboration of basic and clinical investigators, and therefore hastens the application of new knowledge to patient management and treatment evaluation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COXSACKIEVIRUS 3B PERSISTENCE AND REACTIVATION IN VIVO Principal Investigator & Institution: Feuer, Ralph; Scripps Research Institute Tpc7 La Jolla, Ca 92037 Timing: Fiscal Year 2001; Project Start 01-MAR-2001 Summary: Coxsackieviruses have been implicated in a number of different human diseases, including acute and chronic myocarditis, viral-induced insulin-dependent diabetes mellitus (IDDM), pancreatitis, chronic inflammatory myopathy, and chronic fatigue syndrome. The proposed research will examine the mechanisms of persistence in Coxsackievirus B3 (CVB3) infected mice, using a recombinant virus expressing the enhanced green fluorescent protein (eGFP). Our laboratory has established a solid foundation of molecular and immunological techniques and reagents from previous studies of CVB3 persistence and pathogenesis. Preliminary studies with recombinant eGFP-CVB3 indicate that a certain population of Hela RW cells in culture cannot support a productive infection, including quiescent cells (G0) and cells blocked at the G2/M phase of the cell cycle. The following experiments will test the hypothesis that persistence of CVB3 in mice may rely on infection of quiescent cells incapable of supporting viral replication; and that a subsequent change in the cell-cycle status may lead to virus reactivation and further viral/immune mediated pathology (including myocarditis) in the host. SPECIFIC AIMS: 1. To examine the stability of persistent or latent CVB3 RNA. Quiescent cells infected with eGFP-CVB3 and maintained in serum free media without passage will be monitored at multiple time points for viral replication (plaque assay) and for stability of viral RNA (RT-PCR). Virus rescue will be observed (GFP, RT-PCR, and plaque assay) after cell stimulation with 10 % FBS. 2. To investigate what factors or stimuli may be involved in reactivation of CVB3. Transgenic mice expressing SV40 T antigen in cardiac tissues will be characterized for greater pathogenesis following infection with eGFP-CVB3 by histology and GFP fluorescence. Stimulated PBLs from persistently infected mice will be examined for CVB3 reactivation by GFP expression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CYSTEINE STRING PROTEIN AND ACUTE PANCREATITIS Principal Investigator & Institution: Groblewski, Guy E.; Nutritional Sciences; University of Wisconsin Madison 750 University Ave Madison, Wi 53706

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Timing: Fiscal Year 2003; Project Start 01-MAR-2003; Project End 28-FEB-2005 Summary: (provided by applicant): Acute pancreatitis is an inflammatory disease that is triggered by the premature activation of proteolytic zymogens in acinar cells. As a protective mechanism, zymogens are synthesized as inactive pro-enzymes and packaged in specialized secretory granules destined for exocytosis into the pancreatic duct. During pancreatitis, proteolytic zymogens are prematurely activated in acinar cells by aberrantly mixing with hydrolases present in lysosomes. The mixing of lysosomal hydrolases with zymogens occurs in large cytoplasmic vacuoles as a result of pathogenic alterations in acinar cell membrane trafficking. It is well established that the stress-induced expression of heat shock protein-70 (HSP70) in acini provides a natural protective effect against the pathogenic mixing of lysosomal and secretory granule membrane compartments. This proposal is designed to elucidate the mechanism by which HSP70 inhibits the intra-acinar cell activation of zymogens in preventing the onset of acute pancreatitis. HSP70 is a molecular chaperone in the cytosol that requires a co-chaperone protein to stimulate ATPase activation and substrate binding. We have 1) identified an HSP70 co-chaperone protein called cysteine string protein (CSP) in acinar cells, 2) localized this membrane associated molecule throughout the secretory pathway and 3) developed the TAT-fusion protein system to manipulate CSP expression in acinar cells and thereby study its function. We hypothesize that CSP mediates the protective effects of HSP70 against pancreatitis by targeting HSPT0 chaperone activity from the cytosol to the secretory pathway. In Specific Aim 1, mutant forms of CSP that no longer anchor to secretory granule membranes will be overexpressed acinar cells to determine the importance of CSP in targeting HSP70 to these organelles during pancreatitis. In Specific Aim II, short interference RNAs will be used to inhibit CSP expression in pancreatic Iobules and the protective effects of HSP70 on secretagogue-induced acinar cell damage will be evaluated. These studies will allow us to directly evaluate the role of CSP in the secretory pathway of acini under physiological and pathophysiological conditions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DETERMINANTS OF PANCREATIC INJURY IN CYSTIC FIBROSIS Principal Investigator & Institution: Accurso, Frank J.; Professor of Pediatrics; Children's Hospital (Denver) 1056 E 19Th Ave Denver, Co 80218 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-AUG-2005 Summary: (provided by applicant): Marked phenotypic variability in individuals with cystic fibrosis (CF) who have the same CF genotype suggests that modifier genes may play a role in this disorder. Since most abnormalities in CF begin early in life, investigation of determinants of disease in infants and young children may provide insight into pathogenesis. We have observed that circulating immunoreactive trypsinogen (IRT) levels in infants with CF identified through newborn screening are correlated with early pancreatic dysfunction and with pulmonary function at six years of age. IRT is therefore a biochemical marker of early pancreatic disease in CF also carrying implications for early pulmonary disease. In addition, we have observed that IRT is heritable. We therefore hypothesize that early IRT abnormalities in CF are explained in part by genes that modify the CFTR gene effect on pancreatic injury. We will test this hypothesis in infants and young children with cystic fibrosis diagnosed through newborn screening. IRT will be modeled with age using longitudinal mixed effects approaches with a log transformation to produce a quantitative phenotype that will be used in a Transmission Disequilibrium Test (TDT) to determine if IRT is cosegregating with each of the candidate modifiers. Specific modifiers to be tested can

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be categorized as follows: a. Genetic markers lying within the D19S112 region on chromosome 19 that have been linked to intestinal disease in CF, b. Genes coding for pancreatic enzymes that are capable of causing local tissue injury, c. Genes coding for pancreatic proteins capable of modulating local tissue injury, d. Genes coding for pancreatic membrane transporters, and e.Putative modifier genes of other CF organ involvement. Candidate genes with common, known functional variants will be studied through genotyping. Genes with no known functional variants will be sequenced in a subset of patients exhibiting either "rapid" or "slow" decline in IRT to identify potentially useful mutations or polymorphisms. Sequences of interest will then be examined in the entire study population, with priority as follows: obvious mutations (for example nonsense, frameshift and splice type), then promoter or missense alleles, then variants non- randomly segregating among the IRT "rapid" or "slow" decliners, and then more common variants. We also plan to establish a clinical database and a DNA repository for infants identified by newborn screening. Achieving our goals will likely provide: 1. Insight into the mechanisms of early pancreatic injury, 2. Clues to the pathophysiology of other organs involved in CF, 3. Valuable prognostic information for counseling families of newly diagnosed infants, 4. Information useful for future investigation of the pancreatic complications of CF in later life including recurrent pancreatitis and cystic fibrosis related diabetes. Our long-term objectives are to find new approaches to the early treatment of CF in order to delay pancreatic injury and the development of lung disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DETERMINATION OF CFTR GENE MUTATIONS IN RECURRENT & CHRONIC PANCREATI Principal Investigator & Institution: Freedman, Steven D.; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2001; Project Start 01-DEC-2000; Project End 30-NOV-2001 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DIET, DISEASE, AND PANCREATIC ENZYME SYNTHESIS IN HUMANS Principal Investigator & Institution: O'keefe, Stephen J.; Internal Medicine; Virginia Commonwealth University Richmond, Va 232980568 Timing: Fiscal Year 2001; Project Start 01-JUN-2000; Project End 31-MAY-2004 Summary: Acute pancreatitis is a disease of high mortality, induced by premature activation of digestive enzymes in the pancreas, and accompanied by a severe systemic immunoinflammatory response and protein catabolism. Meeting nutritional needs is difficult because food-induced pancreatic stimulation may exacerbate the disease process, and intravenous nutrition (TPN), while "resting the pancreas," increases the risk of septicemia and mucosal atrophy. Recent controlled clinical trials suggest that tubefeeding with elemental diets has advantages over TPN with regard to cost, safety (less infective complications), and efficacy (more anticatabolic). However, it is unknown in humans whether elemental diets stimulate the pancreas, and the beneficial effects may simply reflect better metabolic control and fewer serious complications. Consequently, Dr. O'Keefe and colleagues plan to measure the effects of duodenal infusions of elemental diets on pancreatic enzyme synthesis and secretion in normal volunteers and patients with acute pancreatitis using a unique method that they have developed, based

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on the 6-hr intravenous and enteral infusion of two isotope-labeled amino acids and measurement of their uptake into trypsin and amylase proteins extracted from duodenal secretions. The method also allows them to obtain simultaneous measurements of the rates of protein catabolism and utilization of dietary amino acids for the synthesis of mucosal proteins (obtained by endoscopic biopsy). Studies will be conducted in groups of 8 normal volunteers to compare the relative effects of complex and elemental diets given as duodenal infusions, versus TPN, on the normal response to a complex oral diet. The results will then be used to evaluate the responses in 20 patients with acute pancreatitis randomized to receive enteral elemental or TPN. The results of these investigations are expected to provide valuable new information on both the stimulatory effects of food on the human digestive system and the nutritional value of modern nutritional support techniques, and help determine why elemental diets are more effective than TPN in the management of patients with acute pancreatitis. The results are also expected to form a scientific basis for the design of disease-specific diets for patients with acute pancreatic disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DISEASE VARIABILITY IN PATIENTS WITH CFTR GENE MUTATIONS Principal Investigator & Institution: Durie, Peter; Professor; Hospital for Sick Chldrn (Toronto) 555 University Ave Toronto, Timing: Fiscal Year 2001 Summary: The range and severity of CF disease is extremely heterogeneous. Our evaluation of a large number of well defined patients with "typical" and "atypical" CF disease and those suspected of having CF are elucidating the relative influence on the disease phenotype of genetic factors including the different CFTR gene mutations and other modulatory genetic factors. Our overall goal is to establish a comprehensive understanding of the spectrum of CF disease associated with mutations and/or variants in the CFTR gene. As well, some variability in CF disease expression between patients with the same genotype (and in specific organs) will be due to the effects of "Modifier" genetic variants on a patient's genome. The specific aims of this application are to:. define CF phenotypes by identifying CFTR gene mutations in well defined patient cohorts with: a conventional diagnosis of CF, "atypical" CF and those suspected of having CF. define the natural history of CF disease in patients with CFTR gene mutations who are diagnosed by conventional diagnostic criteria or have "atypical" CF phenotype including males with infertility and patients with idiopathic pancreatitis. determine the frequency of CFTR gene mutations in cohorts with disease phenotypes resembling CF including asthma, chronic lung disease, and neonates with high immunoreactive trypsinogen and normal sweat test. evaluate obligate heterozygotes with different CFTR gene mutations for evidence of CF phenotypes. determine, in the above mentioned patient cohorts, the relative influence in the CF phenotype the different CFTR gene mutations and modifier genes. Taken together, we will help to clarify the diagnosis of CF disease and ultimately, our findings will lea to significant advances in diagnosis and therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ENDOTOXIN ASSAY FOR ANALYSIS OF SEPTICEMIA DAMAGE Principal Investigator & Institution: Segal, Gershon; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218

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Timing: Fiscal Year 2001 Summary: In the United States, septicemia is the 13th leading cause of death, and accounts for $5 - 10 billion health care dollars spent annually. Patients at risk of developing sepsis frequently present initially to the Emergency Department (ED), with a 'preseptic' syndrome, known as 'systemic inflammatory response syndrome' (SIRS). Prompt recognition, evaluation and initiation of therapy in this group of patients is an area of intensive investigation, since early therapeutic intervention with well established modalities (intravenous fluids and antibiotics) has been shown to be associated with improved outcomes. Furthermore, advances in understanding of the pathophysiology of bacteremia has opened the door for the development of additional therapeutics (e.g. antiendotoxin antibodies) for interrupting the cascade of events associated with full blown sepsis. Establishing an early diagnosis of septicemia remains challenging however. Not all patients with SIRS (fever, tachycardia, tachypnea, and elevated white blood cell count) have a bacterial infection. SIRS can also occur in patients with severe trauma, pancreatitis, and burns without infections. Additionally, demonstration that an infection is the inciting stimulus for SIRS is complicated by the fact that culture reports are usually not available for 24-48 hours, and blood cultures are positive in only about 60% of cases of sepsis. A sensitive and specific clinical diagnostic test for earlier detection of infection would allow physicians to make the diagnosis of septicemia more rapidly, and identify patients who would benefit from specific therapy. Previous efforts toward the development of an assay for early detection of bacteremia have focused on gram-negative infections, as these bacteria are responsible for the majority of cases of sepsis in the United States. The only test currently available assay, the Limulus amebocte lysate test (LAL) is an indirect semiquantitative assay, which has variable sensitivity and specificity and is thus utilized only for industry and research purposes. Recent investigations from the sponsor of this protocol (LINK technology) have demonstrated that a ligand binding assay (LBA) exceeds the sensitivity and specificity of the LAL for the detection of endotoxin in plasma, and may therefore provide the first clinically useful test for early identification of patients with gram negative septicemia. LINK's endotoxin test is based on the core discovery that endotoxin binds to an A1 adenosine receptor. A sensitive and specific clinical diagnostic that quantitates the level of endotoxin in blood has a broad range of clinical uses including: (a) early diagnosis of gram negative septicemia allowing for antibiotic specific therapy; (b) early prediction of impending organ dysfunction; and (c) monitoring of the effectiveness of antibiotics or other therapeutic agents targeted at eradicating the infection and treating the complications associated with gram negative bacteremia. We hypothesize that the detection of endotoxin in human blood by a LBA is an early, sensitive, and specific predictor of organ dysfunction associated with gram negative septicemia. The following specific objectives for this pilot study are: 1) to establish the relationship between the LBA and organ dysfunction; 2) to estimate the correlation of diagnostic errors between the LBA and blood culture; and 3) to identify potential confounders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ENOS IS PROTECTIVE IN THE INITIATION OF PANCREATITIS Principal Investigator & Institution: Dimagno, Matthew J.; Internal Medicine; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 01-JAN-2003; Project End 31-DEC-2004 Summary: (provided by applicant): Pharmacological inhibition of nitric oxide synthase (NOS) or enhancement of nitric oxide (NO) in experimental acute pancreatitis (AP) has yielded mixed results, in part because three NOS isoforms exist: neuronal- (nNOS),

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endothelial- (eNOS) and inducible- (iNOS). Our preliminary data clarifies the role of NO during the initiation of AP and shows that pharmacologic NOS blockade and eNOS deletion, but not nNOS or iNOS deletion, enhance the initiation of an in vivo caerulein hyperstimulation model of AP. By contrast pharmacologic NOS blockade during in vitro caerulein AP has no effect on conversion of intraacinar trypsinogen to trypsin, a hallmark of AP, suggesting that eNOS-derived NO arises from a non-acinar source and/or acts on a non-acinar target. Our data also suggests that upregulation of endothelial eNOS by Simvastatin and Cytochalasin D may attenuate in vivo caerulein AP. We hypothesize that eNOS-derived NO indirectly inhibits initiation of AP by enhancing pancreatic microvascular perfusion. We plan to confirm whether eNOSderived NO acts on a non-acinar target by using an in vitro caerulein model of AP in isolated eNOS KO acini vs. WT acini. Secondly we plan to assess differences in pancreatic perfusion between eNOS KO mice and WT mice during AP using dyelabeled microspheres. Third we plan to determine whether the enhanced initiation of in vivo AP in eNOS KO mice (compared with WT mice) may be normalized by augmenting pancreatic perfusion with NO donors. Fourth we plan to upregulate eNOS pharmacologically in WT and eNOS KO mice to assess for protection against in vivo caerulein AP. We hope that this study may further clarify the role of NO in the pathogenesis of AP. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EXOCRINE PANCREATIC ZYMOGEN ACTIVATION Principal Investigator & Institution: Gorelick, Fred S.; Professor of Medicine; Internal Medicine; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2003; Project Start 15-JUL-1998; Project End 31-MAR-2007 Summary: (provided by applicant): The pathologic proteolytic activation of digestive zymogens within pancreatic acinar cells is a key step in the initiation of pancreatitis. The extracellular and intracellular mechanisms responsible for this activation remain unclear. Supraphysiologic concentrations (>10 fold than required for maximal secretion) of the physiologic ligand, cholecystokinin (CCK), given in vivo cause zymogen activation and pancreatitis. Similarly treated isolated acinar cells respond with zymogen activation and are injured. Factors that can sensitize the acinar cell to the pathologic effects of CCK might be relevant to the pathogenesis of acute pancreatitis. Several experimental studies suggest that CCK-activated pathways contribute to disease. These include pancreatitis induced by ischemia, bile salts, the CDE diet, and ethanol. We hypothesize that: 1) clinically relevant agents or conditions can either act alone or sensitize the acinar cell to the effects of CCK on zymogen activation, and 2) such activation will depend on Ca2+-dependent and independent mechanisms. We find that the following relevant factors sensitize the acinar cell to zymogen activation caused by physiologic concentrations of CCK: secretin, VLDL, and short chain fatty acids. With respect to alcohols, sensitization increased with chain length and deceased with branching. At sensitizing concentrations, alcohols caused no detectable changes in either cytosolic Ca2+ signaling or secretion. However, the sensitizing effects of secretin corresponded to effects on CCK induced Ca2+ signaling. Previous studies suggested that a low pH compartment mediated zymogen activation. We find that inhibitors of vacuolar (v) ATPase (bafinomycin and concanomycin) block CCK-induced zymogen activation. Using antibodies to subunits of vATPase, we observed translocation during CCK treatments. Thus, vATPase appears to be activated and contribute to zymogen activation. We plan to examine the cellular signaling pathways stimulated by these sensitizing agents with particular emphasis on Ca2+, cAMP, PKC, and vATPase.

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Further, we will examine the effects of the sensitizing agents on cell injury and the trafficking of active enzymes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FATTY PANCREATITIS

ACID

ETHYL

ESTERS

IN

ETHANOL-INDUCED

Principal Investigator & Institution: Kaphalia, Bhupendra; Pathology; University of Texas Medical Br Galveston 301 University Blvd Galveston, Tx 77555 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2007 Summary: (provided by applicant): Pancreatitis is a major health problem in alcoholics that causes high mortality and morbidity, and after biliary duct diseases, chronic alcohol abuse is the second major cause of chronic pancreatitis. However, the mechanism of alcohol-induced pancreatitis is poorly understood. Oxidative metabolism of ethanol catalyzed by alcohol dehydrogenase (ADH) is negligible in the pancreas, while nonoxidative metabolism of ethanol to fatty acid ethyl esters (FAEEs), catalyzed by FAEE synthase, appears to be the major mechanism of ethanol disposition in the pancreas during chronic alcohol abuse. Surprisingly, very little is known regarding the role of endogenously formed FAEEs in ethanol-induced pancreatitis. Based upon our preliminary studies showing - 14-fold increase in FAEE levels in the pancreas of hepatic ADH-deficient (ADH-) deer mice as compared to those in ADH-normal deer mice, and a dose- and time-dependent formation of FAEEs and FAEE-induced apoptosis upon ethanol exposure of ADH-deficient human hepatocellular carcinoma (HepG2) cells in culture, we hypothesize that increased formation of FAEEs is a triggering event in ethanol-induced pancreatitis, and that FAEEs and FAEE synthase can be early markers of pancreatic injury. Our preliminary studies also indicate that FAEEs are formed in rat pancreatic tumor (AR42J) cells in culture. Therefore, to investigate the toxic potential of endogenously formed FAEEs and elucidate their role in ethanol-induced pancreatic injury, we will use ADH- deer mice and AR42J cells. In Aim 1, we will determine the levels of FAEEs in the plasma and pancreas of ADH- deer mice after ethanol exposure in a dose- and time-dependent manner, and evaluate the biochemical and morphological parameters associated with pancreatic injury. We will evaluate apoptosis in the pancreas of ADH- deer mice, and in AR42J cells, after ethanol exposure (Aim 2). Inhibitors or inducers of FAEE synthase to attenuate or augment formation of FAEEs in AR42J cells, respectively, will be used to further examine the role of endogenously formed FAEEs in ethanol-induced apoptosis and toxicity (Aim 3). Achieving our Specific Aims 1-3 should establish the role of FAEEs in ethanol-induced pancreatic injury, lay the foundation for future human studies to develop these parameters as early markers for ethanol-induced pancreatic damage, and ultimately benefit us in developing new preventive/therapeutic strategies for early intervention before irreversible damage to pancreas occurs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GASTROINTESTINAL PROGRAM PROJECT Principal Investigator & Institution: Potter, John D.; Member & Program Head; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 98109 Timing: Fiscal Year 2001; Project Start 18-AUG-1998; Project End 31-MAY-2003 Summary: Research in colorectal and pancreas cancer is proposed. It takes as its theme the following model: the interaction of cells with DNA damaging agents can result in three classes of cells-normal cells with intact DNA; cells with damaged DNA that undergo apoptosis; and cells which, despite DNA damage, fail to suicide. We propose to

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explore aspects of the differences in these three classes of cells to increase our understanding of the carcinogenesis process, to monitor interventions, identify markers that may be used for population screening, and to exploit for therapeutic purposes. Project 1 focuses on oxidative damage and apoptosis among a high-risk human populations- with pancreatitis- and an animal model in order to establish the roles of oxidative DNA damage and antioxidants in pancreatitis and pancreas cancer, and to develop a clinical screening test. Project 2 also focuses on a high-risk inflammatory disease- ulcerative colitis-in order to determine the role of DNA damage and mutagenesis in the progression of UC dysplasia. In addition, an intervention with antioxidants is proposed to reverse of slow the dysplasia neoplasia sequence. Project 3 focuses on colonoscopy patients with the specific aim of identifying several processes in the pathways to neoplasia, including oxidative damage and changes in expression of apoptosis-related proteins, that will allow the early identification of high-risk individuals in a low-cost, minimally invasive manner. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC CONTRIBUTION TO THE STRESS RESPONSE Principal Investigator & Institution: De Maio, Antonio; Associate Professor; Surgery; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2001; Project Start 01-JAN-1999; Project End 31-DEC-2002 Summary: (Adapted from the applicant's abstract): The sequential collapse of different organ systems days or weeks after severe trauma, sepsis, pancreatitis, and shock, termed multiple organ dysfunction syndrome (MODS), is the most important cause of mortality and morbidity of patients admitted to the surgical intensive care unit. Recent studies have suggested that MODS is caused by an overwhelming inflammatory response as part of the host defense system. One important clinical observation is the heterogeneous response observed in patients after similar stresses. A possible explanation for this observation is that the response to stress is influenced by the patient's genetic background. Thus, the central focus of this proposal is to evaluate whether genetic diversity may contribute to the inflammatory response after stress. Inbred mouse strains will be used to test this hypothesis. This information will provide us with a better understanding of the inflammatory process and the indentification of genes that modulate the inflammatory response. This is a novel approach to a problem whose solution has been elusive using conventional methodologies. The specific aims of the project are: 1) To compare the inflammatory response between C57Bl6/J and A/J mice. The hypothesis to be tested is that the genetically distinct mouse strains, C57Bl6/J (B6) and A/J have significant differences in their inflammatory response. A comparison of the inflammatory response between these two mouse strains will be performed after two different, but related, stresses: administration of E. coli LPS, and peritonitis induced by cecal ligation and puncture (CLP). This study is also pertinent to the development of quantitative assays for the screening of recombinant inbred (RI) mouse strains (Specific Aim 2), and the identification of possible candidate genes for a positional cloning effort (Specific Aim 3). 2) To map loci responsible for strain-specific differences in the inflammatory response. The phenotypes modulating the inflammatory response of B6 (sensitive) and A/J (resistant) mice will be characterized after administration of LPS or following CLP. The assays to be used are: the infiltration of leukocytes in liver and lung, and assessment of plasma cytokine levels (TNFa and IL-B). Loci governing these responses will be mapped using RI strains (AxB and BxA). 3) Identification of candidate genes contributing to differences in the inflammatory response. The positions of those loci with the strongest contribution to the phenotypes described in Specific Aim 2 will

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be refined with backcross and intercross strategies (high resolution mapping) and subjected to a positional cloning effort. The results from this analysis will provide us with candidate genes that contribute to the heterogeneity of the inflammatory response. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HEAT SHOCK PROTEINS AND PANCREATITIS Principal Investigator & Institution: Saluja, Ashok K.; Professor of Surgery and Medicine; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2001; Project Start 15-FEB-2001; Project End 31-JAN-2006 Summary: (Adapted from the Applicant's Abstract): The broad, long-term aim of the work proposed in the present application is to determine the role of prior stress and heat shock proteins in regulating the severity of pancreatitis-a disease with considerable morbidity and mortality. The pathophysiological alterations underlying the development and ultimate severity of pancreatitis are not fully understood, but it is generally believed that premature activation of digestive enzyme zymogens within the pancreatic acinar cells themselves leads to acinar cell injury and pancreatitis. The mechanisms involved in this activation process are still controversial. Recent observations suggest that prior stress by either water immersion or hyperthermia ameliorates subsequent development of pancreatitis in rats. This proposal is based on our hypothesis that prior stress prevents pancreatitis by specifically increasing the expression of heat shock proteins (HSPs). Once upregulated, HSPs prevent premature activation of trypsinogen by blocking its colocalization with lysosomal enzymes. Furthermore, we believe that HSPs affect these phenomena by attenuating the sustained rise in intracellular Ca2+ which is normally observed during pancreatitis. The proposed studies will pursue the following specific aims: (a) to determine whether HSPs are actually responsible for post-stress protection against pancreatitis and whether that protection is generalizable to models of pancreatitis other than the caerulein-induced model; (b) to elucidate the mechanism of stress-induced protection against pancreatitis, and (c) to determine the mechanism by which HSPs alter intracellular Ca2+ homeostasis. These studies will use two different models of pancreatitis: (a) caerulein model in mice and rats and (b) bile salt-induced pancreatitis in rats. Stress and HSP expression will be induced by both physical and chemical approaches. Successful completion of these studies will eventually help us in planning strategies to pharmacologically manipulate the levels of HSPs, so that their induction can be used as a tool to decrease the severity of clinical pancreatitis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HYPOXIA AND FREE RADICALS IN ALCOHOLIC PANCREATITIS Principal Investigator & Institution: Arteel, Gavin E.; Pharmacology; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2001; Project Start 01-AUG-2001; Project End 30-JUN-2002 Summary: APPLICANT'S ABSTRACT: We hypothesize that ethanol-induced chronic pancreatitis is triggered by hypoxia/reoxygenation injury, leading to stimulation of inflammatory cell recruitment and activation of these cells by circulating endotoxins. We recently showed pancreatic injury characteristic of chronic pancreatitis in humans in an enteral model modified to deliver higher amounts of ethanol. Our first goal is to characterize this new model. Wistar rats will receive alcohol internally using our modified protocol for up to 6 months. Pancreatic function and injury will be determined and compared to changes in key molecular events. We expect that alcohol will cause

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progressive, irreversible changes in pancreatic morphology and function, similar to clinical observations. We will next test the hypothesis that alcohol causes hypoxia in pancreas in vivo. Initially, we will determine if the hypoxia marker pimonidazole can be used to index pancreatic hypoxia in rats. We will then determine the effect of alcohol on pancreatic hypoxia in our enteral model. We expect that chronic ethanol will cause early increases in hypoxia, suggesting that hypoxia might play a key early role in the initiation of damage. The effect of removing endotoxin by lactobacillus treatment to displace Gram-negative bacteria, or killing macrophages with silica will next be studied. We expect pancreatic damage will be blunted by these treatments, suggesting a role of endotoxin and macrophages in chronic alcoholic pancreatitis. Next, the hypothesis that free radicals play a causative role in chronic alcoholic pancreatitis will be tested. This question will be addressed using adeno-associated virus (RAAV) to deliver superoxide dismutase (SOD) and cause stable long-term pancreatic expression. First, optimal conditions to confer pancreatic transgene expression will be determined. The effect of RAAV containing superoxide dismutase (SOD) on pancreatic injury will be determined. Free radical formation and oxidative stress will also be quantitated. We expect that preventing oxidative stress with SOD will protect against chronic alcoholic pancreatitis, indicating that free radicals play an important role in the progression of chronic alcoholic pancreatitis. This work will lay the mechanistic foundation for future studies of targeted therapies to prevent alcoholic pancreatitis that can applied in the clinic, where such therapy is desperately needed. Further, through didactic training and interactions with his mentor and key faculty in the enteral model of alcohol exposure, molecular biology, and viral vector gene therapy, the applicant will acquire new skills that will greatly enhance his career development and bridge the gap to becoming a successful member of the academic and scientific community. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IN AUTOIMMUNITY

VIVO

ROLE

OF

CTLA-4

IN

COSTIMULATION

AND

Principal Investigator & Institution: Sharpe, Arlene H.; Associate Professor; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2001; Project Start 01-FEB-1997; Project End 31-JAN-2002 Summary: (Adapted from the Investigator's abstract): The investigator will test the hypothesis that CTLA-4 downregulates T-cell activation and is normally involved in the prevention of autoimmunity. Evidence for this premise comes from the investigator's finding that the CTLA-4-deficient mice develop splenomegaly and lymphadenopathy, multi-organ lymphocytic infiltration and tissue destruction with severe myocarditis and pancreatitis, and die by 3-4 weeks of age. Three specific aims will be tested. The role of CTLA-4 in regulation of T-cell dependent immune responses will be analyzed by determining how CTLA-4 deficiency affects T-cell responses in vitro and whether CTLA-4 mediates its inhibitory effects solely through interactions with B7-1 and B7-2. The mechanisms of CTLA-4-mediated inhibition will be studied using naive and activated T-cells from CTLA-4-deficient, TCR transgenic mice. Emphasis will be placed on susceptibility to apoptosis and lymphokine production. The contribution of CTLA-4 to systemic autoimmune responses will be addressed by assessment of the pathology of in CTLA-4-deficient mice, determination of whether self-reactive T-cells appear in CTLA-4-deficient mice, and whether the course of EAE in MBP-specific TCR transgenic mice is altered when these mice lack CTLA-4. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: LANTHANIDES AS NOVEL ANTI-ARTHRITIC AGENTS Principal Investigator & Institution: Evans, Christopher H.; Professor; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2003; Project Start 25-SEP-2003; Project End 31-AUG-2005 Summary: (provided by applicant): The lanthanides, also known as the rare earths, comprise a series of 15 elements spanning atomic numbers 57-71. Lanthanide ions (Ln3+) are of approximately the same ionic radius as Ca2+ ions, and share many other chemical properties, including ligand preference and geometry. They frequently replace Ca2+ in an isomorphous fashion on biological macromolecules, organelles and cells. Because of their greater charge: volume ratio, binding constants are higher for than Ca2+, and they often interfere with Ca-dependent biological functions. One example of importance to this proposal, is the ability of to suppress macrophage activation in vivo. have been shown to reduce mortality in rats challenged by anaphylaxis, endotoxin, pancreatitis and other macrophage-dependent pathologies. Funding is requested to determine whether also inhibit the development of experimental models of RA in rats. Two such models will be evaluated: antigen-induced arthritis, using ovalbumin as the inciting antigen, and adjuvant arthritis. These two models are selected because has been shown to inhibit anaphylactic responses to ovalbumin in sensitized animals, and also to suppress inflammatory responses to Freund's complete adjuvant, the inciting agent in adjuvant arthritis in rats. Three different members of the lanthanide series will be tested: lanthanum (Ln3+), the largest member of the series, gadolinium (Gd3+), which lies in the middle of the series and has been widely used as a therapeutic agent in rats, and lutetium (Ln3+), the smallest lanthanide. will be evaluated both as free cations and as complexes with citrate to improve their solubility and mobility. Lanthanides will be injected systemically and intra-articularly. A successful outcome to these studies will have identified the basis for a potential new, very inexpensive anti-rheumatic agent whose mode of action differs from that of existing drugs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: LEXIPAFANT IN HIV DEMENTIA--TOLERABILITY AND SAFETY, PLACEBO CONTROLLED Principal Investigator & Institution: Mcarthur, Justin C.; Professor of Neurology; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2001 Summary: Antiretroviral agents are currently the only approved therapy for treatment of HIV dementia, but treatment response is frequently unsatisfactory or short-lived, or agents poorly tolerated in doses adequate for CNS penetration. The reason for the incomplete response may be that the pathophysiology of HIV-related cognitive impairment is initiated by the virus, but involves a complicated inflammatory cascade within the brain. Therefore, effective therapy needs to focus on these indirect mechanisms in addition to viral suppression. One hypothesis for the pathophysiology of dementia is that neurotoxic substances are produced by specific interactions between infected macrophages and astrocytes to damage and destroy neurons. In this schema, we are interested in the role of the lipid inflammatory mediator, platelet activating factor (PAF). This is a potent biological mediator that exerts its effects in as variety of cells and tissues and has been detected at high levels in the CSF of immune-suppressed HIV-1 infected patients with CNS dysfunction. Lexipafant is a PAF antagonist with high affinity for the PAF receptor with an excellent safety profile. Currently, controlled clinical trials of Lexipafant are under way in treatment of asthma, pancreatitis,

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ulcerative colitis and pre-operative ischemia. It has shown to be active via oral route and is well- tolerated in human volunteers using doses up to 750 mg bid. No prior clinical research has been reported with Lexipafant in HIV-infected individuals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LIVER-LUNG INTERACTION DURING ACUTE PANCREATITIS Principal Investigator & Institution: Gray, Keith D.; Surgery; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 05-FEB-2002 Summary: A prominent feature of severe acute systemic inflammatory response syndrome (SIRS) including acute respiratory distress syndrome (ARDS). The physiology of these responses appears remarkably similar to responses to direct liver injury in other settings. Cytokines produced in the liver and lungs, including tumor necrosis factoralpha (TNF-alpha) and interleukin (IL-1), are implicated in the pathogenesis of SIRS and animal experiments have demonstrated them capable of precipitating acute lung injury. During acute pancreatitis, proteases are released into the portal system, exposing the liver to high levels of activated enzymes. Nuclear factor kappa-B (NF-kappaB), a transcriptional regulator of TNF- alpha, IL-1 and other cytokines, is activated in the pancreas within 30 minutes of inducing experimental acute pancreatitis and subsequently within the liver and lung within 24 hours of acute liver injury. Our central hypothesis is that NF-kappaB activation in the pancreas and liver mediates acute lung injury associated with pancreatitis. Using the biliary cerulein/glycodeoxycholic acid model of acute pancreatitis will address two specific aims: 1) to determine whether altering NF-kappaB activation in the liver affects the pulmonary response to severe acute pancreatitis; 2) to determine the role of Kupffer cells in mediating the multisystem effects of pancreatitis by depleting Kupffer cells prior to induction of pancreatitis. These studies may allow the development of strategies to ameliorate multisystem to ameliorate multi-system injury including pulmonary failure, which can be devastating during this illness. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MAT1A NULL MOUSE: MODEL FOR ALCOHOLIC TISSUE INJURY Principal Investigator & Institution: Lu, Shelly Chi-Loo.; Professor of Medicine; Medicine; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, Ca 90033 Timing: Fiscal Year 2003; Project Start 01-MAR-2003; Project End 29-FEB-2008 Summary: (provided by applicant): Methionine adenosyltransferase (MAT) is a critical enzyme responsible for the biosynthesis of S-adenosylmethionine (SAM). Of the two genes (MAT1A, MAT2A) that encode MAT, MAT1A is mainly expressed in adult liver. Due to differences in kinetics and regulatory properties, cells expressing MAT1A have much higher SAM levels than cells expressing MAT2A. Cirrhotic patients have decreased hepatic MAT activity and SAM biosynthesis. SAM has been used therapeutically but the molecular targets remain unclear. Recently we showed the importance of MAT1A in maintaining a normal liver phenotype using the MAT1A null mice. Three-month old MAT1A null mice have reduced hepatic SAM and GSH levels, hyperplasia, spontaneous oxidative stress, increased cytochrome P4502E1 (CYP2E1) expression and are prone to liver injury. On a normal diet, MAT1A null mice develop non-alcoholic steatohepatitis by 8 months and hepatocellular carcinoma by 18 months. Further, we discovered that the once thought to be liver-specific MAT1A is highly

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expressed in normal pancreas and pancreatic acini. MAT expression undergoes dramatic changes and pancreatic SAM level fall in female mice fed a choline-deficient ethionine supplemented diet (a model of necrotizing pancreatitis). SAM supplementation prevented pancreatic injury in this model and ameliorated injury due to cerulein infusion, a more acute model of pancreatitis. Although pancreatic injury is normally absent in rodents fed ethanol, they are more susceptible to cerulein-induced injury. Pancreatic SAM levels fell during ethanol feeding and may sensitize the organ to further injury. Given these provocative results, we hypothesize that MAT1A null and heterozygous mice are more susceptible to ethanol-induced tissue injury and may serve as a novel model to study the pathogenesis and treatment of these diseases. The aims of the proposal are: 1) examine the effect of SAM depletion and treatment in ethanolinduced liver injury-examine whether SAM depletion predisposes to ethanol-induced injury and whether SAM is effective therapeutically in the absence of MAT1A; 2) examine the effect of SAM depletion and treatment in ethanol-induced pancreatic injury-examine whether SAM depletion predisposes to ethanol-induced pancreatic injury and the effect of SAM treatment; 3) elucidate the mechanisms of SAM depiction's sensitizing effect on liver injury-examine the role of CYP2E1, mitochondrial GSH and hepatic macrophage activation in SAM depletion s sensitizing effect; 4) identify the molecular targets of SAM's therapeutic effect in alcoholic liver injury-identify targets of SAM using genomics and proteomics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MEDICAL HISTORY, MEDICATIONS, AND PANCREATIC CANCER RISK Principal Investigator & Institution: Mandelson, Margaret T.; Associate Investigator; Center for Health Studies Seattle, Wa 98101 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2005 Summary: (provided by applicant): Risk factors for pancreatic cancer are not well established. The goal of this pilot study is to investigate the relation between medical history, medication use and pancreatic cancer in a case-control study based on medical record abstraction and electronic laboratory and pharmacy data. Our specific aims are: 1. To investigate the relation between medical conditions and pancreatic cancer risk, focusing on: a. Diabetes mellitus, including disease duration, therapy, and glycemic control. b. Pancreatic inflammation, including acute and chronic pancreatitis. c. History of peptic ulcer disease and/or infection with Helicobacter pylori (H. pylori). d. History of cholecystectomy and/or cholelithiasis. 2. To investigate the relation between the use of medications and pancreatic cancer, focusing on nonsteroidal anti-inflammatory drugs, cholesterol lowering agents including HMG-CoA reductase inhibitors and acid suppressive medications including histamine receptor antagonists and proton pump inhibitors. As a secondary specific aim we propose to examine additional medical conditions and medications in order to generate hypotheses for future studies of the epidemiology and prevention of pancreatic cancer. These include evaluation of medical conditions such as irritable bowel syndrome, allergies and asthma as well as medications including immunosuppressive medications and angiotensin converting enzyme inhibitors. To meet these specific aims we propose to conduct a case-control study of pancreatic cancer comprised of 250 newly diagnosed cases and 1,000 controls in the defined population of Group Health Cooperative, a large health maintenance organization. Data on prior medical conditions and medications will be collected through abstraction of traditional and computerized medical records, including electronic laboratory and pharmacy data. Study strengths include the availability of

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uniformly collected, long-term medical and pharmacy data and the availability of data on important covariates, including smoking. The proposed study will provide a unique opportunity to investigate the role of medical conditions and medications in pancreatic tumorigenesis and to generate new insights into the mechanisms that result in pancreatic cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MODELS OF TYPE 1 AND TYPE II HEREDITARY PANCREATITIS Principal Investigator & Institution: Ulrich, Charles D.; Internal Medicine; University of Cincinnati 2624 Clifton Ave Cincinnati, Oh 45221 Timing: Fiscal Year 2001; Project Start 01-MAY-2001; Project End 31-MAR-2003 Summary: (Applicant's Abstract): Acute and chronic pancreatitis remain major healthcare problems. The lack of effective preventive and therapeutic strategies in these disease states stems from a lack of understanding regarding disease pathogenesis. The investigator's group has identified mutations responsible for two delayed-onset, autosomal dominant inherited forms of acute and chronic pancreatitis. An RI 17H mutation in the human cationic trypsinogen gene links with type I hereditary pancreatitis (HP I). An N211 mutation in the same gene links with type II hereditary pancreatitis (HP II). Biochemical data from other groups when combined with the results of there preliminary studies support the hypothesis that the HP I mutation in cationic trypsin renders the molecule resistant to proteolytic digestion, the persistence of mutant trypsin activity resulting in the creation of a "milieu" sufficient for clinicallyapparent acute pancreatitis. The alterations in protein biochemistry responsible for the HP II phenotype remain unclear. In an initial attempt to develop an animal model of HP I, the investigator generated transgenic mice containing a diet-inducible pancreatic acinar cell-specific promoter coupled to either wild-type or HP I mutant human cationic trypsinogen. Unfortunately, these mice fail to develop pancreatitis spontaneously, and all available antibodies to human cationic trypsin cross-react with an identically sized mouse trypsin. The investigator believes that enhanced expression of antibody epitopetagged human cationic trypsinogens will provide him with the best opportunity to develop a successful animal model of hereditary pancreatitis. Toward this end, the investigator proposes (1) studies comparing the biochemical properties of affinitypurified recombinant wild-type, R117H, and N21I human cationic trypsinogen/trypsin (+ I- epitope tag) utilizing a validated in vitro assay system. By design, these studies will also further test the investigator's hypothesis with regard to HP I mutant trypsin, and discern the biochemical alterations induced by the HP II mutation. The investigator will then (2) characterize murine pancreata and acinar cells expressing varying levels of epitope-tagged wild-type, R117H, and N2 11 human cationic trypsinogen/trypsin. The development of these animal models, in combination with the experimental design, should provide him with important insights into the events underlying the delayedonset and pathophysiology of HP I, HP II and non-hereditary forms of acute and chronic pancreatitis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MOLECULAR GENETICS OF HEREDITARY PANCREATITIS Principal Investigator & Institution: Whitcomb, David C.; Professor of Medicine, Cell Biology & Ph; Medicine; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2001; Project Start 01-APR-1999; Project End 30-NOV-2002

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Summary: Acute and chronic pancreatitis are major health-care problems in the United States causing years of pain and disability. Despite the impact of these diseases, mystery surrounds many of the predisposing causes and early molecular events. Furthermore, the devastating effects of acute pancreatitis and chronic pancreatitis, once established, cannot be reversed. We believe that in the future, advances in the treatment of pancreatic disease rest in the early identification of at-risk individuals as well as in the prevention of limitation of pancreatic injury. Thus, the goal of our program is to determine the molecular mechanisms that predispose to acute and chronic pancreatitis and to identify targets for disrupting pathophysiological processes. We believe that effective preemptive actions will prevent or limit pancreatic injury and thus, result in the reduction of he incidence and severity of acute and chronic pancreatitis. To understand the mechanisms of pancreatitis we will identify previously uncharacterized hereditary pancreatitis families and investigate several striking features of this disease including incomplete penetrance and the mechanisms causing pancreatitis with trypsinogen RR117H and N21I mutations. Answering this question may provide insight into the pathophysiology of acute and chronic pancreatitis and identify targets for new therapies, and help identify individuals at risk through genetic testing. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR MECHANISMS OF PANCREATITIS Principal Investigator & Institution: Logsdon, Craig D.; Professor; Physiology; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2001; Project Start 10-MAY-1998; Project End 31-AUG-2002 Summary: Preliminary data supports an association between activation of stressactivated protein kinase pathway, expression of chemokines, and secretagogue-induced experimental pancreatitis. This work is designed to explore mechanisms and interrelationships between events in these pathways and their role in pancreatitis. The first aim is designed to test the hypothesis that chemokines are specifically and rapidly induced in acinar cells by treatments that induce pancreatitis utilizing the secretagogue hyperstimulation model, intraductal injection of bile salt and protease solutions, and ischemia/reperfusion models of pancreatitis. The second aim explores the hypothesis that activation of the stress kinase pathway is necessary and sufficient for the stimulation of chemokine gene expression. This will utilize both the in vivo animal models of pancreatitis, as well as in vitro studies with dispersed pancreatic acinar cells. The latter allows various manipulations for activation and inhibition of stress kinase signalling cascades, as well as the adenoviral-mediated gene delivery of constitutivelyactive or dominant-negative signalling genes. The third aim tests the hypotheses that NFkB is involved in chemokine gene expression in pancreatic acinar cells. This again utilizes both in vivo and in vitro approaches with various manipulations of NFkB and IkB. The final aim tests the hypothesis that modification of chemokine expression in vivo will influence the severity of pancreatitis. This will attempt to utilize adenoviral vectors to directly express the specific chemokines in the pancreas in vivo and explore effects on the characteristics of pancreatitis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MOLECULAR PATHOGENESIS OF DIGESTIVE DISEASES Principal Investigator & Institution: Omary, M Bishr.; Professor of Medicine; Medicine; Stanford University Stanford, Ca 94305

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Timing: Fiscal Year 2001; Project Start 01-MAY-2001; Project End 28-FEB-2006 Summary: OVERALL (Adapted from the application) The Digestive Disease Center at Stanford University was established in 1987 and has two major areas of focus. The first deals with studying host-pathogen interactions, and the mechanism and signals that target leukocytes to specific digestive organs and pathogens. Infections under study include hepatitis A-D, H. pylori, and the diarrheal agents rotavirus, salmonella, E-coli, cholera and astrovirus. It also addresses mucosal immunity and targeting of immunocytes to the intestine and liver in normal and disease states including inflammatory bowel disease, viral hepatitis, and H. pylori-induced gastritis. The second focus addresses the cell and molecular biology of digestive epithelia with emphasis on normal and abnormal cell growth, differentiation, development, polarity, and the nature and role of signaling pathways and the cytoskeleton in facilitating these processes. This focus targets several digestive diseases including esophageal, pancreatic and colorectal cancer; cryptogenic liver disease; pancreatitis and Barrett?s esophagus. The Center consists of 29 established investigators who blend several clinical and basic science departments. Five core facilities are administered by the Center and they provide several important technologies and services. The Administrative Core offers the Pilot and Feasibility Program which provides one year funding ($20,000/year) to junior investigators or those with a collaborative project, the Named Investigator Program which provides a two year 20-25% effort/year support to a promising junior faculty, and a Collaborative Trainee Program that specifically funds trainees who work with two or more Center investigators. The Fluorescence Activated Cell Sorting/Immunoprobe Core offers an array of services that allow studying single cells. The Cell Imaging Core offers state of the art imaging tools including confocal and electron microscopy. The Microarray/DNA Sequencing Core offers the ability to identify disease-associated regulatory changes in multiple genes, and as such provides potential means to develop diagnostic and therapeutic modalities. Cell Biology & Signaling Core offers expertise and services in cell culture methods, characterizing protein-protein interaction, dissecting signaling pathway and characterizing regulatory modifications such as phosphorylation. In the aggregate, this Center brings together an accomplished group of investigators, creates a highly interactive environment, and makes available state of the art technologies to address important digestive diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PANCREATITIS

MOLECULAR

PATHOMECHANISM

OF

HEREDITARY

Principal Investigator & Institution: Sahin-Toth, Miklos; Associate Professor; Physiology; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2001; Project Start 01-MAY-2001; Project End 30-APR-2004 Summary: (Applicant's abstract): The broad, long-term objectives of this application are to understand the mechanism by which mutations in the human cationic trypsinogen gene (PRSS1) lead to hereditary pancreatitis (HP). HP is an autosomal dominant genetic disorder characterized by early-onset recurrent attacks of acute pancreatitis with frequent progression to chronic pancreatitis and occasionally to pancreatic cancer. HP belongs to the inherited forms of idiopathic chronic pancreatitis, a genetically heterogeneous disease group, where mutations have been found not only in PRSS1, but also in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and in the pancreatic secretory trypsin inhibitor gene (SPINK1). HP has been widely recognized as a highly relevant model system for all forms of human pancreatitis. In the majority of

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cases, three mutations, Arg117-His, Asn2l-,lle, and Ala8-Val, have been identified in PRSSI. The molecular defects caused by the HP mutations will be studied within the context of a current pathogenesis model, which suggests that HP is caused by excessive intrapancreatic trypsin activity via one of 3 mechanisms: (i) increased trypsinogen activation, (ii) decreased trypsin degradation; or (iii) impaired inhibition by pancreatic secretory trypsin inhibitor (PSTI). The principal objective of the experimental design is to study the effects of the HP-mutations in vitro, using recombinant human trypsinogens. Wild-type and mutant trypsinogens will be expressed in Escherichia coli, and purified to homogeneity with ecotin affinity chromatography. Catalytic properties and autocatalytic degradation (autolysis) of trypsins and autoactivation and autocatalytic degradation (zymogenolysis) of trypsinogens will be characterized. In addition, interactions between wild-type and mutant forms of cationic trypsin(ogen) with anionic trypsin(ogen) and mesotrypsin(ogen) will be examined. Finally, inhibition of human trypsin isoforms and HP mutant trypsins by wild-type and mutant PSTI proteins will be studied. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NADPH PANCREATITIS

OXIDASE

INHIBITOR

THERAPY

IN

ACUTE

Principal Investigator & Institution: Weinstein, David; Triage Pharmaceuticals, Llc 1 University Pl, Rm A215 Rensselaer, Ny 12144 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 30-JUN-2003 Summary: (provided by applicant): Triage Pharmaceuticals LLC ("Triage") was chartered in the summer of 1999 to exploit new treatments for vascular leakage related illnesses using NADPH oxidase inhibitors patented by Dr. James Holland, a Triage cofounder. The invention is protected by two issued U.S. patents, granted European and Japanese patents, and a pending Canadian patent application. These cases claim a method of prevention and treatment of diseases related to endothelial hyperpermeability and vascular leakage by therapeutic administration of an NADPH oxidase inhibitor. The scientific rationale for the involvement of NADPH oxidase in mechanisms leading to vascular leakage has been well-documented by Triage in its work on the inhibitory effect of apocynin, a naturally occurring plant extract. In order to further this work, Triage is seeking funding to perform accelerated pharmaceutical development and preclinical testing for drug candidates in a vascular leakage disease indication that has a clear, simple, non-costly end-point and treatment duration that should allow determination of clinical efficacy in very short trial periods. Using its current library of potent NADPH oxidase inhibitors, "proof of concept" will be established in the vascular leakage of acute pancreatitis using an established rat model of the disease. PROPOSED COMMERCIAL APPLICATION: There are no currently available drugs for the treatment of the endothelial hyper-permeability and vascular leakage component of vascular diseases, such as acute pancreatitis, diabetes mellitus, atherosclerosis and hypertension. Despite the effectiveness of currently available medical treatments for these vascular diseases, the risks of morbidity and mortality remain high. A combination approach with currently available medical treatment and an orally administered NADPH oxidase inhibitor would significantly improve the treatment of individuals with a high risk for the diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NEURAL REGULATION OF PANCREATIC FUNCTION Principal Investigator & Institution: Kirkwood, Kimberly S.; Surgery; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 94122 Timing: Fiscal Year 2001; Project Start 15-MAY-1994; Project End 31-JUL-2003 Summary: (Adapted from Applicant's Abstract): Approximately 10% of patients with acute pancreatitis die from uncontrolled pancreatic inflammation that results in massive fluid losses and shock. The regulation of pancreatic inflammation is poorly understood. In the trachea, sensory nerves regulate inflammation by releasing tachykinins that bind to endothelial cells and induce arteriolar vasodilatation, plasma extravasation and neutrophil infiltration. This well-characterized phenomenon is called neurogenic inflammation. The general hypothesis of this proposal is that neurogenic mechanisms are essential to the pathogenesis of acute pancreatitis. Specifically, we hypothesize that a) tachykinins induce plasma extravasation and neutrophil infiltration in the pancreas by interacting with neurokinin receptors, b) the pro-inflammatory effects of tachykinins are terminated by cell surface peptidases, and c) tachykinins and their receptors regulate inflammation in a widely-used model of acute pancreatitis. Due to the recent availability of "knockout" mice in which the genes encoding neurokinin receptors or cell surface peptidases have been deleted by homologous recombination, these experiments will be performed in mice. Pancreatic inflammation will be assessed by 1) quantifying and localizing plasma extravasation using Evans blue and Monastral blue, respectively, 2) identifying and measuring endothelial cell gaps through which plasma extravasates using a silver stain and light microscopy, 3) quantifying and localizing neutrophil infiltration using myeloperoxidase, and 4) defining the extent of edema, and cytoplasmic vacuolization using histological criteria. Specific Aim 1 will define the contribution of exogenous and endogenous tachykinins to the initiation of acute pancreatic inflammation. The time-course and dose-response will be determined, and the neurokinin receptors that mediate these effects will be identified using antagonists and knockout mice, and localized using receptor-specific antisera. Specific Aim 2 will examine the role of peptidases in the termination of tachykinin-induced pancreatic inflammation. The peptidases neutral endopeptidase and angiotensin converting enzyme will be localized in the pancreas using specific antisera, and their importance in tachykinin-induced inflammation will be determined using inhibitors and knockout mice. Specific Aim 3 will define the importance of sensory nerves, and specifically tachykinins, in the pathogenesis of acute pancreatitis. Using neurokinin receptor antagonists, peptidase inhibitors, and knockout mice, we will delineate the neurogenic mechanisms that regulate inflammation in acute pancreatitis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NEUROENDOCRINE REGULATION--PANCREATIC HORMONE SECRETION Principal Investigator & Institution: Greeley, George H.; University of Texas Medical Br Galveston 301 University Blvd Galveston, Tx 77555 Timing: Fiscal Year 2001; Project Start 16-SEP-1985; Project End 31-MAR-2006 Summary: Our principal hypothesis is that secretion of the intestinal hormone, Cholecystokinin (CCK), as mediated by luminal CK-releasing factor (LCRF). Emerging evidence how indicates that mechanisms underlying stimulation of intestinal peptide hormone secretion involve luminal endocrine-like releasing factors. The long sought after luminal releasing factor for cholecystokinin (CCK) or Luminal Cholecystokinin Releasing Factor (LCRF) has recently been isolated. Our laboratory has shown that

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LCRF is expected primarily in the intestinal epithelium Brunner's glands and pancreatic ductules. We have measured secretion of LCRF into the intestinal lumen by radioimmunoassay. We propose that luminal nutrients provoke LCRF release from the intestinal epithelium. Brunner's glands and pancreatic ductules into the lumen; luminal LCRF than triggers intestinal CK secretion. We also have preliminary data to show the existence of large species of LCRF in the intestinal epithelial and lumen, and that a peptide hormone processing enzyme, pro-hormone convertase- 5 (PC-5) is co-localized and co-secreted with LCRF into the lumen. These findings suggest that LCRF is processed before secretion and post- secretory within the intestinal lumen to a biologically active form by PC- 5. The primary objectives of this research proposal are to characterize the biological activity of LCRF on CCK secretion, and to test the hypothesis that luminal LCRF regulates intestinal CCK secretion. The Specific Aims of this research proposal are; 1) to characterize the biological activity of LCRF on CCK secretion; and, 2) to demonstrate that LCRF mediates physiologically relevant intestinal CK secretion. Accomplishment of our proposed aims will result in fundamental new knowledge regarding the role of LCRF in the regulation of CCK secretion and its potential for therapeutic applications in digestive diseases, including pancreatitis, gallstone diseases, motility and eating disorders. LCRF appears to represent a unique model of endocrine peptide secretion and processing since LCRF may be the first described lumone. Lumones are hormone- like factors produced by intestinal cells, secreted into the intestinal lumen and delivered to their target cells residing in the intestinal epithelium. The intestinal lumen may be an important pathway for endocrine secretion and action and regulation of gastrointestinal function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEUROGENIC AMPLIFICATION OF PANCREATITIS PAIN Principal Investigator & Institution: Westlund-High, Karin N.; Professor; Marine Biomedical Institute; University of Texas Medical Br Galveston 301 University Blvd Galveston, Tx 77555 Timing: Fiscal Year 2001; Project Start 01-APR-2000; Project End 31-MAR-2004 Summary: Visceral pain is of great concern since it constitutes a large part of the pain treated by the medical community. Pain is a major complaint in particular of patients with pancreatis or pancreatic cancer. The pain can be severe and intractable, resistant even to morphine. Our previous studies have determined that pain in patients with cancer involving the pelvic visceral organs is relieved by a neurosurgical lesion limited to the midline of the dorsal column of the spinal cord. In rats we determined that sensory input from the colon is primarily transmitted to higher brain sensory processing centers as a midline component of the dorsal column pathways. This raises the possibility of a major visceral pain pathway in the dorsal column which we will consider as an overall hypothesis. We propose further study of this previously unrecognized visceral pain pathway relevant to transmission of pancreatic inputs from thoracic levels. Our preliminary data support the following hypothesis for transmission of pancreatic nociceptive information: Nociceptive information from the pancreas is transmitted to cells located medially in the spinal cord. These cells send their axons up the dorsal columns in a previously undescribed pathway between the gracile and cuneate fasciculi to innervate the edges of the dorsal column nuclei in the medulla. The information is then relayed to the thalamus. One aim of the proposed studies will define the central neuronal pathway responsible for transmission of noxious information evoked by electrical and chemical stimulation of pancreatic afferent fibers in rats. The route of the pathway to sensory processing centers will be mapped. One aim will assess pathway

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disruption as a means of abrogating pancreatic nociceptive transmission. Another aim will examine pharmacological intervention with glutamate receptor antagonists in pancreatitis models. This project using a multidisciplinary approach including electrophysiological, behavioral and anatomical methods should provide information fundamental to the understanding of nociceptive processing in these devastatingly painful conditions involving the pancreas. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FUNCTION

NEUROPEPTIDE

REGULATION

OF

ENTEROPANCREATIC

Principal Investigator & Institution: Mulholland, Michael W.; Professor of Surgery; Surgery; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2001; Project Start 01-JAN-1991; Project End 31-DEC-2003 Summary: The intrinsic nervous system of the gastrointestinal tract affects nearly aspect of digestive activity. While dysfunction of the autonomic nervous system has been postulated to cause or exacerbate several pancreatic diseases, little is known of the factors influencing signal processing and function of the enteropancreatic nervous system. As one of example, chronic pancreatitis is a devastating condition characterized by pain and exocrine insufficiency, in which abnormalities of neural function have been postulated to play a role. The current treatment of chronic pancreatitis is impiric, palliative and unsatisfactory, reflecting our lack of basic information. The following research project is designed to investigate on a fundamental level neural control mechanisms that have relevance to human health. We have hypothesized that: 1. Pancreatic nerves activate a functional domain consisting of multiple acini innervated by a single neuron; 2. Pancreatic neurotransmission is acutely regulated by presynaptic modulation of calcium-dependent signaling pathways; 3. For enteropancreatic neurons, long-term function is regulated, at the transcriptional level, by the duration and intensity of signaling activities; 4. In acinar cells, both enzyme secretion and gene expression are regulated via neural mechanisms. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NON-INVASIVE IMAGING OF INSULITIS IN TYPE 1 DIABETES Principal Investigator & Institution: Denis, Maria C.; Joslin Diabetes Center Boston, Ma 02215 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2005 Summary: (provided by the applicant): Type 1 diabetes develops through an initial phase, termed insulitis, which is characterized by leukocytic infiltration of the islets of Langerhans, and slowly evolves to its overt phase, when more than 90% of the b cells have been destroyed and insulin production is insufficient to regulate blood glucose levels As insulitis is asymptomatic, diabetes is often diagnosed during its overt phase and consequently, very little is known about its progression, in humans in particular We propose to test the hypothesis that the stratification of diabetes progression is reflected in physiologic changes occurring in the pancreas We will exploit recent advances in the fields of optical and magnetic resonance imaging (MRI), to develop and optimize novel techniques for the in vivo imaging of pancreatic inflammation These techniques will be established in well-characterized animal models of type 1 diabetes, including the nonobese diabetic (NOD) and the BDC2 5 T cell receptor (TCR) transgenic (tg) models, which exhibit spontaneous diabetes Subsequently, we will apply the developed

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technology in animal models of type 1 diabetes to address questions regarding the heterogeneity, progression and stratification of the disease and factors that control them. Such information will be invaluable for the detection, prevention and treatment of type 1 diabetes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NOVEL KINASE SIGNALING CASCADES IN PANCREATIC ACINI Principal Investigator & Institution: Williams, John A.; Professor; Physiology; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2001; Project Start 24-JUN-1998; Project End 31-MAY-2003 Summary: Several major pancreatic disease including pancreatitis, cancer and cystic fibrosis involve altered cellular regulation. Secretion of digestive enzymes by pancreatic acinar cells is largely controlled by increases in intracellular Ca2+ and diacylglycerol which result from activation of phospholipase C. However, this mechanism can not explain all the effects of secretagogues and hormones on cell growth, protein synthesis and metabolism. Recently a number of novel protein kinase cascades have been elucidated that play important roles in growth, differentiation and gene expression of a variety of cells. We have shown in published and preliminary studies that CCK activates three mitogen activated protein kinase (MAPK) cascades in rat acini leading to activation of ERKs (p42 and p44 MAPK), Jun Kinase and p38/Reactivating Kinase. In addition, CCK activates a distinct pathway in acini leading to p70 S6 Kinase which is sensitive to rapamycin and wortmannin. The overall aim of this proposal is to understand how the novel kinase cascades are activated in acini, the specific stimuli which activate them, and some of their biological functions. Four specific aims include: 1) to determine the mechanism by which CCK and EGF activate the Ras-Raf-MEK-ERK cascade; the importance of the adapter proteins Sch and Grb2 as well as Ras will be evaluated. 2) To determine the tyrosine kinase activated by CCK which phosphorylates Shc. This will involve analysis of the activation of Src and Src family members and focal adhesion kinase (FAK). 3) To determine the activation of p38MAPK, its mechanism of activation, and its role in regulating phosphorylation of small heat shock protein, and 4) the mechanism of p70 S6K activation and its role in pancreatic acinar protein synthesis. The studies will involve immunoprecipitation of kinases, Western blotting and kinase assays using specific substrates. Selective pathway activation and inhibition using specific inhibitors and expression of dominant negative mutant proteins by adenoviral vectors will be used to evaluate pathways leading to biological effects including amylase secretion, growth and protein synthesis. While the work is aimed at understanding the pancreatic acinar cell, it will also have implications for the regulation of other gastrointestinal cell types. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NOVEL PROTEASE FORMULATION BASED ON CROSSLINKED CRYSTALS Principal Investigator & Institution: Shenoy, Bhami C.; Altus Biologics, Inc. 625 Putnam Ave Cambridge, Ma 021394807 Timing: Fiscal Year 2003; Project Start 01-JUL-2000; Project End 31-MAR-2005 Summary: (provided by applicant): Design of stable and efficient formulation of proteins for therapeutic use as drugs has been a major focus of biotechnology and pharmaceutical companies. In the Phase I grant, we developed a stable, active formulation of protease from Aspergillus melleus, TheraCLEC-Protease, for use in the

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treatment of chronic abdominal pain in chronic pancreatitis and also along with TheraCLEC-Lipase and amylase for the treatment of malabsorption as a result of pancreatic insufficiency in cystic fibrosis and chronic pancreatitis. TheraCLEC-Protease exhibited product characteristics superior to commercially available pancreatic enzyme products. TheraCLEC-Protease exhibited a very high level of activity against casein and stability under low pH and towards various proteases present in the intestine. Moreover, in the preliminary investigations, the TheraCLEC-Protease did not show any toxicity. Based on these results in Phase II, we will prepare a drug product prototype for use in the treatment of abdominal pain in chronic pancreatitis and along with TheraCLEC-Lipase for use in the treatment of pancreatic insufficiency, azotorrhea and steatorrhea in cystic fibrosis and chronic pancreatitis patients. As a first step, we will crystallize and crosslink the protease with methods developed in Phase I Subsequently, we will mix TheraCLEC-Protease with TheraCLEC-Lipase and amylase for use in a final formulation or alone depending on the disease and type of treatment. The final formulation will be tested for efficacy in digesting proteins and fats in dogs with ligated pancreatic ducts. Using radiolabeled TheraCLEC-Protease, we will follow the lack of absorption into the systemic circulation. In addition, we will test the subacute, subchronic and long-term effects of feeding TheraCLEC-Protease in two species. If successful, a TheraCLEC-Protease prototype will provide an efficient treatment for abdominal pain. TheraCLEC-Protease will be ready to enter clinical trials, and will provide a novel treatment for pancreatic insufficiency in chronic pancreatitis and cystic fibrosis along with TheraCLECLipase. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: OXIDATIVE DAMAGE IN PANCREATITIS AND PANCREATIC NEOPLASIA Principal Investigator & Institution: Bell, Richard; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 98109 Timing: Fiscal Year 2001 Summary: Carcinoma of the pancreas if the fifth leading cause of cancer death in the United States; treatment for established carcinoma is largely ineffective, with mean survival measured in months. The possibility of detection of early neoplasms in a highrisk group forms the rationale for the current proposal. Chronic pancreatitis is the most significant risk factor for pancreatic cancer yet identified. Acute and chronic pancreatitis are associated with injury from reactive oxygen radicals. Oxidative damage to DNA during the development of chronic pancreatitis may lead to mutations which ultimately cause the development of subsequent pancreatic cancer. The eventual fate of oxidatively damaged cells may depend on anti-oxidant defense against further injury, changes in the ability of cells to undergo apoptosis, or changes in cell proliferation. These further changes may be a result of continued oxidative damage. In the first specific aim of the current proposal, normal pancreas and tissue with chronic pancreatitis and pancreatic cancer will be examined for markers of oxidative DNA damage, antioxidant defense, apoptosis, and proliferation. The second specific aim will address whether oxidative damage sensitizes the pancreatic duct epithelium to further changes in antioxidant defense, apoptosis and proliferation. We will determine whether antioxidant treatment can prevent these changes. This aim will also determine if cells exposed to oxidative stress are more sensitive to carcinogen challenge than normal duct cells. To examine similar questions in an in vivo model, chronic pancreatitis will be induced in hamsters and the resultant oxidative damage in pancreatic tissue measured, as well as changes in antioxidant defense, apoptosis, and proliferation. These animals will be observed for the

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development of spontaneous tumors and tested for the development of cancer in response to low doses of the carcinogen N-nitrosobis (2-oxopropyl) amine (BOP). Animals with chronic pancreatitis will be treated with antioxidants during the course of pancreatitis will be analyzed for markers of oxidative damage, antioxidant defense, apoptosis or proliferation which are found to be associated with neoplastic change in Aims 1 and 2. Aim 2, we will establish the feasibility of measuring these markers in pancreatic juice and brushing, determine the incidence of marker positivity in patients with chronic pancreatitis, validate the markers, and develop a cohort of chronic pancreatitis patients for long=term cancer surveillance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PAIN RELIEF FROM ADL 10-0101 IN CHRONIC PANCREATITIS Principal Investigator & Institution: Eisenach, James C.; Professor; Wake Forest University 2240 Reynolda Rd Winston-Salem, Nc 27106 Timing: Fiscal Year 2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PANCREAS AND ISLET TRANSPLANTATION IN HUMANS Principal Investigator & Institution: Robertson, R Paul.; Scientific Director and Ceo; Pacific Northwest Research Institute 720 Broadway Seattle, Wa 98122 Timing: Fiscal Year 2001; Project Start 01-DEC-1988; Project End 31-JUL-2002 Summary: "The overall goal of the work described in this proposal is to fully understand the metabolic consequences of long term, successful pancreas and islet transplantation in Type 1 Diabetic patients and to ascertain the long term metabolic consequences of hemi pancreatectomy in healthy human donors. For recipients of pancreas transplantation, the two specific aims are: Specific Aim 1: To compare insulin secretory reserve in pancreas transplant recipients receiving either cyclosporin or FK 506 as immunosuppressive therapy. Specific Aim 2: To assess counter- regulatory responses of glucagon and epinephrine during hypoglycemic, hyperinsulinemic clamps pretransplant and longitudinally posttransplant and to ascertain whether differences in responses exist in patients receiving cyclosporin or FK506. For normal patients who have undergone hemi pancreatectomy to donate hemi organs to relatives, the two specific aims are Specific Aim 3: To assess glycemic regulation and insulin secretory reserve pre operatively and longitudinally post operatively in donors. Specific Aim 4: To assess insulin mediated glucose disposal, glucose mediated glucose disposal, and glycemic regulation pre operatively and longitudinally post operatively in healthy human donors. For type 1 patients receiving auto or allotransplantation of islets, the three specific aims are: Specific Aim 5: To correlate measurements of post transplant insulin secretory reserve with the number of islets autotransplanted in non diabetic chronic pancreatitis patients. Specific Aim 6: To compare glycemic regulation and insulin secretory reserve longitudinally in islet recipients receiving steroids or no steroid and cyclosporin or FK 506. Specific Aim 7: To assess glucagon responses during hypoglycemic, hyperinsulinemic clamps pre operatively and longitudinally in type 1 diabetic patients receiving alloislets. The research design and methods for achieving these goals will include measurements of glucose and hemoglobin AlC levels; insulin, C peptide, and glucagon secretion; hypoglycemic, hyperinsulinemic and euglycemic, hyperinsulinemic (with and without concurrent somatostatin infusion) clamps; and studies of glucose potentiation of arginine induced insulin secretion."

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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PANCREAS TRANSCRIPTION FACTORS AND CANCER MODEL SYSTEMS Principal Investigator & Institution: Konieczny, Stephen F.; Associate Professor; Biological Sciences; Purdue University West Lafayette West Lafayette, in 479072040 Timing: Fiscal Year 2001; Project Start 01-MAR-2000; Project End 28-FEB-2005 Summary: (adapted from investigator's abstract): The development of the mammalian pancreas represents an attractive model system to study the molecular signals that direct the commitment and differentiation of epithelial cells along different cell lineages. The pancreas consists of two distinct tissue types which carry out different essential functions. The endocrine pancreas regulates blood sugar levels by secreting glucagon or insulin whereas the exocrine pancreas secretes digestive enzymes into the duodenal part of the small intestine. Although many of the transcription factors responsible for endocrine pancreas formation have been identified and extensively studied, the molecular regulatory circuits that control the establishment and maintenance of the exocrine pancreas are just beginning to be elucidated. Towards a goal of identifying key transcriptional regulators of pancreatic development and function, a novel basic helixloop-helix (bHLH) transcription factor (Mistl) recently was identified that accumulates to high levels in pancreatic exocrine cells. Mistl gene expression is initially detected at mouse embryonic day E10.5 in the developing pancreas and remains expressed to high levels in the acinar cells of the adult. Although the Mistl nuclear protein is capable of binding to specific DNA targets as a homodimer or as a heterodimer with other bHLH transcription factors, it lacks a typical transcription activation domain and instead can serve as a transcriptional repressor in some experimental systems. At this time, a true role for Mistl activity in pancreatic function has not been established, although its expression pattern and DNA binding capabilities suggest that Mistl likely serves as a key regulator of exocrine pancreas gene activity. In order to characterize further the biochemical properties of the Mistl protein and the role of Mistl in pancreatic development, studies are proposed to (1) examine the activity of Mistl using a pancreatic cell line model system, (2) identify pancreas-specific Mistl protein binding partners and (3) utilize mouse genetic approaches to create Mistl homozygous null mice and to identify Mistl target genes. In addition, targeted replacement of the Mistl gene with an activated K-ras allele will be performed to generate novel pancreatic cancer models. A complete characterization of Mistl activity in exocrine pancreatic cells will add critical new information regarding normal pancreatic development and function and may provide future strategies for combating several key human diseases, including acute pancreatitis and pancreatic cancer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PANCREATIC DEVELOPMENT IN MODELING PANCREATIC DISEASE Principal Investigator & Institution: Grippo, Paul J.; Surgery; Northwestern University Office of Sponsored Programs Chicago, Il 60611 Timing: Fiscal Year 2003; Project Start 20-SEP-2003; Project End 31-AUG-2004 Summary: (provided by applicant): The Role of Pancreatic Development in Modeling Pancreatic Disease in Mice. September 4-5, 2003 Northwestern University and Northwestern Memorial Hospital The pancreas serves both an endocrine and exocrine function and has distinct roles in glucose homeostasis and digestion. Several debilitating

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Pancreatitis

diseases, with virtually no curative measures, arise when cell types undergo genetic mutations, altering cell function and/or inducing cellular transformation. Diabetes, pancreatitis, and pancreatic cancer have serious health consequences beginning with a greatly reduced quality of life and ending in death. These diseases are associated with each other. For example, people with diabetes and/or pancreatitis have a greater incidence of pancreatic cancer. In order to introduce curative paradigms against these diseases, it is critical to evaluate therapies outside the clinic, which include using animal models that recapitulate these human diseases. A few mouse models do exist for these diseases yet seldom do these models provide phenotypic or molecular mimicry to their human counterpart. To better understand the sequential genetic and cellular events that lead to diabetes, pancreatitis, and pancreatic cancer and engineer models for therapeutic evaluation, it becomes critical to understand the underlying mechanisms responsible for differentiation and cell fate. Evidence is accumulating on the pathway from a progenitor cell type to the three primary cells of the pancreas: islet, acinar, and ductal cells. In order to improve pancreatic development and disease modeling research, I propose holding a conference that brings both groups together. I am hoping to foster a critical link that is not entirely in place. That link is between scientists exploring pancreatic development and the signals that determine differentiation patterns and cell fate with those investigators who desire to model pancreatic disease in mice. New information that defines which embryonic cell(s) and/or cell signal(s) that are responsible for generating mature endocrine and exocrine cells in the pancreas is critical for engineering new transgenic mouse models that recapitulate diabetes, pancreatitis, and pancreatic cancer. Targeting pancreatic progenitor cells with various genetic alterations will provide valuable information for the developmental biologist and clinical pathologist alike. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PH II STUDY RECOMBINANT PLATELET ACTIVATING FACTOR ACETYLHYDROLASE Principal Investigator & Institution: Slivka, Adam; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2001 Summary: The objectives of this study are: 1)to determine if the prophylactic administration of rPAF-AH decreases in incidence and severity of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis in a dose-dependent manner. 2)to evaluate the cost-efficacy of rPAH-AH when administered prophylactically to prevent post-ERCP pancreatitis. 3)to characterize the safety and pharmacokinetic behavior of rPAH-AH after intravenous administration in patients scheduled to undergo ERCP. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PANCREATITIS

PHARMACOGENETICS

OF

ASPARAGINASE-INDUCED

Principal Investigator & Institution: Silverman, Lewis B.; Dana-Farber Cancer Institute 44 Binney St Boston, Ma 02115 Timing: Fiscal Year 2003; Project Start 07-JUL-2003; Project End 31-MAY-2008 Summary: (provided by applicant): We seek to determine whether there is a genetic predisposition for the development of asparaginase-related pancreatitis. Asparaginase is a highly effective drug in the treatment of childhood acute lymphoblastic leukemia (ALL), but is associated with significant side effects in up to one-third of patients.

Studies

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Patients who are unable to receive all of their intended doses of asparaginase have a higher relapse rate than those who are able to tolerate all or nearly all of their doses, with a 5-year event-free survival rate of 73% for asparaginase-intolerant and 90% for asparaginase-tolerant patients (p ile stabilizes rat trypsinogen in vitro. Author(s): Sahin-Toth M. Source: The Journal of Biological Chemistry. 1999 October 15; 274(42): 29699-704. Erratum In: J Biol Chem 2000 May 5; 275(18): 14004. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10514442&dopt=Abstract

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High dose octreotide in the management of acute pancreatitis. Author(s): Karakoyunlar O, Sivrel E, Tanir N, Denecli AG. Source: Hepatogastroenterology. 1999 May-June; 46(27): 1968-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10430379&dopt=Abstract

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Hyperbaric oxygen therapy attenuates pancreatic microcirculatory derangement and lung edema in an acute experimental pancreatitis model in rats. Author(s): Chen HM, Shyr MH, Ueng SW, Chen MF. Source: Pancreas. 1998 July; 17(1): 44-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9667519&dopt=Abstract

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Hyperbaric oxygen therapy in the treatment of refractory peripancreatic abscess associated with severe acute pancreatitis. Author(s): Izawa K, Tsunoda T, Ura K, Yamaguchi T, Ito T, Kanematsu T, Tsuchiya R. Source: Gastroenterol Jpn. 1993 April; 28(2): 284-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8486216&dopt=Abstract

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Hyperbaric oxygen, allopurinol, and diet-induced acute pancreatitis. Author(s): Degertekin H, Ertan A, Yater RD, Van Meter K, Akdamar K.

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Source: Annals of Internal Medicine. 1985 September; 103(3): 474-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4026099&dopt=Abstract •

Induction of apoptosis reduces the severity of caerulein-induced pancreatitis in mice. Author(s): Saluja A, Hofbauer B, Yamaguchi Y, Yamanaka K, Steer M. Source: Biochemical and Biophysical Research Communications. 1996 March 27; 220(3): 875-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8607859&dopt=Abstract

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Induction of apoptosis with an extract of Artemisia asiatica attenuates the severity of cerulein-induced pancreatitis in rats. Author(s): Hahm KB, Kim JH, You BM, Kim YS, Cho SW, Yim H, Ahn BO, Kim WB. Source: Pancreas. 1998 August; 17(2): 153-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9700946&dopt=Abstract

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Is there a place for pancreatic enzymes in the treatment of pain in chronic pancreatitis? Author(s): Mossner J. Source: Digestion. 1993; 54 Suppl 2: 35-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7693533&dopt=Abstract

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Issues in hyperlipidemic pancreatitis. Author(s): Yadav D, Pitchumoni CS. Source: Journal of Clinical Gastroenterology. 2003 January; 36(1): 54-62. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12488710&dopt=Abstract

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Lack of association between cassava consumption and tropical pancreatitis syndrome. Author(s): Narendranathan M, Cheriyan A. Source: Journal of Gastroenterology and Hepatology. 1994 May-June; 9(3): 282-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8054529&dopt=Abstract

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Letter 1: Randomized clinical trial of specific lactobacillus and fibre supplement to early enteral nutrition in patients with acute pancreatitis (Br J Surg 2002; 89: 11031107). Author(s): Weale R, Edwards A. Source: The British Journal of Surgery. 2003 January; 90(1): 122-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12520591&dopt=Abstract

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Lymphoma-associated pancreatitis as a presenting manifestation of immunoblastic lymphoma. Author(s): Safadi R, Or R, Bar Ziv J, Polliack A.

Alternative Medicine 143

Source: Leukemia & Lymphoma. 1994 January; 12(3-4): 317-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7513221&dopt=Abstract •

Lysolecithin concentration in pancreatic tissue during therapy with phospholipase A2-inhibitors in acute necrotizing pancreatitis. Author(s): Kahle M, Konig H, Filler RD. Source: Klin Wochenschr. 1989 February 1; 67(3): 177-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2494378&dopt=Abstract

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Mechanisms of Chinese herb emodin and somatostatin analogs on pancreatic regeneration in acute pancreatitis in rats. Author(s): Gong Z, Yuan Y, Lou K, Tu S, Zhai Z, Xu J. Source: Pancreas. 2002 August; 25(2): 154-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12142738&dopt=Abstract

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Mutations in the lipoprotein lipase gene as a cause of hypertriglyceridemia and pancreatitis in taiwan. Author(s): Jap TS, Jenq SF, Wu YC, Chiu CY, Cheng HM. Source: Pancreas. 2003 August; 27(2): 122-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12883259&dopt=Abstract

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No effect of long-term treatment with pancreatic extract on recurrent abdominal pain in patients with chronic pancreatitis. Author(s): Malesci A, Gaia E, Fioretta A, Bocchia P, Ciravegna G, Cantor P, Vantini I. Source: Scandinavian Journal of Gastroenterology. 1995 April; 30(4): 392-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7610357&dopt=Abstract

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Nutrition supplementation in patients with acute and chronic pancreatitis. Author(s): Scolapio JS, Malhi-Chowla N, Ukleja A. Source: Gastroenterology Clinics of North America. 1999 September; 28(3): 695-707. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10503145&dopt=Abstract

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Omega-3 fatty acid supplementation increases anti-inflammatory cytokines and attenuates systemic disease sequelae in experimental pancreatitis. Author(s): Foitzik T, Eibl G, Schneider P, Wenger FA, Jacobi CA, Buhr HJ. Source: Jpen. Journal of Parenteral and Enteral Nutrition. 2002 November-December; 26(6): 351-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12405646&dopt=Abstract

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Organic matrix of pancreatic stones associated with nutritional pancreatitis. Author(s): Montalto G, Multigner L, Sarles H, De Caro A.

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Source: Pancreas. 1988; 3(3): 263-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3387420&dopt=Abstract •

Paclitaxel-induced pancreatitis: a case report. Author(s): Hoff PM, Valero V, Holmes FA, Whealin H, Hudis C, Hortobagyi GN. Source: Journal of the National Cancer Institute. 1997 January 1; 89(1): 91-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8978416&dopt=Abstract

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Pancreatic microvascular permeability in caerulein-induced acute pancreatitis. Author(s): Sweiry JH, Mann GE. Source: The American Journal of Physiology. 1991 October; 261(4 Pt 1): G685-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1928354&dopt=Abstract

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Pancreatitis and intravenous fat: an association in patients with inflammatory bowel disease. Author(s): Noseworthy J, Colodny AH, Eraklis AJ. Source: Journal of Pediatric Surgery. 1983 June; 18(3): 269-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6410038&dopt=Abstract

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Pancreatitis and pulmonary hemorrhage complicating closed-chest cardiac massage. Author(s): Cowan D. Source: Can Med Assoc J. 1966 November 5; 95(19): 976-7. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=5922913&dopt=Abstract

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Pancreatitis and the lungs. Author(s): McWilliams H, Gross R. Source: The American Surgeon. 1974 August; 40(8): 448-52. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4602093&dopt=Abstract

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Pancreatitis during combination chemotherapy. Author(s): Newman CE, Ellis DJ. Source: Clin Oncol. 1979 March; 5(1): 83-4. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=421389&dopt=Abstract

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Pancreatitis following ingestion of a homeopathic preparation. Author(s): Kerr HD, Yarborough GW. Source: The New England Journal of Medicine. 1986 June 19; 314(25): 1642-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3713765&dopt=Abstract

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Pancreatitis Partners: a sharing and educational support group. Author(s): Shepp PH, Chase P, Rawls E.


Source: Gastroenterology Nursing : the Official Journal of the Society of Gastroenterology Nurses and Associates. 1999 July-August; 22(4): 155-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10745743&dopt=Abstract •

Pathological events in experimental acute pancreatitis prevented by the bradykinin antagonist, Hoe 140. Author(s): Griesbacher T, Tiran B, Lembeck F. Source: British Journal of Pharmacology. 1993 February; 108(2): 405-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8448591&dopt=Abstract

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Phospholipase A2 inhibitors and their possible clinical use in the treatment of acute pancreatitis. Author(s): Tykka H, Mahlberg K, Pantzar P, Tallberg T. Source: Scandinavian Journal of Gastroenterology. 1980; 15(5): 519-28. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=6777862&dopt=Abstract

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Phospholipase activity in pancreatic exudate in experimental acute pancreatitis. Author(s): Gjone E, Ofstad E, Marton PF, Amundsen E. Source: Scandinavian Journal of Gastroenterology. 1967; 2(3): 181-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=4963682&dopt=Abstract

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Possible drug-associated pancreatitis after paclitaxel-cremophor administration. Author(s): Mills KM, Johnson DM, Middlebrooks M, Burton GV. Source: Pharmacotherapy. 2000 January; 20(1): 95-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10641981&dopt=Abstract

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Protective effect of a microtubule stabilizer taxol on caerulein-induced acute pancreatitis in rat. Author(s): Ueda T, Takeyama Y, Kaneda K, Adachi M, Ohyanagi H, Saitoh Y. Source: The Journal of Clinical Investigation. 1992 January; 89(1): 234-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1370296&dopt=Abstract

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Re: Vinorelbine-induced pancreatitis: a case report. Author(s): Raderer M, Kornek G, Scheithauer W. Source: Journal of the National Cancer Institute. 1998 February 18; 90(4): 329. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9486821&dopt=Abstract

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Secondary pancreatic involvement by diffuse large B-cell lymphoma presenting as acute pancreatitis: treatment and outcome. Author(s): Bernardeau M, Auroux J, Cavicchi M, Haioun C, Tsakiris L, Delchier JC.

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Source: Pancreatology : Official Journal of the International Association of Pancreatology (Iap). [et Al.]. 2002; 2(4): 427-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12138234&dopt=Abstract •

Severe hypertriglyceridemia and pancreatitis when estrogen replacement therapy is given to hypertriglyceridemic women. Author(s): Glueck CJ, Lang J, Hamer T, Tracy T. Source: The Journal of Laboratory and Clinical Medicine. 1994 January; 123(1): 59-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8288962&dopt=Abstract

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Soybean trypsin inhibitor and cerulein accelerate recovery of cerulein-induced pancreatitis in rats. Author(s): Jurkowska G, Grondin G, Masse S, Morisset J. Source: Gastroenterology. 1992 February; 102(2): 550-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1370663&dopt=Abstract

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The effect of hyperbaric oxygen treatment on oxidative stress in experimental acute necrotizing pancreatitis. Author(s): Yasar M, Yildiz S, Mas R, Dundar K, Yildirim A, Korkmaz A, Akay C, Kaymakcioglu N, Ozisik T, Sen D. Source: Physiological Research / Academia Scientiarum Bohemoslovaca. 2003; 52(1): 111-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12625815&dopt=Abstract

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The effect of microtubule stabilizer on rat caerulein-induced pancreatitis. Author(s): Ueda T. Source: The Kobe Journal of Medical Sciences. 1991 April; 37(2): 97-109. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1717741&dopt=Abstract

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The effects of free oxygen radical scavenger and platelet-activating factor antagonist agents in experimental acute pancreatitis. Author(s): Soybir G, Koksoy F, Ekiz F, Yalcin O, Fincan K, Haklar G, Yuksel M. Source: Pancreas. 1999 August; 19(2): 143-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10438161&dopt=Abstract

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The effects of green tea catechins (Polyphenon) on DL-ethionine-induced acute pancreatitis. Author(s): Takabayashi F, Harada N, Hara Y. Source: Pancreas. 1995 August; 11(2): 127-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7479668&dopt=Abstract

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Therapeutic efficacy of high-dose vitamin C on acute pancreatitis and its potential mechanisms.


Author(s): Du WD, Yuan ZR, Sun J, Tang JX, Cheng AQ, Shen DM, Huang CJ, Song XH, Yu XF, Zheng SB. Source: World Journal of Gastroenterology : Wjg. 2003 November; 9(11): 2565-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=14606098&dopt=Abstract •

Transcutaneous electrical nerve stimulation in the management of pancreatitis pain. Author(s): Roberts HJ. Source: Southern Medical Journal. 1978 April; 71(4): 396-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=76340&dopt=Abstract

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Treatment of acute pancreatitis with liyi tang--a report of 50 cases. Author(s): Chen Q, Lu J. Source: J Tradit Chin Med. 1997 December; 17(4): 250-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10437205&dopt=Abstract

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Treatment of late allograft pancreatitis with oral pancreatic extract. Author(s): Garvin PJ, Lindsey L, Aridge DL, Burton FR, Patel BK, George E, Reese J. Source: Transplantation. 1991 October; 52(4): 733-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1926355&dopt=Abstract

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Use of a synthetic protease inhibitor for the treatment of L-asparaginase-induced acute pancreatitis complicated by disseminated intravascular coagulation. Author(s): Murakawa M, Okamura T, Shibuya T, Harada M, Otsuka T, Niho Y. Source: Annals of Hematology. 1992 May; 64(5): 249-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=1623061&dopt=Abstract

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Vinorelbine-induced pancreatitis: a case report. Author(s): Tester W, Forbes W, Leighton J. Source: Journal of the National Cancer Institute. 1997 November 5; 89(21): 1631. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9362167&dopt=Abstract

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Wilson's disease associated with pancreatitis. Author(s): Weizman Z, Picard E, Barki Y, Moses S. Source: Journal of Pediatric Gastroenterology and Nutrition. 1988 November-December; 7(6): 931-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=3199280&dopt=Abstract

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Zinc in mononuclear leucocytes in alcoholics with liver cirrhosis or chronic pancreatitis and in patients with Crohn's disease before and after zinc supplementation. Author(s): Bro S, Stokholm M, Jorgensen PJ.

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Source: J Trace Elem Electrolytes Health Dis. 1989 December; 3(4): 243-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=2535348&dopt=Abstract

Additional Web Resources A number of additional Web sites offer encyclopedic information covering CAM and related topics. The following is a representative sample: •

Alternative Medicine Foundation, Inc.: http://www.herbmed.org/

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AOL: http://search.aol.com/cat.adp?id=169&layer=&from=subcats

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Chinese Medicine: http://www.newcenturynutrition.com/

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drkoop.com: http://www.drkoop.com/InteractiveMedicine/IndexC.html

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Family Village: http://www.familyvillage.wisc.edu/med_altn.htm

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Google: http://directory.google.com/Top/Health/Alternative/

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Healthnotes: http://www.healthnotes.com/

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MedWebPlus: http://medwebplus.com/subject/Alternative_and_Complementary_Medicine

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Open Directory Project: http://dmoz.org/Health/Alternative/

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HealthGate: http://www.tnp.com/

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WebMDHealth: http://my.webmd.com/drugs_and_herbs

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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html

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Yahoo.com: http://dir.yahoo.com/Health/Alternative_Medicine/

The following is a specific Web list relating to pancreatitis; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: •

General Overview Celiac Disease Source: Healthnotes, Inc.; www.healthnotes.com High Cholesterol Source: Integrative Medicine Communications; www.drkoop.com High Triglycerides Source: Healthnotes, Inc.; www.healthnotes.com Hypercholesterolemia Source: Integrative Medicine Communications; www.drkoop.com


Hyperparathyroidism Source: Integrative Medicine Communications; www.drkoop.com Malabsorption Source: Healthnotes, Inc.; www.healthnotes.com Morning Sickness Source: Healthnotes, Inc.; www.healthnotes.com Mumps Source: Integrative Medicine Communications; www.drkoop.com Pancreatic Insufficiency Source: Healthnotes, Inc.; www.healthnotes.com •

Herbs and Supplements Digestive Enzymes Source: Healthnotes, Inc.; www.healthnotes.com Lipase Source: Healthnotes, Inc.; www.healthnotes.com Medium-Chain Triglycerides Source: Prima Communications, Inc.www.personalhealthzone.com Methionine Source: Healthnotes, Inc.; www.healthnotes.com

General References A good place to find general background information on CAM is the National Library of Medicine. It has prepared within the MEDLINEplus system an information topic page dedicated to complementary and alternative medicine. To access this page, go to the MEDLINEplus site at http://www.nlm.nih.gov/medlineplus/alternativemedicine.html. This Web site provides a general overview of various topics and can lead to a number of general sources.

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CHAPTER 4. DISSERTATIONS ON PANCREATITIS Overview In this chapter, we will give you a bibliography on recent dissertations relating to pancreatitis. We will also provide you with information on how to use the Internet to stay current on dissertations. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical dissertations that use the generic term “pancreatitis” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on pancreatitis, we have not necessarily excluded nonmedical dissertations in this bibliography.

Dissertations on Pancreatitis ProQuest Digital Dissertations, the largest archive of academic dissertations available, is located at the following Web address: http://wwwlib.umi.com/dissertations. From this archive, we have compiled the following list covering dissertations devoted to pancreatitis. You will see that the information provided includes the dissertation’s title, its author, and the institution with which the author is associated. The following covers recent dissertations found when using this search procedure: •

A Randomized Controlled Trial and Cost Effectiveness Analysis of Parenteral Nutrition and Enteral Nutrition in Severe Pancreatitis: A Model for Health Technology Assessment by Louie, Brian Edward; Mph from University of Alberta (Canada), 2002, 114 pages http://wwwlib.umi.com/dissertations/fullcit/MQ69674

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Antioxidants, Nitric Oxide and Chronic Pancreatitis by Fredstrom, Susan Beth; PhD from University of Minnesota, 2002, 220 pages http://wwwlib.umi.com/dissertations/fullcit/3047627

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The Bile Factor in Experimental Pancreatitis by Poncelet, Paul; PhD from McGill University (Canada), 1973 http://wwwlib.umi.com/dissertations/fullcit/NK15967

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The Role of Cyclooxygenase-2 (COX-2) in Acute Pancreatitis by Ethridge, Richard Thomas; PhD from The University of Texas Graduate Sch. of Biomedical Sci. at Galveston, 2003, 108 pages http://wwwlib.umi.com/dissertations/fullcit/3083540

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The Role of Proelastase-Elastase Enzyme in the Pathogenesis of Experimental Pancreatitis by Geokas, Michael C; AdvDeg from McGill University (Canada), 1966 http://wwwlib.umi.com/dissertations/fullcit/NK00450

Keeping Current Ask the medical librarian at your library if it has full and unlimited access to the ProQuest Digital Dissertations database. From the library, you should be able to do more complete searches via http://wwwlib.umi.com/dissertations.

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CHAPTER 5. CLINICAL TRIALS AND PANCREATITIS Overview In this chapter, we will show you how to keep informed of the latest clinical trials concerning pancreatitis.

Recent Trials on Pancreatitis The following is a list of recent trials dedicated to pancreatitis.8 Further information on a trial is available at the Web site indicated. •

A study to determine if antibiotics prevent infection in the pancreas of patients where part of the pancreas has died. Condition(s): Pancreatitis, Acute Necrotizing Study Status: This study is currently recruiting patients. Sponsor(s): AstraZeneca Purpose - Excerpt: This is a research study in patients having a condition known as necrotizing pancreatitis. This is inflammation of the pancreas (an intestinal organ which assists with digestion) that has resulted in the damage and death of some pancreatic tissue. This damaged pancreatic tissue may develop a bacterial infection, which can cause further -sometimes very serious- health problems. It may be possible to prevent or delay infection by giving 'prophylactic' antibiotics (that is - to provide protection before any infection starts). However, it is not certain that this antibiotic therapy will be successful. This study is being carried out to see whether the antibiotic 'Meropenem' (which is also known as MERREM I.V.) provides protection from developing a pancreatic infection. This will be done by comparing the progress of patients who receive meropenem with those who receive a non-active placebo solution (a solution that does not contain any active medication). Meropenem or placebo would be given in addition to the standard treatment received for pancreatitis. It is not known if meropenem will help prevent infections associated with necrotizing pancreatitis. Approximately 240 patients will take part in this study. Study participation will be

8

These are listed at www.ClinicalTrials.gov.

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carried out for up to 6 weeks, and patients will receive the study treatment up to a maximum of 21 days. Phase(s): Phase IV Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00061438 •

Genetic Linkage Study for Hereditary Pancreatitis Condition(s): Pancreatitis Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); University of Pittsburgh Purpose - Excerpt: Objectives: I. Establish linkage in families with hereditary pancreatitis between the phenotype and a chromosomal locus (loci) that contains the responsible gene. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004475

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Videoscopic Drainage of Infected Pancreatic Collections Condition(s): Pancreatitis, Acute Necrotizing Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: The VARD (Videoendoscopic Assisted Retroperitoneal Drainage) approach as treatment for necrotizing pancreatitis proposes an alternative to standard complicated open abdomen treatment methods. This treatment involves making a small incision and looking inside the abdomen with a videoendoscope. A videoendoscope is an instrument with a small camera and light on the end. It also has an extension tool that the surgeon can use to clean out any dead and infected tissue in the abdomen. This approach may reveal a treatment opportunity with faster recovery potential and shorter hospitalizations for patients with necrotizing pancreatitis. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00061269

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Safety and efficacy study of IL-10 (Tenovil TM) in the prevention of Post-ERCP Acute Pancreatitis Condition(s): Bile Duct Diseases; Biliary Tract Diseases; Gallbladder Diseases; Pancreatitis; Pancreatic Diseases Study Status: This study is terminated. Sponsor(s): Schering-Plough

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Purpose - Excerpt: The purpose of this study is to determine if a single dose of IL-10 compared to placebo is safe and effective in reducing the incidence of post-ERCP acute pancreatitis for subjects with increased risk. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00040131

Keeping Current on Clinical Trials The U.S. National Institutes of Health, through the National Library of Medicine, has developed ClinicalTrials.gov to provide current information about clinical research across the broadest number of diseases and conditions. The site was launched in February 2000 and currently contains approximately 5,700 clinical studies in over 59,000 locations worldwide, with most studies being conducted in the United States. ClinicalTrials.gov receives about 2 million hits per month and hosts approximately 5,400 visitors daily. To access this database, simply go to the Web site at http://www.clinicaltrials.gov/ and search by “pancreatitis” (or synonyms). While ClinicalTrials.gov is the most comprehensive listing of NIH-supported clinical trials available, not all trials are in the database. The database is updated regularly, so clinical trials are continually being added. The following is a list of specialty databases affiliated with the National Institutes of Health that offer additional information on trials: •

For clinical studies at the Warren Grant Magnuson Clinical Center located in Bethesda, Maryland, visit their Web site: http://clinicalstudies.info.nih.gov/

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For clinical studies conducted at the Bayview Campus in Baltimore, Maryland, visit their Web site: http://www.jhbmc.jhu.edu/studies/index.html

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For cancer trials, visit the National Cancer Institute: http://cancertrials.nci.nih.gov/

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For eye-related trials, visit and search the Web page of the National Eye Institute: http://www.nei.nih.gov/neitrials/index.htm

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For heart, lung and blood trials, visit the Web page of the National Heart, Lung and Blood Institute: http://www.nhlbi.nih.gov/studies/index.htm

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For trials on aging, visit and search the Web site of the National Institute on Aging: http://www.grc.nia.nih.gov/studies/index.htm

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For rare diseases, visit and search the Web site sponsored by the Office of Rare Diseases: http://ord.aspensys.com/asp/resources/rsch_trials.asp

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For alcoholism, visit the National Institute on Alcohol Abuse and Alcoholism: http://www.niaaa.nih.gov/intramural/Web_dicbr_hp/particip.htm

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For trials on infectious, immune, and allergic diseases, visit the site of the National Institute of Allergy and Infectious Diseases: http://www.niaid.nih.gov/clintrials/

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For trials on arthritis, musculoskeletal and skin diseases, visit newly revised site of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health: http://www.niams.nih.gov/hi/studies/index.htm

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For hearing-related trials, visit the National Institute on Deafness and Other Communication Disorders: http://www.nidcd.nih.gov/health/clinical/index.htm

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For trials on diseases of the digestive system and kidneys, and diabetes, visit the National Institute of Diabetes and Digestive and Kidney Diseases: http://www.niddk.nih.gov/patient/patient.htm

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For drug abuse trials, visit and search the Web site sponsored by the National Institute on Drug Abuse: http://www.nida.nih.gov/CTN/Index.htm

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For trials on mental disorders, visit and search the Web site of the National Institute of Mental Health: http://www.nimh.nih.gov/studies/index.cfm

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For trials on neurological disorders and stroke, visit and search the Web site sponsored by the National Institute of Neurological Disorders and Stroke of the NIH: http://www.ninds.nih.gov/funding/funding_opportunities.htm#Clinical_Trials

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CHAPTER 6. PATENTS ON PANCREATITIS Overview Patents can be physical innovations (e.g. chemicals, pharmaceuticals, medical equipment) or processes (e.g. treatments or diagnostic procedures). The United States Patent and Trademark Office defines a patent as a grant of a property right to the inventor, issued by the Patent and Trademark Office.9 Patents, therefore, are intellectual property. For the United States, the term of a new patent is 20 years from the date when the patent application was filed. If the inventor wishes to receive economic benefits, it is likely that the invention will become commercially available within 20 years of the initial filing. It is important to understand, therefore, that an inventor’s patent does not indicate that a product or service is or will be commercially available. The patent implies only that the inventor has “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States. While this relates to U.S. patents, similar rules govern foreign patents. In this chapter, we show you how to locate information on patents and their inventors. If you find a patent that is particularly interesting to you, contact the inventor or the assignee for further information. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical patents that use the generic term “pancreatitis” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on pancreatitis, we have not necessarily excluded nonmedical patents in this bibliography.

Patents on Pancreatitis By performing a patent search focusing on pancreatitis, you can obtain information such as the title of the invention, the names of the inventor(s), the assignee(s) or the company that owns or controls the patent, a short abstract that summarizes the patent, and a few excerpts from the description of the patent. The abstract of a patent tends to be more technical in nature, while the description is often written for the public. Full patent descriptions contain much more information than is presented here (e.g. claims, references, figures, diagrams, etc.). We will tell you how to obtain this information later in the chapter. The following is an 9Adapted from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.

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example of the type of information that you can expect to obtain from a patent search on pancreatitis: •

Antibodies specific for human pancreatitis associated protein Inventor(s): Dagorn; Jean-Charles (Marseille, FR), Iovanna; Juan-Lucio (Marseille, FR), Keim; Volker (Heddesheim, DE) Assignee(s): Institut National de la Santa et de la Recherche Medicale (Paris Cedex, FR) Patent Number: 5,959,086 Date filed: April 14, 1995 Abstract: The invention relates to the family of the protein (PAP) associated with acute pancreatitis in man and in the rat. It also relates to the nucleotide fragments coding for the above proteins. Also included in the framework of the invention are antibodies which recognize the PAP and which are capable of being used for the purpose of diagnosing pancreatitis. The invention also relates to the production of the PAP, in particular by genetic engineering. Excerpt(s): The present invention relates to proteins associated with acute pancreatitis and agents for the diagnosis of this disease. Acute pancreatitis is an inflammatory disease of the pancreas which, pathologically speaking, extends from the simple edematous form to the complete hemorrhagic necrosis of the gland. Necro-hemorrhagic pancreatitis is a very serious disease since, depending on the authors, its mortality is estimated to vary from 30 to 70%. In certain cases it is very difficult to establish the diagnosis of acute pancreatitis with certainty (Sarner, M. et al, Gastroenterol. (1984), 13: 865-870). This diagnosis is based in particular on clinical examination (acute abdominal pain), on the determination of a certain number of substances in the plasma or in the peritoneal fluid (Bradley, J. et al., Br. J. Surg. (1981), 68: 245-246; and Dubick, M. et al., Dig. Dis. Sci. (1987), 32: 305-312). The analytical determinations employed include those for amylase, lipase, trypsin, elastase, ribonuclease, phospholipase A2,.alpha.-2 macroglobulin, calcium, LDH, protease inhibitors and others. However, none of them has proved to be specific, practical or above all, discriminating. Hence, it is usually considered sufficient to determine amylasemia. Recently, ultrasonography and computerized tomography have appeared to be able to facilitate the diagnosis of pancreatitis without, however, decisive progress being made (Silverstein, W. et al., Am. J. Roentgenol., (1981), 137: 497-502). In 1984, Keim et al. published (Digestion, (1984), 29: 242-249) results of the consequences of cannulation of the pancreatic duct and the induction of pancreatitis on the protein composition of the pancreatic juice in the rat, this animal being used an experimental model. After the operation of cannulation (1 to 2 days later), the authors observed a fall in the level of amylase in the pancreatic juice followed, 3 to 4 days after the operation, by a return to the normal amylase level. Web site: http://www.delphion.com/details?pn=US05959086__

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Apparatus and method for abdomino-pelvic chemotherapy perfusion and lavage Inventor(s): Sugarbaker; Paul H. (3629 Fulton St., NW., Washington, DC 20007) Assignee(s): none reported Patent Number: 6,383,162 Date filed: November 12, 1999

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Abstract: An abdomino-pelvic perfusion and lavage apparatus is disclosed to which skin surrounding an incision formed through an abdominal wall of a patient can be attached and suspended. The apparatus includes a containment vessel impermeable to water and air, having a wall having a base, wherein the wall has an upper end with a perimeter which defines an upper opening, a lower end with a perimeter which defines a base opening, a cranial end with a perimeter edge which defines an opening, and a caudal end with a perimeter edge which defines an opening. The containment vessel can be carried by a table on which a patient is positioned. Scaffolding carried by the containment vessel supports and elevates the skin surrounding the incision made through the abdominal wall of the patient and thereby forms a well above, and extending into, an abdomino-pelvic cavity. A plurality of fluid ports communicate through the wall of the containment vessel. The cranial opening and the caudal opening can be sealed around the patient's torso. A base seal can seal the base of the containment vessel to the table. Perfusion fluid can be supplied from a reservoir to one of the fluid ports communicating through the wall of the containment vessel and delivered to the well and can be withdrawn from the well and returned to the reservoir. A removable cover can be sealed over the upper opening of the containment vessel. The cover can be removed for visual inspection and manual manipulation of the lavage fluid and the patient's viscera. An air evacuation system can be connected to the fluid port and can evacuate aerosols and gasses from within the containment vessel. A heater can be used to heat the perfusion fluid when carrying out hyperthermic perfusion. The apparatus can be left in place on a patient for up to 5-10 days particularly when using cell-cycle specific chemotherapy agents which require long-term contact with tissues in order to achieve their optimal effect. Similarly, the apparatus can be used for repeated access to the abdomino-pelvic space in patients with peritonitis or pancreatitis. Excerpt(s): This invention relates to surgical appliances and methods, and more particularly to an improved apparatus and method for perfusion and lavage of an abdomino-pelvic area both during and after surgery; and in particular when using cellcycle specific chemotherapy drugs which require long-term contact with tissues in order to achieve their optimal effect. By allowing prolonged and repeated access to an abdominal cavity the apparatus can assist in the management of serious intra-abdominal infections. Additionally, by permitting repeated access to the abdominal cavity, the apparatus is adapted for non-oncologic use in the treatment of intra-abdominal sepsis, peritonitis and pancreatitis. One of the mechanisms of the dissemination of gastrointestinal and gynecologic cancers is the intraperitoneal dissemination of the disease. Without special treatments all patients with peritoneal dissemination of cancer die; most patients die within one year. In an attempt to improve the control of intraabdominal cancer, large doses of anti-cancer drugs can be injected directly into the peritoneal cavity. This therapy has shown beneficial effects in selected patients. Also other therapies in addition to intraperitoneal chemotherapy have been developed in an effort to better control the peritoneal dissemination of cancer. It has been observed that hyperthermia seems to have a direct anti-cancer effect and synergy with some types of anti-cancer drugs, so that the toxicity for cancer cells is significantly increased at an elevated temperature. Examples of chemotherapy drugs which have been found effective in hyperthermic perfusion of the peritoneal cavity are cisplatin (CDDP) and mitomycin C (MMC). Accordingly, hyperthermic peritoneal lavage with a chemotherapy solution has been utilized to wash away free cancer cells in the peritoneal cavity by irrigation with a large volume of perfusate, to kill cancer cells by hyperthermia, and to kill cancer cells by the direct effects of chemotherapy. However, due to the inherent long and short term toxicity of chemotherapy solutions to operating room personnel, lavage with a chemotherapy solution can only be safely performed in a

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contained environment that prevents splashing, spillage and aerosol contaminants from escaping into the local atmosphere creating an environmental hazard to health care personnel. Web site: http://www.delphion.com/details?pn=US06383162__ •

Assay of free and complexed trypsinogen-2 Inventor(s): Hedstrom; Johan (Helsingfors, FI), Stenman; Ulf-H.ang.kan (Heikelsvagen 10, Grankulla, FI) Assignee(s): Stenman; Ulf-Hakan (Grankulla, FI) Patent Number: 5,976,809 Date filed: August 13, 1997 Abstract: The invention relates to an immunoassay for trypsinogen-2 wherein an amount of analyte in a sample is measured, said analyte being either trypsin-2 complexed with alpha-1-antitrypsin (trypsin-2-AAT) in serum, or trypsinogen-2 in urine. According to a preferred embodiment, the trypsin-2-AAT complex or free trypsinogen-2 are measured by non-competitive methods employing at least two different antibodies. The methods are useful for the diagnosis of patients with pancreatic disease, especially pancreatitis. Excerpt(s): The present invention provides an immunoassay for the measurement of trypsinogen-2 either as free trypsinogen-2 in urine or as its complex with alpha-1antitrypsin (trypsin-2-AAT) in serum. The invention relates further to a method for differentiating between pancreatitis and other pancreatic disease on one hand and nonpancreatic gastrointestinal disease on the other hand by determining either free trypsinogen-2 in urine or trypsin -2-AAT in serum. The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated by reference. The trypsinogens are serine proteases secreted by exocrine cells of the pancreas (Travis J and Roberts R. Biochemistry 1969; 8: 2884-9; Mallory P and Travis J, Biochemistry 1973; 12: 2847-51). Two major types of trypsinogen isoenzymes have been characterized, trypsinogen-1, also called cationic trypsinogen, and trypsinogen-2 or anionic trypsinogen. The trypsinogen proenzymes are activated to trypsins in the intestine by enterokinase, which removes an activation peptide from the N-terminus of the trypsinogens. The trypsinogens show a high degree of sequence homology, but they can be separated on the basis of charge differences by using electrophoresis or ion exchange chromatography. The major form of trypsinogen in the pancreas and pancreatic juice is trypsinogen-1 (Guy CO et al., Biochem Biophys Res Commun 1984; 125: 516-23). In serum of healthy subjects, trypsinogen-1 is also the major form, whereas in patients with pancreatitis, trypsinogen-2 is more strongly elevated (Itkonen et al., J Lab Clin Med 1990; 115:712-8). Trypsinogens also occur in certain ovarian tumors, in which trypsinogen-2 is the major form (Koivunen et al., Cancer Res 1990; 50: 2375-8). Trypsin-1 in complex with alpha-1-antitrypsin, also called alpha-1-antiprotease, has been found to occur in serum of patients with pancreatitis (Borgstrom A and Ohlsson K, Scand J Clin Lab Invest 1984; 44: 381-6) but determination of this complex has not been found useful for differentiation between pancreatic and other gastrointestinal diseases (Borgstrom et al., Scand J Clin Lab Invest 1989; 49:757-62). Web site: http://www.delphion.com/details?pn=US05976809__

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Composition to improve digestibility and utilization of nutrients Inventor(s): Scharpe; Simon Lodewijk (Wieze, BE) Assignee(s): Medzyme N.V. and Simon Lodewijk Scharpe (BE) Patent Number: 6,051,220 Date filed: February 25, 1998 Abstract: The invention relates to a composition to improve digestibility and utilisation of nutrients, comprising one or more acid stable lipases and/or one or more acid stable amylases. Both the lipase and the amylase may be of fungal origin. The lipase preferably originates from Rhizopus arrhizus or Rhizopus javanicus and the amylase from Aspergillus niger. The composition is for example a pharmaceutical composition for use in the treatment of exocrine pancreas insufficiency which may be the result of or a sideeffect of acquired chronic pancreatitis, alcoholism, cystic fibrosis or pancreatic carcinomas. Excerpt(s): The present invention relates to a composition for the improvement of digestibility and utilisation of nutrients. The invention also relates to the use of fungal acid stable amylase and acid stable lipase for the treatment of clinical conditions associated with an inadequate digestive capacity such as exocrine pancreas insufficiency and in the preparation of these compositions. The efficiency with which nutrients are absorbed (and thus utilized) by the human and animal body depends among other things on the efficiency of digestion. Digestion is inter alia mediated by various enzymes that have specific functions at various locations in the digestive tract. Impairment of the activity of these enzymes will have an influence on the degradation of the food constituents and consequently on the up-take of nutrients. An impaired up-take will inter alia result in reduced growth. In the whole process of digestion the pancreas has an important role. It secretes a juice having two major components, an alkaline fluid and enzymes, into the duodenum. The two components occur in variable proportions depending on the stimuli. The alkaline fluid component, ranging in volume from 200800 ml/day, has a high concentration of bicarbonate, which neutralizes the gastric content entering the duodenum and helps to regulate the pH of the intestinal tract. Web site: http://www.delphion.com/details?pn=US06051220__

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Compounds Inventor(s): Burgess; Nicola Anne (Edmonton, GB), Clinkenbeard; Helen Elizabeth (Hertford, GB), Southan; Christopher Donald (Bishop's Stortford, GB) Assignee(s): SmithKline Beecham p.l.c. (Middlesex, GB) Patent Number: 6,100,059 Date filed: April 30, 1998 Abstract: HGBAB90 polypeptides and polynucleotides and methods for producing such polypeptides by recombinant techniques are disclosed. Also disclosed are methods for utilizing HGBAB90 polypeptides and polynucleotides in the design of protocols for the treatment of pulmonary emphysema, arthritis, multiple sclerosis, periodontal disease, cystic fibrosis, respiratory disease, thrombosis, cancer, cachexia, angina, glaucoma, inflamatory disorders, osteoporosis, cardiovascular disorders such as hypertension, atherosclerotic disorders such as cardiac infarction, and stroke, asthma, psoriasis, chronic neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's,

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demyelinating diseases, AIDS immune deficiency, disorders of photoreceptor degeneration, and lens cataract formation, organ transplant rejection, cataracts, restenosis, muscular dystrophy, renal failure, cerebral vasospasm, pancreatitis, and diabetic nephropathy, among others, and diagnostic assays for such conditions. Excerpt(s): This invention relates to newly identified polynucleotides, polypeptides encoded by them and to the use of such polynucleotides and polypeptides, and to their production. More particularly, the polynucleotides and polypeptides of the present invention relate to serine protease family, hereinafter referred to as HGBAB90. The invention also relates to inhibiting or activating the action of such polynucleotides and polypeptides. Proteases perform a variety of important functions in human physiology. Increasingly diseases are being identified where proteases are critical for the pathology of a particular disease. For these key proteases designing or screening for selective antagonists or agonists can lead to the development of new drugs. The serine proteases are a major family of proteases for which a large number are known. These have been reviewed by Rawlings & Barrett, (Methods Enzymol 244: 19-61, 1994). An example of the serine proteases is the mouse neuropsin (Chen et al. J Neurosci 15 (7 Pt 2): 5088-5097 1995). There remains a need for identification and characterization of further members of the serine protease family which can play a role in preventing, ameliorating or correcting dysfunctions or diseases, including, but not limited to, pulmonary emphysema, arthritis, multiple sclerosis, periodontal disease, cystic fibrosis, respiratory disease, thrombosis, cancer, cachexia, angina, glaucoma, inflamatory disorders, osteoporosis, cardiovascular disorders such as hypertension, atherosclerotic disorders such as cardiac infarction, and stroke, asthma, psoriasis, chronic neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's, demyelinating diseases, AIDS immune deficiency, disorders of photoreceptor degeneration, and lens cataract formation, organ transplant rejection, cataracts, restenosis, muscular dystrophy, renal failure, cerebral vasospasm, pancreatitis, and diabetic nephropathy. Web site: http://www.delphion.com/details?pn=US06100059__ •

Detection of pancreatitis-associated protein for screening for cystic fibrosis Inventor(s): Dagorn; Jean-Charles (Marseilles, FR), Iovanna; Juan-Lucio (Marseilles, FR), Keim; Volker (Heddesheim, DE), Sarles; Jacques (Gemenos, FR) Assignee(s): Institut National de la Sante et de la Recherche Medicale (Paris, FR) Patent Number: 5,834,214 Date filed: August 30, 1995 Abstract: The invention relates to in vitro detection of human pancreatitis-associated protein (hPAP) for the purpose of screening for cystic fibrosis. hPAP is quantitated in a biological sample, preferably blood, and a high value is indicative of pancreatic dysfunction. Immunoassays as rapid, reliable methods for hPAP quantitation are provided as are antibodies for use in the assays and hybridomas for production of monoclonal antibodies preferred for use in the assays. Excerpt(s): The human pancreatitis-associated protein (PAP) was isolated, purified and characterized in man and described in the PCT patent application published on 31 Oct. 1991 under the No 91/16428. In the earlier application the PAP was suggested as a means for the detection of a specific disease, acute pancreatitis. Mucoviscidosis, also called "cystic fibrosis" in English is a very frequent genetic disease in certain populations, which is characterized by a global insufficiency of exocrine secretions of

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the pancreas and the lung and the exocrine glands in general. Clinically, the disease is associated with abnormally viscous secretions, the mucus formed being capable of obstructing the bronchi and causing serious or mortal disorders. The mucoviscidosis gene has been localized on human chromosome 7. This gene, called the CFTR gene ("cystic fibrosis transmembrane conductance regulator") shows mutations in different regions in the subjects suffering from mucoviscidosis. Mutations of the same type may be detected on only one of the two chromosomes 7 in subjects called "carriers" but not showing clinical signs of the disease. These persons are heterozygous for the mutation in the CFTR gene. Web site: http://www.delphion.com/details?pn=US05834214__ •

Healing device applied to persistent wounds, fistulas, pancreatitis, varicose ulcers, and other medical or veterinary pathologies of a patient Inventor(s): Fernandez; Ernesto Ramos (Artigas 1087 1 flr, A, Buenos Aires, AR) Assignee(s): none reported Patent Number: 6,203,563 Date filed: May 26, 1999 Abstract: A healing device applied to wounds, fistulas, pancreatitis, varicose ulcers, and other medical or veterinary pathologies includes a compacting chamber for covering the wound over the affected or diseased zone of the patient. The compacting chamber is defined by a self adhesive polymeric material laminar sheet, made out of a waterproof material. The compacting chamber has a replaceable mass of aerated polymer fiber flock therewithin, as a wound-stabilizing dressing. The compacting chamber uses a vacuum for deforming and compacting a mass of polymer fiber flock into effective healing contact with the wound. The vacuum means is terminated upon achieving compaction of the mass of polymer fiber flock and upon effective healing contact of the mass of polymer fiber flock with the wound. Excerpt(s): The main object for this invention is a healing device applied to wounds, fistulas, pancreatis, varicose ulcers and other medical or veterinary pathologies requiring compacting into said wound an aerated material by means of atmospheric depression, and it has as its secondary object the method for applying said device. It is well know to professionals skilled in the art of healing, that a wound at any part of the human body can be provoked either by a pathological agent, as well through a traumatic agent. In either cases, the final result is a wound which segregates fluids, accumulates detritus and creates a bacteria breeding site, which in direct function of the nature and size of the wound, may impede its healing. On the other hand, a fistula is an orifice open from within an organ or limb in the human body, with an outlet. A healing process implies cleansing the wound, drying same of noxious fluids, and since a wound may be considered as an infectious cavity within the body, a fistula is a wound defining a passage or opening communicating one of more internal organs with the outer environment. The healing process for these medical pathologies are successful when the wound is clean and dry, ceasing in its emission of humorous fluids and detritus. Most of these are provoked by the activity of bacteria and pathogenic agents, which according to their nature must have a sufficient threshold of oxygen pressure in order to live and multiply, or in the case of gangrene, the absence of oxygen is required for same to infest the body. Web site: http://www.delphion.com/details?pn=US06203563__

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Human elastate IV Inventor(s): Adams; Mark D. (North Potomac, MD), Green; John M. (Gaithersburg, MD) Assignee(s): Human Genome Sciences, Inc. (Rockville, MD) Patent Number: 5,851,814 Date filed: April 24, 1997 Abstract: Human elastase IV polypeptides and DNA (RNA) encoding such polypeptides and a procedure for producing such polypeptide by recombinant techniques and utilizing such polypeptide for therapeutic purposes, for example, restoration of elasticity of arterial walls, improvement of serum lipid abnormality and improvement of serum lipoprotein metabolism are disclosed. Also disclosed are antagonist/inhibitors against such polypeptides and their use in treating inflammation, arthritis, e.g. rheumatoid arthritis and osteoarthritis, septic shock, pancreatitis and limiting tissue damage in ulceration. Diagnostic assays for identifying mutations in nucleic acid sequence encoding a polypeptide of the present invention and for detecting altered levels of the polypeptide of the present invention are also disclosed. Excerpt(s): This invention relates to newly identified polynucleotides, polypeptides encoded by such polynucleotides, the use of such polynucleotides and polypeptides, as well as the production of such polynucleotides and polypeptides. More particularly, the polypeptide of the present invention is Human Elastase IV, sometimes hereinafter referred to as "HE IV". The invention also relates to inhibiting the action of such polypeptides. Elastase is a serine protease, capable of hydrolyzing the fibrous insoluble protein known as elastin. Elastin is a scleroprotein forming connective tissues, tendons, aortic integuments and cervical bundles of higher animals. Elastin is only slightly degraded by other proteases such as pepsin and trypsin. During the course of study on arteriosclerosis, Balo, et al. observed degradation of the elastin fibers of arterial walls, and postulated the presence of a degrading enzyme (Schweiz, Z., Pathol. Bacteriol., 12: 350 (1949)). Subsequently, in 1952, Banga discovered an enzyme in the pancreas which specifically hydrolyses elastin. The enzyme was isolated in the form of crystals and named elastase (Acta. Physiol. Acad. Sci. Hung, 3: 317 (1952). Web site: http://www.delphion.com/details?pn=US05851814__

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Human pancreatitis-associated protein Inventor(s): Goli; Surya K. (Sunnyvale, CA), Hillman; Jennifer L. (Mountain View, CA) Assignee(s): Incyte Pharmaceuticals, Inc. (Palo Alto, CA) Patent Number: 5,935,813 Date filed: March 20, 1997 Abstract: The present invention provides a novel human C-type lectin (human PAP-2) and polynucleotides which identify and encode human PAP-2. The invention also provides expression vectors, host cells, agonists, antibodies or antagonists. The invention also provides methods for treating or preventing diseases associated with expression of human PAP-2. Excerpt(s): The present invention relates to nucleic acid and amino acid sequences of a novel human pancreatitis-associated (PAP) protein, which comprises a soluble C-type

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lectin. This novel human PAP protein shares features with other proteins in the reg/PSP multigene family which are involved in the regulation of cell growth. The present invention relates to the use of these novel sequences in the diagnosis, prevention and treatment of disease. Lectins are proteins which are defined by their ability to bind carbohydrates specifically and to agglutinate cells. Lectins have been shown to be involved in a wide variety of cellular functions including cell-cell and cell-matrix interactions. Lectins are widespread among plants, invertebrates and mammals. Animal lectins have been grouped into four distinct families: 1) C-type lectins, which include selectins; 2) P-type lectins; 3) galectins (formerly termed S-type lectins or S-Lac lectins); and 4) pentraxins ›Barondes SH et al. (1994) J. Biol. Chem. 269:20807-10!. The C-type lectins bind carbohydrate ligands in a Ca.sup.2+ -dependent manner and are structurally related to the asialoglycoprotein receptor. Selectins, a subcategory of the Ctype lectins, are composite transmembrane molecules which are involved in cell-cell interactions. The selectins include lymphocyte homing receptors and platelet/endothelial cell surface receptors ›Stoolman (1989) Cell 56:907-10!. Web site: http://www.delphion.com/details?pn=US05935813__ •

Method for decreasing severity of acute and chronic pancreatitis Inventor(s): Norman, Jr.; James G. (Tampa, FL) Assignee(s): University of South Florida (Tampa, FL) Patent Number: 5,919,444 Date filed: February 20, 1996 Abstract: A method for treating acute or chronic pancreatitis comprising administering an effective amount of an Interleukin-1 (IL-1) block to antagonize IL-1 production, and in one embodiment by inhibiting IL-1 production at the source, or a pharmaceutically acceptable salt thereof to a person who has pancreatitis. One such IL-1 block is an Interleukin-1 converting enzyme (ICE) antagonist. Excerpt(s): The present invention relates to a method for treating acute and chronic pancreatitis. Acute pancreatitis is a common clinical problem which remains evasive of specific therapy (Leach et al., 1992). Each year more than 210,000 admissions to U.S. hospitals are caused by acute pancreatitis while another 150,000 are due to chronic pancreatitis. Pancreatitis is most often caused by alcoholism or biliary tract disease. Less commonly, it is associated with hyperlipemia, hyperparathyroidism, abdominal trauma, vasculitis or uremia. The average length of hospitalization for the acute disease is 12.4 days, with a significant number of patients staying much longer because of associated complications. Chronic ethanol abuse is the most common cause of acute and chronic pancreatitis in the West, yet the pathophysiology of this disease remains poorly understood (Steinberg and Tenner, 1994). There are few medical therapies or pharmacologic agents currently available which have been shown to decrease the severity, duration, complication rate, or mortality for this common disease. Care for these patients, regardless of the etiology, remains primarily supportive, with attention directed towards maintaining an adequate circulating blood volume, supporting renal and respiratory systems, and providing adequate nutrition. This lack of specific therapy has prompted a great number of prospective trials during the past two decades in hopes of finding some way to decrease the progression and severity of this disease. To date, specific therapy remains unknown and a search for new, more effective modalities is necessary.

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Web site: http://www.delphion.com/details?pn=US05919444__ •

Method for determining whether a human patient is susceptible to hereditary pancreatitis, and primers therefore Inventor(s): Ehrlich; Garth D. (Pittsburgh, PA), Gorry; Michael C. (Pittsburgh, PA), Whitcomb; David (9609 Parkedge Dr., Allison Park, PA 15101) Assignee(s): Whitcomb; David (Allison Park, PA) Patent Number: 6,406,846 Date filed: October 14, 1997 Abstract: A method for determining whether a human patient is susceptible to hereditary pancreatitis. The method comprises the steps of obtaining nucleic acid from the human patient. Then there is the step of checking the nucleic acid for a mutation that indicates hereditary pancreatitis. A primer which reacts with a human trypsinogen gene to identify hereditary pancreatitis. A method for detecting in a human a mutation in a trypsinogen gene indicative of hereditary pancreatitis. The invention comprises the steps of obtaining a sample having DNA of the patient. Then there is the step of processing the sample so the DNA will be recognized by a desired restriction enzyme. Next there is the step of introducing the desired restriction enzyme to the DNA wherein the recognizing of the desired restriction enzyme to the DNA indicates the presence of the mutation. Excerpt(s): The present invention is related to determining whether a human patient is susceptible to hereditary pancreatitis. More specifically, the present invention is related to determining whether a human patient is susceptible to hereditary pancreatitis by identifying a single G to A transition mutation in the third exon of cationic trypsinogen, or digesting the trypsinogen gene in exon III with Afl III. Hereditary pancreatitis (HP) is an autosomal dominant disorder with 80% penetrance and variable expressivity [Perrault, J. Hereditary pancreatitis. Gastroenterol. Clin. North Am. 23:743-752 (1994); Madraso-de la Garza, J., Hill, I., Lebenthal, E. Hereditary pancreatitis. In: Go V, ed. The Pancreas: Biology, Pathobiology, and Disease. 2nd ed. New York: Raven, 1095-1101 (1993); Whitcomb, D. C., Preston, R. A., Aston, C. E., Sossenheimer, M. J., Barua, P. S., Zhang, Y., Wong-Chong, A., White, G., Wood, P., Gates, L. K., Jr., Ulrich, C., Martin, S. P., Post, J. C., and Ehrlich, G. D. A gene for hereditary pancreatitis maps to chromosome 7q35. Gastroenterology 110, 1975-1980 (1996); Bodic, L. L., Bignon, J. D., Raguenes, O., Mercier, B., Georgelin, T., Schnee, M., Soulard, F., Gagne, K., Bonneville, F., Muller, J. Y., Bachner, L., and Ferec, C. The hereditary pancreatitis gene maps to long arm of chromosome 7. Hum. Molec. Genet. 5, 549-554 (1996)]. Nearly 100 kindreds have been reported world-wide since the genetic nature of this disorder was recognized by Comfort and Steinberg in 1952 [Madraso-de la Garza, J., Hill, I., Lebenthal, E. Hereditary pancreatitis. In: Go V, ed. The Pancreas: Biology, Pathobiology, and Disease. 2nd ed. New York: Raven, 1095-1101 (1993); Comfort, M. and Steinberg, A. Pedigree of a family with hereditary chronic relapsing pancreatitis. Gastroenterology 21, 54 (1952)]. The majority of the families are of white European ancestry, but affected kindreds have been reported in Japan, India, and among other ethnic groups [Perrault, J. Hereditary pancreatitis. Gastroenterol. Clin. North Am. 23:743-752 (1994)]. HP is characterized by recurrent bouts of severe epigastric pain with onset, usually developing before ten years of age. The clinical, laboratory and pathologic features of HP are indistinguishable from attacks of pancreatitis from other causes. In addition to recurrent acute attacks, many HP patients progress to complicated chronic pancreatitis characterized by pancreatic

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calcifications, pseudocysts, chronic abdominal pain, pancreatic exocrine failure, diabetes mellitus and/or pancreatic cancer [Perrault, J. Hereditary pancreatitis. Gastroenterol. Clin. North Am. 23:743-752 (1994); Madraso-de la Garza, J., Hill, I., Lebenthal, E. Hereditary pancreatitis. In: Go V, ed. The Pancreas: Biology, Pathobiology, and Disease. 2nd ed. New York: Raven, 1095-1101 (1993)]. Despite years of research, no unique morphologic or biochemical markers have been identified for HP, and the pathophysiologic mechanisms that lead to intermittent attacks of acute pancreatitis remain obscure. Therefore, no rational or effective preventative strategies have been developed, and treatment consists solely of supportive care. Because of the absence of biochemical markers specific for HP, attention has focused on identifying the HP disease gene. The availability of a high-density map of the human genome, based on polymorphic simple tandem repeat (STR) markers, and familial S0 linkage analysis made it possible to identify an HP gene locus within the q35 region of chromosome seven [Whitcomb, D. C., Preston, R. A., Aston, C. E., Sossenheimer, M. J., Barua, P. S., Zhang, Y., Wong-Chong, A., White, G., Wood, P., Gates, L. K., Jr., Ulrich, C., Martin, S. P., Post, J. C., and Ehrlich, G. D. A gene for hereditary pancreatitis maps to chromosome 7q35. Gastroenterology 110, 1975-1980 (1996); Bodic, L. L., Bignon, J. D., Raguenes, O., Mercier, B., Georgelin, T., Schnee, M., Soulard, F., Gagne, K., Bonneville, F., Muller, J. Y., Bachner, L., and Ferec, C. The hereditary pancreatitis gene maps to long arm of chromosome 7. Hum. Molec. Genet. 5, 549-554 (1996)]. It was thus desired to identify and sequence the HP gene to determine the site of the disease-causing mutation(s) in an effort to understand the molecular mechanism leading to HP. Several previously mapped genes on chromosome 7q were considered candidates for the HP disease gene because they are known to be expressed in the exocrine pancreas and encode enzymes that could potentially activate digestive enzymes within the pancreas. The hypothesis that pancreatitis results from inappropriate activation of pancreatic proenzymes was first promulgated 100 years ago and subsequently was demonstrated to be an experimental model for pancreatitis [Chiara, H. Ueber selbstverdauung des menschlichen pankreas. Zeitschrift fur heilkunde 17, 69-96 (1896); Steer, M. L., and Meldolesi, J. The cell biology of experimental pancreatitis. N. Engl. J. Med. 316 (3), 14450, (1987)]. Although carboxypeptidase A1 (CPA1) was considered the primary candidate by Le Bodic [Bodic, L. L., Bignon, J. D., Raguenes, O., Mercier, B., Georgelin, T., Schnee, M., Soulard, F., Gagne, K., Bonneville, F., Muller, J. Y., Bachner, L., and Ferec, C. The hereditary pancreatitis gene maps to long arm of chromosome 7. Hum. Molec. Genet. 5, 549-554 (1996)], this gene mapped centromeric to the HP locus defined by obligate recombinations in an HP linkage study [Whitcomb, D. C., Preston, R. A., Aston, C. E., Sossenheimer, M. J., Barua, P. S., Zhang, Y., Wong-Chong, A., White, G., Wood, P., Gates, L. K., Jr., Ulrich, C., Martin, S. P., Post, J. C., and Ehrlich, G. D. A gene for hereditary pancreatitis maps to chromosome 7q35. Gastroenterology 110, 1975-1980 (1996); Stewart, E. A., Craik, C. S., Hake, L., and Bowcock, A. M. Human carboxypeptidase A identifies a Bg1II RFLP and maps to 7q31-qter. Am. J. Hum. Genet. 46 (4): 795-800, (1990); Rommens, J. M., Zengerling, S., Burns, J., Melmer, G., Kerem, B. S., Plavsic, N., Zsiga, M., Kennedy, D., Markiewicz, D., Rozmahel, R., et al. Identification and regional localization of DNA markers on chromosome 7 for the cloning of the cystic fibrosis gene. Am. J. Hum. Genet. 43 (5), 645-63 (1988); Rommens, J. M., Iannuzzi, M. C., Kerem, B., Drumm, M. L., Melmer, G., Dean, M., Rozmahel, R., Cole, J. L., Kennedy D., Hidaka, N., et al. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science. 245 (4922): 1059-65 (1989); Martise, T. C., Perlin, M., and Chakravarti, A. Automated construction of genetic linkage maps using an expert system (MultiMap): a human genome linkage map. Nature Genetics. 6 (4), 384-90 (1994)] and was, therefore, excluded from further consideration. However, at least eight trypsinogen genes are located on chromosome 7q35 between the STR markers D7S495 and D7S498 and within

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the V and D-C segments of the complex T-cell receptor.beta. chain gene locus (TCR.beta.) [Rowen, L., Koop, B. F., Hood, L. The Complete 685-Kilobase DNA Sequence of the Human_T Cell Receptor Locus. Science (1996)]. Trypsinogen is an inactive proenzyme for trypsin, which becomes active when an eight amino acid aminoterminal peptide is removed. Although small amounts of trypsin are normally generated within the pancreas, this active trypsin is usually rapidly inactivated before pancreatic autodigestion occurs. Thus, the trypsinogen genes were considered primary candidates for the HP disease gene. Web site: http://www.delphion.com/details?pn=US06406846__ •

Method of using IL-11 for inflammation associated with acute pancreatitis Inventor(s): Keith; James (Andover, MA), Schendel; Paul (Wayland, MA) Assignee(s): Genetics Institute, Inc. (Cambridge, MA) Patent Number: 6,274,135 Date filed: June 22, 1999 Abstract: Provided by the present invention are methods of treating a variety of disorders including AIDS, arthritis (rheumatoid arthritis, osteoarthritis, spondyloarthropathies), antibiotic induced diarrheal diseases (Closbidium difficile), multiple sclerosis, osteoporosis, gingivitis, peptic ulcer disease, esophagitis, diabetes, retinitis, uveitis, reperfusion injury after myocardial infarction (MI) or cerebral vascular accident (CVA), aphthous ulcers (oral), atherosclerosis (plaque rupture), prevention of tumor metastases, asthma, preeclampsia, acute pancreatitis, psoriasis, infertility and allergic disorders such as rhinitis, conjunctivitis, and urticaria. Excerpt(s): The present invention relates generally to methods of treating disorders such as AIDS, arthritis (rheumatoid arthritis, osteoarthritis, spondyloarthropathies), antibiotic induced diarrheal diseases (Clostridium difficile), multiple sclerosis, osteoporosis, gingivitis, peptic ulcer disease, esophagitis, diabetes, retinitis, uveitis, reperfusion injury after myocardial infarction (MI), cerebral vascular accident (CVA), aphthous ulcers (oral), atherosclerosis (plaque rupture), prevention of tumor metastases, asthma, preeclampsia, acute pancreatitis, psoriasis, infertility and allergic disorders such as rhinitis, conjunctivitis, and urticaria. Inflammatory responses include a broad range of host reaction to a variety of insults, such as injury, infection, or rejection. It is the over production of mediators that is believed to be associated with a broad range of disorders, including AIDS, arthritis (rheumatoid arthritis, osteoarthritis, spondyloarthropathies), antibiotic induced diarrheal diseases (Clostridium difficile), multiple sclerosis, osteoporosis, gingivitis, peptic ulcer disease, esophagitis, diabetes, retinitis, uveitis, reperfusion injury after myocardial infarction (MI), cerebral vascular accident (CVA), aphthous ulcers (oral), atherosclerosis (plaque rupture), tumor metastases, asthma, preeclampsia, acute pancreatitis, psoriasis, infertility and allergic disorders such as rhinitis, conjunctivitis, and urticaria. These disorders and their symptoms are briefly summarized below. According to the methods of the present invention, IL-11 is administered to modulate the hosts' over reaction to insult thereby treating the following disorders. Web site: http://www.delphion.com/details?pn=US06274135__

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Methods for synthesizing ether compounds and intermediates therefor Inventor(s): Dasseux; Jean-Louis Henri (Brighton, MI), Oniciu; Carmen Daniela (Gainesville, FL) Assignee(s): Esperion Therapeutics, Inc. (Ann Arbor, MI) Patent Number: 6,410,802 Date filed: March 31, 2000 Abstract: The present invention relates to novel ether compounds, compositions comprising ether compounds, and methods useful for treating and preventing cardiovascular diseases, dyslipidemias, dysproteinemias, and glucose metabolism disorders comprising administering a composition comprising an ether compound. The compounds, compositions, and methods of the invention are also useful for treating and preventing Alzheimer's Disease, Syndrome X, peroxisome proliferator activated receptor-related disorders, septicemia, thrombotic disorders, obesity, pancreatitis, hypertension, renal disease, cancer, inflammation, and impotence. In certain embodiments, the compounds, compositions, and methods of the invention are useful in combination therapy with other therapeutics, such as hypocholesterolemic and hypoglycemic agents. Excerpt(s): The present invention relates to ether compounds and pharmaceutically acceptable salts thereof; methods for synthesizing the ether compounds; compositions comprising an ether compound or a pharmaceutically acceptable salt thereof; and methods for treating or preventing a disease or disorder selected from the group consisting of a cardiovascular disease, dyslipidemia, dyslipoproteinemia, a disorder of glucose metabolism, Alzheimer's Disease, Syndrome X; a peroxisome proliferator activated receptor-associated disorder, septicemia, a thrombotic disorder, obesity, pancreatitis, hypertension, renal disease, cancer, inflammation, and impotence, comprising administering a therapeutically effective amount of a composition comprising an ether compound or a pharmaceutically acceptable salt thereof. The ether compounds and compositions of the invention may also be used to reduce the fat content of meat in livestock and reduce the cholesterol content of eggs. Obesity, hyperlipidemia, and diabetes have been shown to play a casual role in atherosclerotic cardiovascular diseases, which currently account for a considerable proportion of morbidity in Western society. Further, one human disease, termed "Syndrome X" or "Metabolic Syndrome", is manifested by defective glucose metabolism (insulin resistance), elevated blood pressure (hypertension), and a blood lipid imbalance (dyslipidemia). See e.g. Reaven, 1993, Annu. Rev. Med. 44:121-131. The evidence linking elevated serum cholesterol to coronary heart disease is overwhelming. Circulating cholesterol is carried by plasma lipoproteins, which are particles of complex lipid and protein composition that transport lipids in the blood. Low density lipoprotein (LDL) and high density lipoprotein (HDL) are the major cholestrol-carrier proteins. LDL are believed to be responsible for the delivery of cholesterol from the liver, where it is synthesized or obtained from dietary sources, to extrahepatic tissues in the body. The term "reverse cholesterol transport" describes the transport of cholesterol from extrahepatic tissues to the liver, where it is catabolized and eliminated. It is believed that plasma HDL particles play a major role in the reverse transport process, acting as scavengers of tissue cholesterol. HDL is also responsible for the removal non-cholesterol lipid, oxidized cholesterol and other oxidized products from the bloodstream. Web site: http://www.delphion.com/details?pn=US06410802__

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Methods for treating disorders in which docosahexaenoic acid (DHA) levels are affected Inventor(s): Alvarez; Juan G. (Boston, MA), Freedman; Steven (Brighton, MA) Assignee(s): Beth Israel Deaconess Medical Center, Inc. (Boston, MA) Patent Number: 6,180,671 Date filed: February 11, 1999 Abstract: A method of treating disorders in which DHA levels are affected is described. The method includes administering to a subject suffering from the disorder a therapeutically affective amount of DHA. This method is particularly useful in treating subjects suffering from a disorder characterized by a defect in the CF, gene, e.g. cystic fibrosis, or a chronic inflammatory disorder, e.g., ulcerative colitis, Crohn's disease, chronic pancreatitis, asthma, rheumatoid arthritis or chronic gastritis. A method of ameliorating affects of cystic fibrosis in a newborn and a method of increasing surfactant levels in a fetus are also described. Excerpt(s): Cystic Fibrosis (CF) is the most prevalent autosomal recessive disorder in the Caucasian population (Gorelick (1991) Gastroenterology 103 :681-693). Approximately 1 in 2000 live births are afflicted with CF and 5% of Caucasians in the United States are carriers of the abnormal CF gene. CF individuals rarely survive past their mid-thirties, and most mortalities are a result of recurrent pulmonary infection and, ultimately, pulmonary failure. Two other major clinical manifestations of CF are pancreatic dysfunction and male infertility. By 1989, the CF gene had been cloned and was found to code for a chloride channel. Activation of the channel in the normal pancreas activates the chloride/bicarbonate exchanger, resulting in a net secretion of bicarbonate into the lumenal space and alkalinization of the pancreatic juice. Mutations in the chloride channel like those found in CF result in a reduced chloride conductance and a reduced ability of ductal cells to secrete bicarbonate into the lumenal space. This results in the formation of inspissated plugs within the ducts leading to obstruction of the pancreatic ducts. In recent years, the focus in CF research has shifted towards the coupling of defective chloride channel function and membrane recycling. Recent research has demonstrated that membrane internalization at the apical plasma membrane of the pancreatic acinar cell is dependent on pH of the acinar lumen (Freedman et al., Eur. J Cell Biol. (1998) 75:153-63), Freedman et al., (1994) Am. J. Physiol. 267:G40-G51, and Freedman et al., (1994) Eur. J. Cell Biol. 65:354-365). Since pH of the acinar lumen is reflective of ductal bicarbonate secretion from the proximal duct cells, a phenomenon regulated via the chloride channel, a coupling may exist between duct and acinar cell function, (Freedman et al., (1994) Am. J. Physiol. 267:G40-G51, and Freedman et al., (1994) Eur. J. Cell Biol. 65:354-365). Research has also confirmed the hypothesis that lack of alkalinization of the acinar lumen leads to inhibition of apical membrane internalization and defective apical endocytosis in pancreatic acinar cells from CF mice. This block in the recycling of membranes following exocytosis leads to eventual deficiency in membranes for reformation of secretory granules. Thus, pancreatic insufficiency appears to be a result of defects in membrane recycling with obstruction of the ducts occurring as a secondary event. Web site: http://www.delphion.com/details?pn=US06180671__

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Monoclonal antibodies against type I phospholipase A.sub.2 as a diagnostic and antiinflammatory therapeutic agent Inventor(s): Hubner-Parajsz; Christa (Tutzing, DE), Scheuer; Werner (Penzberg, DE), Tibes; Ulrich (Frankfurt, DE) Assignee(s): Boehringer Mannheim GmbH (Mannheim, DE) Patent Number: 5,767,249 Date filed: August 8, 1995 Abstract: The invention provides for monoclonal antibodies which specifically bind to type I phospholipase A.sub.2 for use as a diagnostic agent and as an anti-inflammatory therapeutic agent, which is particularly suitable for application in acute pancreatitis. The invention further provides for pharmaceutical compositions including the antibodies of the invention. The invention also provides for a method for treating subjects suffering from inflammatory symptoms and for detecting the activity of type I phospholipase A.sub.2 in a sample. Excerpt(s): The invention concerns the use of monoclonal antibodies against type I phospholipase A.sub.2 for the production of an anti-inflammatory therapeutic agent which is particularly suitable for application in acute pancreatitis. There is neither a causal nor symptomatic therapy for acute pancreatitis (The Merck Manual of Diagnosis and Therapy 15 (1987), pages 763-767). The pathogenetic basis of acute pancreatitis is autolysis of the pancreas. Phospholipase A.sub.2 has been attributed a decisive function in this process. It has a lysing action on the cell membrane and liberates arachidonic acid from the membrane phospholipids in this process. The metabolites of arachidonic acid (prostaglandins and leukotrienes) are an important component of the inflammatory reaction. Phospholipase A.sub.2 occurs in two forms. The phospholipase A.sub.2 designated type I is mainly found in pancreatic tissue and plays an important role in acute pancreatitis. In contrast type II phospholipase A.sub.2 occurs in many different tissues. Web site: http://www.delphion.com/details?pn=US05767249__

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Substituted pyrido[3,2-d]pyrimidines capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family Inventor(s): Bridges; Alexander James (Saline, MI), Denny; William Alexander (Auckland, NZ), Fry; David (Ypsilanti, MI), Kraker; Alan (Ann Arbor, MI), Meyer; Robert Frederick (Ann Arbor, MI), Rewcastle; Gordon William (Auckland, NZ), Thompson; Andrew Mark (Auckland, NZ) Assignee(s): Warner-Lambert Company (Morris Plains, NJ) Patent Number: 6,084,095 Date filed: March 6, 1997 Abstract: Novel 4-substituted amino pyrido [3,2-d]pyrimidine inhibitors of epidermal growth factor receptor family of tyrosine kinases are described, as well as pharmaceutical compositions of the same, which are useful in treating proliferative diseases such as cancer, synovial pannus invasion in arthritis, psoriasis, vascular restenosis and angiogenesis and additionally useful in the treatment of pancreatitis and kidney disease as well as a contraceptive agent.

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Excerpt(s): The present invention relates to bicyclic heteroaromatic compounds which inhibit the epidermal growth factor receptor and related receptors and, in particular, their tyrosine kinase enzymic activity. Cancer is generally a disease of the intracellular signalling system, or signal transduction mechanism. Cells receive instructions from many extracellular sources, instructing them to either proliferate or not to proliferate. The purpose of the signal transduction system is to receive these and other signals at the cell surface, get them into the cell, and then pass the signals on to the nucleus, the cytoskeleton, and transport and protein syntheses machinery. The most common cause of cancer is a series of defects, either in these proteins, when they are mutated, or in the regulation of the quantity of the protein in the cell such that it is over or under produced. Most often, there are key lesions in the cell which lead to a constitutive state whereby the cell nucleus receives a signal to proliferate, when this signal is not actually present. This can occur through a variety of mechanisms. Sometimes the cell may start to produce an authentic growth factor for its own receptors when it should not, the socalled autocrine loop mechanism. Mutations to the cell surface receptors, which usually signal into the cell by means of tyrosine kinases, can lead to activation of the kinase in the absence of ligand, and passing of a signal which is not really there. Alternatively, many surface kinases can be overexpressed on the cell surface leading to an inappropriately strong response to a weak signal. There are many levels inside the cell at which mutation or overexpression can lead to the same spurious signal arising in the cell, and there are many other kinds of signalling defect involved in cancer. This invention touches upon cancers which are driven by the three mechanisms just described, and which involve cell surface receptors of the epidermal growth factor receptor tyrosine kinase family (EGFR). This family consists of the EGF receptor (also known as Erb-B1), the Erb-B2 receptor, and its constituitively active oncoprotein mutant Neu, the Erb-B3 receptor and the Erb-B4 receptor. Additionally, other biological processes driven through members of the EGF family of receptors can also be treated by compounds of the invention described below. The EGFR has as its two most important ligands Epidermal Growth Factor (EGF) and Transforming Growth Factor alpha (TGFalpha). The receptors appear to have only minor functions in adult humans, but are apparently implicated in the disease process of a large portion of all cancers, especially colon and breast cancer. The closely related Erb-B2 Erb-B3 and Erb-B4 receptors have a family of Heregulins as their major ligands, and receptor overexpression and mutation have been unequivocally demonstrated as the major risk factor in poor prognosis breast cancer. Additionally, it has been demonstrated that all four of the members of this family of receptors can form heterodimeric signalling complexes with other members of the family, and that this can lead to synergistic transforming capacity if more than one member of the family is overexpressed in a malignancy. Overexpression of more than one family member has been shown to be relatively common in human malignancies. Web site: http://www.delphion.com/details?pn=US06084095__ •

Transgenic non-human mammals that express human BSSL/CEL Inventor(s): Tornell; Jan Birger Fredrik (Vastra Frolunda, SE) Assignee(s): Astra Aktiebolag (Sodertalje, SE) Patent Number: 5,716,817 Date filed: May 17, 1995 Abstract: The present invention relates to a DNA molecule containing intron sequences and encoding a human protein which is, depending on the site of action, called Bile Salt-

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Stimulated Lipase (BSSL) or Carboxyl Ester Lipase (CEL). The DNA molecule is advantageously used in the production of recombinant human BSSL/CEL, preferably by means of production in transgenic non-human mammals. The recombinant human BSSL/CEL can be used as a constituent of infant formulas used for feeding infants as a substitute for human milk, or in the manufacture of medicaments against e.g. fat malabsorption, cystic fibrosis and chronic pancreatitis. Excerpt(s): Dietary lipids are an important source of energy. The energy-rich triacylglycerols constitute more than 95% of these lipids. Some of the lipids, e.g. certain fatty acids and the fat-soluble vitamins, are essential dietary constituents. Before gastrointestinal absorption the triacylglycerols as well as the minor components, i.e. esterified fat-soluble vitamins and cholesterol, and diacylphosphatidylglycerols, require hydrolysis of the ester bonds to give rise to less hydrophobic, absorbable products. These reactions are catalyzed by a specific group of enzymes called lipases. In the human adult the essential lipases involved are considered to be Gastric Lipase, Pancreatic Colipase-Dependent Lipase (hydrolysis of tri- and diacylglycerols), Pancreatic Phospholipase A2 (hydrolysis of diacylphosphatidylglycerols) and Carboxylic Ester Lipase (CEL) (hydrolysis of cholesteryl- and fat soluble vitamin esters). In the breast-fed newborn, Bile Salt-Stimulated Lipase (BSSL) plays an essential part in the hydrolysis of several of the above mentioned lipids. Together with bile salts the products of lipid digestion form mixed micelles from which absorption occurs. Web site: http://www.delphion.com/details?pn=US05716817__ •

Treatment and prophylaxis of pancreatitis Inventor(s): Fujiwara; Toshihiko (Ebina, JP), Fukami; Masaharu (Yokohama, JP), Horikoshi; Hiroyoshi (Funabashi, JP) Assignee(s): Sankyo Company, Limited (Tokyo, JP) Patent Number: 5,753,681 Date filed: March 17, 1997 Abstract: Insulin sensitizers, especially thiazolidinedione compounds, such as troglitazone, are useful for the treatment and prevention of pancreatitis. Excerpt(s): The present invention relates to a new use for a series of known compounds, including thiazolidinedione compounds, oxazolidinedione compounds, isoxazolidinedione compounds and oxadiazolidinedione compounds, in the treatment and prophylaxis of pancreatitis. Pancreatitis is commonly classified roughly as either acute pancreatitis or chronic pancreatitis depending on whether or not the condition persists after removal of the etiological agent. Except where the context otherwise requires, the term "pancreatitis", as used herein, includes both acute pancreatitis and chronic pancreatitis. Probably about 40% of cases of acute pancreatitis may be attributed to alcohol abuse. Other causes include idiopathic, cholelithiasis, overeating and traumatic origins. The top three causes account for 70 to 80% of this disease. Web site: http://www.delphion.com/details?pn=US05753681__

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Treatment of inflammation with 2,4,6-trihydroxy-alpha-rhomethoxyphenylacetophenone, or its pharmaceutically acceptable derivatives Inventor(s): Malaviya; Ravi (St. Paul, MN), Uckun; Fatih M. (White Bear Lake, MN) Assignee(s): Parker Hughes Institute (Roseville, MN) Patent Number: 6,248,790 Date filed: June 29, 2000 Abstract: 2,4,6-trihydroxy-.alpha.-p-methoxyphenylacetophenone (also identified herein as "D-58"), or its pharmaceutically acceptable derivatives such as salt and ester forms, is administered for inhibiting inflammatory reactions. The treatment can be remedial or prophylactic. Examples of the conditions that can be treated include acute inflammatory reactions and allergic inflammatory reactions, and specific examples include allergy, asthma, arthritis, psoriasis, skin sunburn, inflammatory pelvic disease, inflammatory bowel disease, urethritis, uvitis, senusitis, pneumonitis, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholocystitis and cholangitis. The 2,4,6-trihydroxy.alpha.-p-methoxyphenylacetophenone can be administered by various routes as needed. Excerpt(s): The present invention is directed to the treatment of acute and chronic inflammatory responses, for example resulting from the presence of an allergen, injury, infection, etc. Allergic and acute inflammatory responses to injury, infection, or other tissue damage can set into motion a complex series of events. A variety of host cells that guard the host environment interface, including macrophages, mast cells, and epithelial/epidermal cells serve as the initiators of the inflammatory responses. These cells release various mediators during an inflammatory response, which include histamine, prostaglandins (PGs), leukotrienes (LTs) and proinflammatory cytokines (refs 1-4). These mediators have been implicated in the pathogenesis of a number of acute and chronic inflammatory conditions such as allergy, asthma, arthritis, psoriasis, and skin sunburn (refs 3-5). The release of inflammatory agents is mediated by a cascade of intracellular signaling events which include activation of phosphoinositide turnover (ref 6), increase in cAMP levels (ref 7), activation of protein kinase C, and an increase in intracellular calcium levels and tyrosine phosphorylation of several cytosolic proteins (refs 7 and 8). Considerable efforts have been made for identification of chemical compounds that can interrupt these signaling events as potential anti-inflammatory agents (refs 9-12). However, the need for agents providing improved inhibition continues. In accordance with the present invention, 2,4,6-trihydroxy-.alpha.-pmethoxyphenylacetophenone (also identified herein as "D-58"), or its pharmaceutically acceptable derivatives such as salt and ester forms, is administered for inhibiting inflammatory reactions to a subject in need thereof. The treatment can be remedial or prophylactic. Examples of the conditions that can be treated include acute as well as chronic inflammatory reactions and allergic inflammatory reactions, and specific examples include allergy, asthma, arthritis, psoriasis, skin sunburn, inflammatory pelvic disease, inflammatory bowel disease, urethritis, uvitis, sinusitis, pneumonitis, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholocystitis and cholangititis. The 2,4,6-trihydroxy-.alpha.-p-methoxyphenylacetophenone can be administered by one of a variety of routes as needed. Web site: http://www.delphion.com/details?pn=US06248790__

Patents 175

Patent Applications on Pancreatitis As of December 2000, U.S. patent applications are open to public viewing.10 Applications are patent requests which have yet to be granted. (The process to achieve a patent can take several years.) The following patent applications have been filed since December 2000 relating to pancreatitis: •

7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)amino]-quinoline-3-carboxylic amides, and methods of inhibiting the secretion of apolipoprotein B

acid

Inventor(s): Ruggeri, Roger; (Waterford, CT), Wilson, Douglas; (Groton, CT) Correspondence: Gregg C. Benson; Pfizer INC.; Patent Department, MS 4159; Eastern Point Road; Groton; CT; 06340; US Patent Application Number: 20020132806 Date filed: January 22, 2002 Abstract: This invention relates to compounds of Formula I 1that inhibit the secretion of apolipoprotein B, to pharmaceutical compositions comprising the compounds, and to methods of treating and/or preventing atherosclerosis, obesity, diabetes, hyperlipidemia, hyperliproproteinemia, hypercholesterolemia, hypertriglyceridemia, hypoalphalipoproteinemia, pancreatitis, myocardial infarction, stroke, restenosis, or Syndrome X. This invention also relates to methods of reducing the secretion of apolipoprotein B and/or inhibiting microsomal triglyceride transfer protein. Excerpt(s): This is a divisional application of U.S. application number 09/711,281, filed Nov. 9, 2000, now allowed, which claims priority from U.S. provisional application number 60/164,803, filed Nov. 10, 1999 and U.S. provisional application number 06/224,956, filed Aug. 11, 2000. This invention relates to compounds that inhibit the secretion of apolipoprotein B, and to methods of treating and/or preventing atherosclerosis, obesity, diabetes, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, hypoalphalipoproteinemia, pancreatitis, myocardial infarction, stroke, restenosis, or Syndrome X. This invention also relates to methods of reducing the secretion of apolipoprotein B and/or inhibiting microsomal triglyceride transfer protein. Microsomal triglyceride transfer protein (MTP) catalyzes the transport of triglycerides, cholesteryl esters and phospholipids, and MTP is involved in the assembly of lipoproteins that contain apolipoprotein B (apo B). Examples of lipoproteins that contain apo B include lipoprotein (a) [Lp(a)], low density lipoprotein (LDL), and very low density lipoprotein (VLDL), which is a precursor to LDL. Compounds that contain apo B are known to contribute to the formation of atherosclerotic lesions. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

10

This has been a common practice outside the United States prior to December 2000.

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•

AGENT FOR PREVENTING AND/OR TREATING MULTIPLE ORGAN FAILURE Inventor(s): ARISAWA, HIROHIKO; (TOCHIGI, JP), HIGASHIO, KANJI; (SAITAMA, JP), MASUNAGA, HIROAKI; (TOCHIGI, JP), OGAWA, HIROMI; (TOCHIGI, JP) Correspondence: Testa Hurwitz & Thbeault; High Street Tower; 125 High Street; Boston; MA; 02110 Patent Application Number: 20010051146 Date filed: August 27, 1999 Abstract: The present invention is to provide an agent for preventing and/or treating multiple organ failure comprising Tumor cytotoxic factor-II (TCF-II) or Hepatocyte growth factor (HGF) as an effective ingredient.The agent of the present invention will be useful for preventing and/or treating the development from burn, disseminated intravascular coagulation (DIC), circulatory failure, hemorrhagic shock, infectious disease, acute pancreatitis, ischemic disorder, hepatorenal syndrome, gastrointestinal hemorrhage, nutritional metabolic failure, terminal cancer, acquired immunodeficiency syndrome (AIDS), deterioration of systemic conditions due to radiation affection and cachexia etc. to multiple organ failure. Excerpt(s): The present invention relates to a novel agent for preventing and/or treating multiple organ failure. Development from burn, disseminated intravascular coagulation (DIC), circulatory failure, hemorrhagic shock, infectious disease, acute pancreatitis, ischemic disorder, hepatorenal syndrome, gastrointestial hemorrhage, nutritional metabolic failure, terminal cancer, acquired immunodeficiency syndrome (AIDS), deterioration of systemic conditions due to radiation affection and cachexia etc. to multiple organ failure can be prevented or treated by the present invention. Onset or exacerbation of multiple organ failure can be classified into the following 3 categories with respect to mechanism: (1) Parallel induction of several organ disorders due to the same factor; (2) Induction of a specific organ dysfunction due to disorder of an organ; and (3) Participation of an iatrogenic factor. Excessive insults due to severe trauma or major surgeries, infectious diseases, shock etc. directly or through various kinds of mediator participate in the onset or deterioration of multiple organ failure by mechanism (1). In the case of multiple organ failure accompanied with organ disorder due to trauma or primary hepatic insufficiency, participation of mechanism (2) through organ correlation mechanism will largely contribute to the onset or deterioration thereof. By mechanism (3), medical care carried out during intensive care or care to correspond with an organ disorder may result in the other organ disorder. In patients, these 3 mechanisms participate to the development or deterioration of disorder in a complexed manner. The prognosis of patients of multiple organ failure is generally very poor and, in fact, the survival rate is low as 20-30% in spite of a wide variety of corresponding treatment. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

Patents 177

•

Aminoalcohol derivatives and their use as beta 3 adrenergic agonists Inventor(s): Fujii, Naoaki; (Takatsuki-shi, JP), Sakurai, Minoru; (Toyonaka-shi, JP), Takasugi, Hisashi; (Sakai-shi, JP), Taniguchi, Kiyoshi; (Kobe-shi, JP), Tomishima, Yasuyo; (Osaka-shi, JP) Correspondence: Oblon, Spivak, Mcclelland, Maier & Neustadt, P.C.; 1940 Duke Street; Alexandria; VA; 22314; US Patent Application Number: 20030181726 Date filed: March 4, 2003 Abstract: This invention relates to new aminoalcohol derivatives or salts thereof represented by the following formula [I]: 1wherein each symbol is as defined in the specification or salts thereof which have gut selective sympathomimetic, anti-ulcerous, anti-pancreatitis, lipolytic, anti-urinary incontinence and anti-pollakiuria activities, to processes for the preparation thereof, to a pharmaceutical composition comprising the same and to a method for the prevention and/or treatment diseases indicated in the specification to a human being or an animal. Excerpt(s): This invention relates to new aminoalcohol derivatives and salts thereof which are.beta.sub.3 adrenergic receptor agonists and useful as a medicament. This invention relates to new aminoalcohol derivatives which are.beta.sub.3 adrenergic receptor agonists and salts thereof. More particularly, it relates to new aminoalcohol derivatives and salts thereof which have gut selective sympathomimetic, anti-ulcerous, anti-pancreatitis, lipolytic, anti-urinary incontinence and anti-pollakiuria activities, to processes for the preparation thereof, to a pharmaceutical composition comprising the same and to a method of using the same therapeutically in the treatment and/or prevention of gastro-intestinal disorders caused by smooth muscle contractions in human beings or animal. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

•

Antagonists of MCP-1 function and methods of use thereof Inventor(s): Anuskiewicz, Steven E.; (San Bruno, CA), Inagaki, Hideaki; (Anjoh-shi, JP), Ishiwata, Yoshiro; (Aichi-gun, JP), Jomori, Takahito; (Nagoya-shi, JP), Kakigami, Takuji; (Inabe-gun, JP), Laborde, Edgardo; (Foster City, CA), Matsumoto, Yukiharu; (Gifu-shi, JP), Matsushima, Kouji; (Matsudo-shi, JP), Meng, Fanying; (San Francisco, CA), Peterson, Brian T.; (San Francisco, CA), Robinson, Louise; (San Carlos, CA), Villar, Hugo O.; (La Jolla, CA), Yokochi, Shoji; (Inabe-gun, JP) Correspondence: Heller Ehrman White & Mcauliffe Llp; 275 Middlefield Road; Menlo Park; CA; 94025-3506; US Patent Application Number: 20030105085 Date filed: February 27, 2002 Abstract: Compounds which are antagonists of MCP-1 function and are useful in the prevention or treatment of chronic or acute inflammatory or autoimmune diseases, especially those associated with aberrant lymphocyte or monocyte accumulation such as arthritis, asthma, atherosclerosis, diabetic nephropathy, inflammatory bowel disease, Crohn's disease, multiple sclerosis, nephritis, pancreatitis, pulmonary fibrosis, psoriasis, restenosis, and transplant rejection; pharmaceutical compositions comprising these

178 Pancreatitis

compounds; and the use of these compounds and compositions in the prevention or treatment of such diseases. Excerpt(s): This application claims the priority under 35 USC 119(e) of U.S. Provisional Application No. 60/272,792, filed Mar. 1, 2001, which is incorporated herein by reference. The present invention relates to compounds which are antagonists of MCP-1 function and are useful in the prevention or treatment of chronic or acute inflammatory or autoimmune diseases, especially those associated with aberrant lymphocyte or monocyte accumulation such as arthritis, asthma, atherosclerosis, diabetic nephropathy, inflammatory bowel disease, Crohn's disease, multiple sclerosis, nephritis, pancreatitis, pulmonary fibrosis, psoriasis, restenosis, and transplant rejection; and to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases. The migration of leukocytes from blood vessels into diseased tissues is an important process in the initiation of normal inflammatory responses to certain stimuli or insults to the immune system. However, this process is also involved in the onset and progression of lifethreatening inflammatory and autoimmune diseases; blocking leukocyte recruitment in these disease states, therefore, can be an effective therapeutic strategy. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Compositions and methods for inhibiting islet dysfunction and autoimmune disorders Inventor(s): Hill, David J.; (London, CA), Remacle, Claude; (Louvain-la-Neuve, BE), Reusens, Brigitte; (Braine-I'Alleud, BE) Correspondence: Kenneth I. Kohn; Kohn & Associates, Pllc; Suite 410; 30500 Northwestern Highway; Farmington Hills; MI; 48334; US Patent Application Number: 20030180345 Date filed: February 10, 2003 Abstract: The invention relates to a composition comprising an amino acid like structure carrying a sulfur moiety and a biologically acceptable carrier for inhibiting islet dysfunction and/or autoimmune disorders. The structure may be taurine, L-cysteine, Lmethionine, or a combination of these. Conditions of islet dysfunction include insulitis, Type 1 diabetes (IDDM), Type 2 diabetes (NIDDM), mature onset diabetes of the young (MODY), and gestational diabetes. Autoimmune disorders include insulitis, Type 1 diabetes, rheumatoid arthritis, thyroiditis and pancreatitis. The composition can act to inhibit islet dysfunction through exerting anti-apoptotic or immunomodulatory activity. Methods are provided for inhibiting islet dysfunction and/or autoimmune disorders by administering an amino acid like structure carrying a sulfur moiety to an individual. Excerpt(s): This application is a continuation-in-part of International Patent Application PCT/CA01/01137, which was filed Aug. 9, 2001, and published Feb. 21, 2002, and claims the benefit of priority from International Patent Application PCT/CA00/00925, filed on Aug. 11, 2000, which was published Feb. 21, 2002, the entirety of which is herein incorporated by reference. The present invention relates to a compositions and methods for inhibiting pancreatic islet dysfunction and for inhibiting autoimmune disorders. The compositions and methods are prophylactic and therapeutically effective against such conditions as insulitis, Type 1 diabetes, and Type 2 diabetes. Diabetes involves dysfunction of the pancreatic islet cells. In the case of Type 1 diabetes, also referred to as insulin dependent diabetes mellitus (IDDM), dysfunction is initiated in the event of an

Patents 179

immunological challenge. In the case of Type 2 diabetes, also referred to as non-insulin dependent diabetes mellitus (NIDDM), islet dysfunction occurs in upon exposure to a homeostatic challenge. Diabetes can alter total.beta. cell mass, as well as the properties of individual.beta. cells. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Feline pancreatic lipase composition and method of preparing and using such composition Inventor(s): Steiner, Jorg M.; (College Station, TX), Williams, David A.; (College Station, TX) Correspondence: Bracewell & Patterson, L.L.P.; Attention: J. Wendy Davis, PH.D.; P.O. Box 61389; Houston; TX; 77208-1389; US Patent Application Number: 20030207333 Date filed: May 2, 2003 Abstract: A novel form of lipase, namely feline pancreatic lipase (also termed feline classical pancreatic lipase) has an N-terminal amino acid sequence as shown in SEQ ID NO. 1. A method of purifying this lipase includes collecting pancreatic tissue from cats, delipidating the pancreatic tissue to produce a delipidated pancreatic extract, extracting pancreatic lipase from the delipidated pancreatic extract, and eluting the extracted pancreatic lipase through various columns. This lipase can be used for measuring pancreatic lipase immunoreactivity in serum thereby diagnosing pancreatitis in cats. To do so, antiserum against feline pancreatic lipase is prepared, and immunoassays are then performed in serum samples using this antiserum. In the event that increased concentration of pancreatic lipase immunoreactivity above the control range is detected in the serum, the cat might have pancreatitis. Excerpt(s): This nonprovisional application claims priority of U.S. Provisional Patent Application Serial No. 60/377,522, filed on May 3, 2002. The present invention relates generally to the field of biology and medicine. More particularly, the present invention relates to feline pancreatic lipase compositions, methods for preparing such compositions, and methods for employing such compositions to detect the concentration of pancreatic lipase in cat serum for diagnosis and management of pancreatitis. Lipases are water-soluble enzymes that hydrolyze water-insoluble substrates into more polar lipolysis products (Petersen and Drabl.o slashed.s, 1994). In 1856 Claude Bernard identified the first lipase (Petersen and Drabl.o slashed.s, 1994). Since then a plethora of lipases has been identified in microorganisms, plants, and animals (Lin et al., 1986; Jaeger et al., 1994; Petersen and Drabl.o slashed.s, 1994; Mukherjee and Hills, 1994; Lawson et al., 1994). Lipases share a common triad of amino acids (serine, aspartic or glutamic acid, and histidine) in the active site, which is also shared with serine proteases (Svendsen, 1994). Another common feature of almost all lipases are glycosylation site motifs (Antonian, 1988). Many lipases have been shown to be related phylogenetically. The pancreatic lipase gene family is a large gene family with 9 subfamilies (Petersen and Drabl.o slashed.s, 1994; Carrire et al., 1997; Carrire et al., 1998; Hirata et al., 1999). In addition there are other groups of phylogenetically related lipases, and yet other lipases that do not belong to a defined gene family (Anderson and Sando, 1991). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Glypican-1 in human breast cancer Inventor(s): Korc, Murray; (Irvine, CA), Lander, Arthur D.; (Laguna Beach, CA) Correspondence: Reed Smith Crosby Heafey Llp; 1901 Avenue OF The Stars, Suite 700; Los Angeles; CA; 90067; US Patent Application Number: 20030103980 Date filed: July 31, 2002 Abstract: Glycosylphosphatidylinositol-(GPI-) anchored HSPG glypican-1 is strongly expressed in human breast and pancreatic cancer--both by the cancer cells and in the case of pancreatic cancer the adjacent fibroblasts--whereas expression of glypican-1 is low in the normal pancreas and in chronic pancreatitis. Treatment of two pancreatic cancer cell lines, which express glypican-1, with the enzyme phosphoinositide-specific phospholipase-C (PI-PLC) abrogated their mitogenic responses to two heparin-binding growth factors: fibroblast growth factor-2 (FGF2) and heparin-binding EGF-like growth factor (HB-EGF). Treatment of MDA-MB-231 and MDA-MB-468 breast cancer cells with PI-PLC abrogates the mitogenic response to two heparin-binding growth factors, heparin-binding epidermal growth factor-like growth factor (HB-EGF) and fibroblast growth factor-2 (FGF-2). Syndecan-1 is also expressed at high levels in breast cancer tissues as well as breast cancer cells by comparison with breast normal tissues. Temporary or permanent transfection of a glypican-1 antisense construct attenuated glypican-1 protein levels and the mitogenic response to FGF2 and HB-EGF. Glypican can be used to detect the carcinoma in vitro and therapeutics that either bind to (e.g., antibodies or drugs), remove (e.g., enzymes) or prevent the expression (e.g., antisense constructs) of surface of the extracellular domain of glypican-1 are effective in retarding the growth of glypican-responsive carcinomas. Excerpt(s): The present application is a continuation-in-part of application Ser. No. 09/807,575, filed on Jul. 12, 2001, which is the National Phase filing of PCT/US99/24176, filed on Oct. 15, 1999, which claims priority from U.S. Provisional Application No. 60/104,510 (filed Oct. 16, 1998) and Ser No. 60/121,624 (filed Feb. 25, 1999). The present application is also a continuation-in-part of and claims priority from U.S. Provisional Application No. 60/309,722 (filed Jul. 31, 2001). All of the above applications are incorporated herein by reference. The present application concerns medical sciences and more particularly detection and treatment of human cancers, especially breast cancer. Membrane associated heparan sulfate proteoglycans (HSPGs) are thought to play important roles in many aspects of cell behavior, including cell-cell and cell-extracellular matrix adhesion (59, 104) and growth factor signaling (13, 89). Two families of polypeptides appear to carry the majority of the heparan sulfate on mammalian cells: glypicans, which are attached to the plasma membrane via glycosylphophatidylinositol (GPI) anchors, and syndecans, which are transmembrane proteins (13, 7). Four syndecans and five glypicans, all encoded by separate genes, have been described to date (6, 14, 107, 23, 117 and 97). Many of these polypeptides exhibit tissue specific patterns of expression, although these patterns often overlap (38, 64, 2 and 9). In vitro, at least, it is common for cells to express multiple HSPGs, often from both the glypican and syndecan families. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

Patents 181

•

Heterocyclic carboxamide derivatives as inhibitors of nitric oxide production Inventor(s): Ohkawa, Takehiko; (Ibaraki, JP), Ohne, Kazuhiko; (Ibaraki, JP), Oku, Teruo; (Tokyo, JP), Setoi, Hiroyuki; (Ibaraki, JP), Shima, Ichiro; (Ibaraki, JP), Yoshihara, Kousei; (Ibaraki, JP), Zenko, Tatsuya; (Tokyo, JP) Correspondence: Oblon Spivak Mcclelland Maier & Neustadt PC; Fourth Floor; 1755 Jefferson Davis Highway; Arlington; VA; 22202; US Patent Application Number: 20020132809 Date filed: February 25, 2002 Abstract: 1wherein each symbol is as defined in the specification, and pharmaceutically acceptable salts thereof. The compound (I) of the present invention and pharmaceutically acceptable salts thereof possess a strong inhibitory activity on the production of nitric oxide (NO), and are useful for prevention and/or treatment of NOmediated diseases such as adult respiratory distress syndrome, cardiovascular ischemia, myocarditis, heart failure, synovitis, shock, diabetes, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, glomerulonephritis, peptic ulcer, inflammatory bowel disease, cerebral infarction, cerebral ischemia, cerebral hemorrhage, migraine, rheumatoid arthritis, gout, neuritis, postherpetic neuralgia, osteoarthritis, osteoporosis, systemic lupus erythematosus, rejection by organ transplantation, asthma, metastasis, Alzheimer's disease, arthritis, CNS disorders, dermatitis, hepatitis, liver cirrhosis, multiple sclerosis, pancreatitis, atherosclerosis, and the like in human being and animals. Excerpt(s): This invention relates to new amide compounds and pharmaceutically acceptable salts thereof which are useful as medicament. Some peptide compounds have been known as described in, for example, EP 0 394 989 A2. This invention relates to new amide compounds. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

•

Immunoprotective methods for beta cell neogenesis Inventor(s): Van Antwerp, William P.; (Valencia, CA) Correspondence: Gates & Cooper Llp; Howard Hughes Center; 6701 Center Drive West, Suite 1050; Los Angeles; CA; 90045; US Patent Application Number: 20030212000 Date filed: May 9, 2003 Abstract: The invention is based on the disclosure provided herein that a biologically active fragment of pancreatitis associated polypeptide can be used to stimulate beta cell growth and at the same avoid and overcome the T-cell mediated autoimmune attack on the pancreas. Typical embodiments of the invention include methods of inhibiting the onset of Type I diabetes in a mammalian subject predisposed to Type I diabetes comprising administering to the subject a therapeutically effective amount of a pancreatitis associated polypeptide comprising the amino acid sequence IGLHDPTQGTEPNGE (SEQ ID NO: 3). Excerpt(s): This application claims the benefit of U.S. provisional patent application serial No. 60/379,202, filed May 9, 2002. The entire content of this provisional patent application is incorporated herein by reference. The present invention relates to the prevention and treatment of diseases associated with pancreatic dysfunction. Of the

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millions of individuals who are afflicted with diabetes, a large portion of them suffer from Type I diabetes, a syndrome caused by a lack of insulin which results from the loss of function and/or the destruction of insulin producing beta cells that are found in the pancreatic islets. In non-diabetic individuals, the beta cells produce sufficient amounts of insulin, a polypeptide which functions to regulate the ability of various tissues to absorb glucose as well as to maintain a steady blood-glucose concentration. If the body is unable to produce sufficient amounts of insulin, a high concentration of glucose will remain in the blood, and organs will not receive the glucose needed to function properly. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Leptin-mediated gene-induction Inventor(s): Broekaert, Daniel; (Waarschool, BE), Tavernier, Jan; (Balegem, BE), Vandekerckhove, Joel S.; (Loppem, BE), Verhee, Annick; (Lichtervelde, BE), Waelput, Wim; (Nieuwerkerken-waas, BE) Correspondence: Trask Britt; P.O. Box 2550; Salt Lake City; UT; 84110; US Patent Application Number: 20030036526 Date filed: September 4, 2002 Abstract: Methods of activating a signaling cascade comprising, introducing leptin and/or a cytokine to a receptor complex comprising gp 130, optionally in combination with a compound acting on adenylate cyclase or acting on one or more downstream targets of adenylate cyclase, thereby inducing genes in neuro-endocrine cells or cells of neuro-endocrine origin. Two distinct gene-sets are induced, immediate early response genes (STAT-3, SOCS-3, Metallothionein-II, the serine/threonine kinase Fnk and the rat homologue of MRF-1), and late induced target genes (Pancreatitis Associated Protein I, Squalene Epoxidase, Uridinediphosphate Glucuronyl Transferase and Annexin VIII). Strong co-stimulation with the adenylate cyclase activator forskolin was shown with respect to late induced target genes. Transcripts encoding Leptin Induced Protein I (LIPI) and Leptin Induced Protein II (LIP-II) were identified; however, no forskolin costimulatory effect was observed. It is also demonstrated that leptin modulates in vivo expression of MT-II, Fnk and Pancreatitis Associated Protein I genes. Excerpt(s): This application is a continuation of U.S. patent application Ser. No. 09/770,735, filed on Jan. 26, 2001 now U.S. Pat. No.______, which is a continuation of International Application No. PCT/EP99/05489, filed on Jul. 27, 1999, designating the United States of America, (International Publication No. WO 00/017014, published Feb. 10, 2000) the entire contents of each of which are incorporated by this reference. The current invention relates to leptin and/or a cytokine that binds to a receptor complex comprising gp 130, optionally in combination with a compound acting on adenylate cyclase or one of its downstream targets, to activate a signaling cascade wherein, as a result thereof, immediate early response and/or late target genes are induced in neuroendocrine cells or in cells of neuro-endocrine origin. In healthy conditions, assimilation, storage and utilization of nutrient energy constitute a highly integrated homeostatic system. Maintaining a relatively constant level of energy stores, and hence body weight, requires the achievement of a balance between food intake and energy expenditure. The "set point" hypothesis proposes coordinated regulation by control centers in the central nervous system. Hypothalamic nuclei are believed to be the sites at which the "set point" is regulated, given their important role in establishing homeostasis through regulation of food intake (hunger versus satiety), body weight, energy expenditure (adaptive

Patents 183

thermogenesis) and hormone integration involving substrate inter-conversion, storage and mobilization as appropriate. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Macromolecular enzyme substrates Inventor(s): Hortin, Glen L.; (Gaithersburg, MD) Correspondence: Needle & Rosenberg, P.C.; Suite 1000; 999 Peachtree Street; Atlanta; GA; 30309-3915; US Patent Application Number: 20030186345 Date filed: January 30, 2003 Abstract: The present invention features methods for measuring the activity of an enzyme (such as a proteinase or an endosaccharidase) in a sample, using a macromolecular substrate of the enzyme. Also featured are methods for: detecting the level of peptidase activity of a proteinase; measuring amylase activity in a sample; diagnosing pancreatitis in a subject; measuring the activity of a target isoenzyme in a sample; identifying a compound that modulates the activity of a proteinase or an endosaccharidase; and identifying an antibody that modulates the activity of a proteinase or an endosaccharidase, using the macromolecular substrates provided by the present invention. Excerpt(s): This application claims benefit of priority to U.S. Ser. No. 60/221,790, filed Jul. 31, 2001. This invention relates generally to measurement of enzyme activity using synthetic macromolecular enzyme substrates. Artificial substrates are commonly used in a broad variety of clinical, industrial, and research assays to measure the activities of various enzymes. One significant drawback of artificial substrates, however, is that they usually are substantially smaller than the natural substrate of the enzyme for which activity is being measured. The small size of these artificial substrates often limits the accuracy and/or sensitivity of an assay employing such a substrate, thereby leading to inaccurate estimates of enzyme activity in a sample. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

•

Method for treating and preventing pancreatitis Inventor(s): Cohard, Marielle; (Summit, NJ), Deviere, Jacques; (Genappe, BE) Correspondence: Schering-plough Corporation; Patent Department (k-6-1, 1990); 2000 Galloping Hill Road; Kenilworth; NJ; 07033-0530; US Patent Application Number: 20030133906 Date filed: November 26, 2002 Abstract: This invention relates to the use of interleukin-10 (IL-10) for the prevention and treatment of pancreatitis. It provides methods for preventing the onset or worsening of pancreatitis in patients at risk of developing such condition by administering a therapeutically effective amount of IL-10. In a specific embodiment, IL10 is administered to patients at risk of developing pancreatitis due to a procedure such as endoscopic retrograde pancreotography.

184 Pancreatitis

Excerpt(s): This application is a non-provisional application that claims priority under 35 U.S.C.sctn. 119(e) of provisional application, U.S. Ser. No. 60/333,983 filed Nov. 28, 2001, the contents of which are hereby incorporated by reference in their entireties. This invention relates to the use of interleukin-10 (IL-10) for the prevention and treatment of pancreatitis, and the like. Acute pancreatitis is a major complication of endoscopic retrograde cholangiopancreatography (ERCP). Unlike hemorrhage, duodenal perforation, or cholangitis, the incidence of pancreatitis has not decreased with the technical improvements of recent years and expertise of the operators [Freeman et al., N. Engl. J. Med. 335:909-918 (1996); Huibregtse K, N. Engl. J. Med. 335:961-963 (1996)]. The risk of post-ERCP pancreatitis varies greatly with the indications, being

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