WO2006042186A2 - Gastrointestinal examination preparation - Google Patents

Gastrointestinal examination preparation Download PDF

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WO2006042186A2
WO2006042186A2 PCT/US2005/036331 US2005036331W WO2006042186A2 WO 2006042186 A2 WO2006042186 A2 WO 2006042186A2 US 2005036331 W US2005036331 W US 2005036331W WO 2006042186 A2 WO2006042186 A2 WO 2006042186A2
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method
agent
cannulation
patient
gastrointestinal
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PCT/US2005/036331
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French (fr)
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Qiang Cai
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Emory University
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic, hydroximic acids

Description

GASTROINTESTINAL EXAMINATION PREPARATION

FIELD OF THE INVENTION

The present invention relates to methods and compositions for diagnosing and facilitating the diagnosis of gastrointestinal disorders using gastrointestinal procedures. Methods and compositions for facilitating gastrointestinal procedures, particularly endoscopic retrograde cholangiopancreatography (ERCP), are also provided.

BACKGROUND OF THE INVENTION The accurate diagnosis and treatment of gastrointestinal disorders and diseases are of paramount importance. Various gastrointestinal procedures have been developed and are used in the diagnosis of gastrointestinal disorders. Such procedures include, for example, endoscopic ultrasound (EUS), magnetic resonance imaging (MRI), magnetic resonance cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography (ERCP), esophagogastroduodenoscopy (EGD), and computerized axial tomography (CT scan). While these procedures play an important role in diagnosing gastrointestinal disorders, these procedures as currently employed limit the rapid and accurate diagnosis of certain gastrointestinal disorders. Therefore, additional methods for diagnosing and facilitating the diagnosis of gastrointestinal disorders using such gastrointestinal procedures are needed in the art. Magnetic resonance imaging (MRI) and magnetic resonance cholangiopancreatography (MRCP) have been used recently as new and non-invasive imaging modalities in the diagnosis of pancreatobiliary diseases, allowing direct visualization of the pancreatobiliary system. See, for example, Wallner et al. (1991) Radiology 181 :805-808; Soto et al. (1995) Radiology 196:459-464; and Lomanto et al. (1997) Am. J. Surg. 174:33-38. MRI and MRCP, however, have limitations in the diagnosis of certain pancreatobiliary diseases, such as pancreatic divisum and chronic pancreatitis. Secretin increases secretion to the pancreatic ducts, and administration of secretin has been reported to improve MRCP image quality. See, for example, Mariani et al. (2003) Gastrointest. Endosc. 58:847-852; Monill et al. (2004) AJR 183:1267-1274; and Shinchi et al. (2004) J. Hepatobiliary P ancr eat. Surg. 11:50-55. Secretin, however, is expensive, costing $200-$400 per patient. Therefore, other methods that permit the diagnosis of gastrointestinal disorders using MRI or MRCP by improving image quality are needed.

Endoscopic retrograde cholangiopancreatography (ERCP) is another important gastrointestinal endoscopic procedure, which first came into use about 30 years ago. See, for example, Cotton (1972) Gut 3:1014-1025; Cotton (1977) Gut 18:316-341; Sherman et al. (1999) in Textbook of Gastroenterology, ed. Yamada et al. (3rd edition; Lippincott Williams & Wilkins, Philadelphia, PA); and National Institutes of Health, State-of Science Conference Statement: Endoscopic Retrograde Cholangiopancreatography for Diagnosis and Therapy (2002). Together with radiography, ERCP provides high-quality visualization of the entire hepatobiliary ducts and pancreatic duct system. Using brush and biopsy techniques, ERCP obtains cells or tissue for pathology diagnosis. In addition to its diagnostic role, ERCP has a therapeutic role in many clinical situations, such as the removal of bile and pancreatic duct stones, treatment of biliary strictures, and the palliation of pancreatic cancer or bile duct cancer (see, for example, Sherman et al., supra). Diseases of the hepatobiliary system and pancreas, such as gallstone disease, pancreatic and biliary malignancy, pancreatitis and its complications, and abdominal pain of possible pancreatic or biliary origin (sphincter of Oddi Dysfunction, SOD), are frequently encountered in clinical practice. ERCP has important diagnostic and therapeutic roles in the management of all of these diseases.

ERCP is an invasive procedure that must be performed by a skilled and highly trained gastroenterologist. Potential complications of ERCP include pancreatitis, hemorrhage, perforation, cholangitis, cholecystitis, stent-related complications, and cardiopulmonary complications. An important step in this procedure is cannulation of the common bile duct (CBD) and/or the pancreatic duct (PD). Cannulation can be a technical challenge, and sometimes cannulation is not possible, even for a trained gastroenterologist. See, generally, Goff ( 1999) Gastrointest. Endosc. 50:642-645; Wehrmann et al. (2001) Endoscopy 33:323-328; Devereaux et al. (2002) Am. J. Gastroenterol. 97:2279-2281; and Hashiba et al. (2004) Endoscopy 36:317-321. Failure to obtain a cholangiogram using standard catheter techniques in ERCP occurs with a frequency varying from 10% to 50%. See Kumar et al. (1995) Gastrointest. Endosc. 41:445-447; Siegel (1981) Endoscopy 12:130-133; Silivka (1996) Gastrointest. Endosc. 44:636; Goff (1995) Gastrointest. Endosc. 41:502-505; and Silvis et al. (1994) in Text and Atlas of Endoscopic Retrograde Cholangiopancreatography, ed. Silvis et al. (Igaku-Sham Medical Publishers, New York). If the CBD and PD cannot be cannulated, then ERCP cannot be performed, resulting in wasted resources and manpower and unnecessary x-ray exposure of the staff and the patient. In some situations, if ERCP is not successful, the patient will have to undergo alternative procedures, such as percutaneous transhepatic cholangiogram (PTC) or surgical operation. PTC usually requires the placement of an external drain, and surgery is more traumatic for the patient.

Furthermore, even in cases where cannulation is achieved, the time for cannulation can vary significantly. In difficult cases, cannulation may take an hour or longer and can be the most time-consuming step in ERCP. Prolonged cannulation can result in significant morbidity to patients, anxiety for endoscopists, unnecessary radiation exposure, and inefficiency in patient care. Freeman (2003) Gastrointestinal Endoscopy Clinics of North America 13:775-789. Moreover, the rate of post-ERCP complications is positively correlated with the duration of the procedure. See, for example, Freeman et al. (1996) New Engl. J. Med. 335:909-918; Vandervoort et al. (2002) Gastrointest. Endosc. 56:652-656; and Baillie (2002) Curr. Gastroenterol. Rep. 4:112-119.

Methods reported to date to facilitate cannulation can be described as mechanical or pharmacological. See Goff (1999) Gastrointest. Endosc. 50:642-645; Wehrmann et al. (2001) Endoscopy 33:323-328; Devereaux et al. (2002) Am. J. Gastroenterol. 97:2279-2281; Siegel (1981) Endoscopy 12:130-133; Silivka (1996) Gastrointest. Endosc. 44:636; Weston (1997) J. Clin. Gastroenterol. 24:227-230; Thompson et al. (1986) Endoscopy 18:251; Igarashi et al. (2002) Endoscopy 34:628- 631; Cortas et al. (1999) Gastrointest. Endosc. 50:775-779; and Fogel et al (1998) Gastrointest. Endosc. 47:396-400. Mechanical approaches include the following: use of different types of ERCP catheters (such as taper-tipped, metal-tipped sphincterotomes, or a guide wire protruding from the tip of a catheter) (Silivka (1996), supra; Silvis et al. (1994) in Text and Atlas of Endoscopic Retrograde Cholangiopancreatography, ed. Silvis et al. (Igaku-Sham Medical Publishers, New York); Igarashi et al. (2002), supra; Cortas et al. (1999), supra), precut papillotomy (Goff (1999), supra; Siegel (1981), supra), and placement of a temporary pancreatic duct stent (Fogel et al. (1998), supra). One mechanical technique is a pre-cut approach to cannulate the CBD (Goff (1999) Gastrointest. Endosc. 50:642-645). However, this is a more invasive way and also requires considerable time to perform. Pharmacological methods to facilitate cannulation include the following: topical use of nitrate (Wehrmann et al. (2001), supra), intravenous application of sincalide (a synthetic cholecystokinin (CCK) agonist) (Weston (1997), supra) and CCK (Thompson et al. (1986), supra), and intravenous application of secretin (Devereaux et al. (2002), supra). Recently, a study to determine if topical application of nitrates facilitates CBD and PD cannulation was reported, but the result was not satisfactory. (Goff (1999) Gastrointest. Endosc. 50:642-645). More recently, facilitation of PD cannulation using a new synthetic porcine secretin (SPS) was reported. This study showed that SPS is safe and efficacious in facilitating cannulation of either the major or minor pancreatic orifice in ERCP in the subset of patients who represent cannulation difficulties (Devereaux et al. (2002) Am. J. Gastroenterol. 97:2279- 2281). However, SPS is very expensive. Current pharmacological approaches tend to be expensive and/or lack efficacy. Therefore, cannulation of the CBD and the PD in ERCP remains a technical challenge to both trainees and experienced pancreaticobiliary endoscopists. Thus, methods and compositions for facilitating cannulation of the CBD and the PD are also needed.

In addition to improved diagnostic methods for gastrointestinal disorders, new methods and compositions for the treatment and management of these diseases are also needed. For example, improved treatments for cholestasis are desired. Cholestasis is common in patients receiving total parenteral nutrition (TPN) and may be severe or even fatal. See generally Kelly et al. (1998) Nutrition 14:153-157 and Sandhu et al. (1999) Clinics in Liver Diseases 3:489-508. TPN has been used in the last two decades and is indicated for those patients who, for a prolonged period, are unable to meet their nutritional needs through the gastrointestinal tract, such as post gastrointestinal surgeries and shoot bowel syndrome. Many patients who receive long-term TPN develop liver disease.

The pathogenesis of TPN- induced liver cholestasis is poorly understood. Cholestasis generally occurs late in TPN therapy in association with elevated serum alkaline phosphatase and total bilirubin concentrations. Factors such as pre-existing medical conditions, excessive nutrient infusion, amino acid deficiency, absence of enteral stimulation, protracted duration of therapy, continuous infusion schedule, and hypoalbuminemia have all been suggested as possible etiologies. Various treatments including administration of bile salt, cholecystokinin (CCK), tumor necrosis factor- alpha antibodies, methionine, ursodeoxycholic acid, cisapride, fish oil, nonsteroidal anti-inflammatory drugs, and antibiotics have been proposed for the treatment of TPN-induced cholestasis. Cyclic infusion of the nutrients has also been shown to reduce TPN-induced cholestasis. None of these treatments, however, is ideal for management of TPN-induced cholestasis, as they are expensive or cause other side effects and complications. Therefore, methods and compositions for the treatment of gastrointestinal disorders such as cholestasis are needed in the art.

BRIEF SUMMARY OF THE INVENTION Methods and compositions for diagnosing or facilitating the diagnosis of a gastrointestinal disorder in a patient using a gastrointestinal procedure are disclosed. The present invention further provides methods and compositions for facilitating cannulation of the common bile duct or the pancreatic duct of a patient during a gastrointestinal procedure, such as ERCP. The methods of the invention comprise administering to the patient at least one agent that is selected from the group consisting of fats, fatty acids, long-chain triglycerides, oils (e.g., corn oil), and magnesium sulfate. In other embodiments, the methods of the invention comprise administering at least one agent that stimulates secretion of cholecystokinin (CCK). Administering an agent of the invention may comprise such methods as oral administration, tube feeding, or topical application to the major and/or minor papilla in the duodenum. The methods and compositions disclosed herein find use in, for example, diagnosing and/or treating such conditions as gall stones (cholelithiasis), common duct stones (choledocholithiasis), microlithiasis, cholestasis, bile duct obstruction, pancreatic or biliary cancer, any cancers with liver metastasis, chronic pancreatitis, pancreatic divisum, bile duct stricture, bile duct leak, and sphincter of Oddi dysfunction (SOD). BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 outlines the study profile for the investigation of oral administration of a liquid fatty meal prior to ERCP.

Figure 2 outlines bile secretion and activity of the sphincter of Oddi before and after fat ingestion.

Figure 3 outlines the study profile for the investigation of topical administration of magnesium sulfate prior to ERCP.

DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to methods and compositions for diagnosing a gastrointestinal disorder in a patient using a gastrointestinal procedure comprising administering to the patient at least one agent that is selected from the group consisting of fats, fatty acids, long-chain triglycerides, oils, particularly corn oil, and magnesium sulfate. While not intending to be limited to a particular mechanism, these agents may function in the diagnostic methods of the invention by producing one or more physiological or neurohormonal changes in the body of the patient, including, for example, possibly stimulating cholecystokinin (CCK) secretion. "Diagnosing a gastrointestinal disorder" is intended to include, for example, diagnosing or detecting the presence of a gastrointestinal disease, facilitating the diagnosis of the gastrointestinal disease, or monitoring the progression of the gastrointestinal disease. The terms diagnosing, detecting, and identifying a gastrointestinal disorder are used interchangeably herein. By "facilitating the diagnosis of a gastrointestinal disorder" is intended that employing the disclosed methods assists a physician in more accurately or more easily determining that a patient is afflicted with a particular gastrointestinal disorder.

In other embodiments, methods and compositions for diagnosing a gastrointestinal disorder in a patient using a gastrointestinal procedure comprise administering to the patient at least one agent that stimulates CCK secretion. Any agent that stimulates CCK secretion may be used to practice the diagnostic methods of the invention.

As used herein, the term "agent" comprises any substance that is administered to a patient in accordance with any method of the invention, hi particular embodiments, the agent is selected from the group consisting of fats, fatty acids, long- chain triglycerides, oils (e.g., corn oil), and magnesium sulfate. In other embodiments, an agent refers to any agent that stimulates CCK secretion.

In certain aspects of the invention, the methods are used to diagnose or facilitate the diagnosis of a gastrointestinal disorder using a gastrointestinal procedure. In accordance with the diagnostic methods of the invention the agent may be administered to the patient before, during, or after the gastrointestinal procedure is performed. Typically, an agent of the invention (i.e., a fat, fatty acid, long-chain triglyceride, oil, particularly corn oil, magnesium sulfate, or an agent that stimulates CCK secretion) is administered before the gastrointestinal procedure is initiated. While not intending to be limited to any particular mechanism, administration of at least one fat, fatty acid, long-chain triglyceride, oil (e.g., corn oil), magnesium sulfate, or agent that stimulates CCK secretion may permit or facilitate the diagnosis of a gastrointestinal disorder using a gastrointestinal procedure by, for example, causing gall bladder contraction and increased bile secretion in the patient. Gall bladder contraction and increased bile secretion may permit or facilitate diagnosis of a gastrointestinal disorder by, for example, permitting improved visualization of affected portions of the gastrointestinal system, by providing a sufficient volume of bile needed for diagnostic analysis, or by facilitating cannulation of the common bile duct or pancreatic bile duct, as described herein below. The methods and compositions of the invention may be used to diagnose or facilitate the diagnosis of any gastrointestinal disorder. As used herein, "gastrointestinal disorder" or "gastrointestinal disease" refers to any disease, disorder, or dysfunction of the gastrointestinal system, including but not limited to pancreatic divisum, chronic pancreatitits, gall stones (cholelithiasis), common duct stones (choledocholithiasis), microlithiasis, cholestasis, bile duct obstruction, biliary cancer, any cancers with liver metastasis, pancreatic cancer, bile duct stricture, bile duct leak, and sphincter of Oddi dysfunction (SOD).

"Gastrointestinal procedure" is intended to include any diagnostic or therapeutic procedure or examination of the gastrointestinal tract or any particular organ or anatomical structure within the gastrointestinal system. Gastrointestinal procedures as defined herein include but are not limited to invasive, non-invasive, endoscopic, radiological, and imaging procedures. Exemplary gastrointestinal procedures include endoscopic ultrasound (EUS), magnetic resonance imaging (MRI), magnetic resonance cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography (ERCP), esophagogastroduodenoscopy (EGD), endoscopic examination of pancreatic function, HIDA hepatic scan, and computerized axial tomography (CT scan). Such procedures are used in the diagnosis and treatment of a variety of gastrointestinal diseases.

Particular embodiments of the invention are directed to methods and compositions for diagnosing or facilitating the diagnosis of pancreatic diseases, such as, for example, pancreatic divisum and chronic pancreatitis, using gastrointestinal procedures. Gastrointestinal procedures of particular interest for the diagnosis of pancreatic diseases include but are not limited to EUS, MRI, MRCP, and CT scans. MRI, MRCP, and CT scans are non-invasive procedures that permit visualization of the gastrointestinal system, including the pancreatobiliary system. Although these methods are currently employed for the diagnosis of pancreatic diseases, they have diagnostic limitations and more sensitive methods are desired. As noted above, administration of secretin, which increases secretion to the pancreatic ducts, has been reported to improve MRCP image quality, thereby facilitating the diagnosis of certain pancreatobiliary diseases. While not intending to be limited to one mechanism, administration of an agent of the invention (i.e., a fat, fatty acid, long-chain triglyceride, oil, particularly corn oil, magnesium sulfate, or an agent that stimulates CCK secretion) may facilitate diagnosis of pancreatic diseases such as pancreatic divisum and chronic pancreatitis by stimulating gall bladder contraction and increasing bile or pancreatic juice production, thereby permitting better visualization of the pancreas during a gastrointestinal procedure. In particular, administration of an agent such as magnesium sulfate or corn oil prior to performing an MRI, MRCP, or CT scan may improve the quality of the images of the pancreatobiliary system obtained during these procedures, thereby facilitating the diagnosis of certain gastrointestinal disorders.

The methods of the invention also find use in facilitating the collection of bile from a patient during a gastrointestinal procedure. Such methods facilitate the diagnosis of, for example, microlithiasis in the bile duct, particularly in those patients classified as suffering from non-ulcer dyspepsia (NUD). Dyspepsia generally includes abdominal pain, abdominal discomfort, nausea, and other upper gastrointestinal complaints and results from a variety of causes. In a large percentage of dyspepsic patients, though, no explanation for the dyspepsia can be identified by EGD. Such patients are classified as suffering from NUD.

While the cause of NUD is poorly understood, microlithiasis in the bile duct may be one cause. The traditional method for diagnosing microlithiasis in the bile duct requires the aspiration of a large volume of bile from the duodenum of the patient during EGD or ERCP and the microscopic examination of the collected bile for the presence of crystals. Aspiration of sufficient volumes of bile for analysis is often difficult and requires the injection of CCK prior to the aspiration. Because of the expense and difficulties associated with current methods for diagnosing microlithiasis, this condition is under-investigated in the NUD patient population. In particular embodiments, the methods of the invention facilitate the collection of bile from a patient during a gastrointestinal procedure, such as EGD or ERCP, by stimulating the contraction of the gall bladder and increasing the secretion of bile. The methods thereby permit the collection of sufficient volumes of bile to permit the detection of microlithiasis and other gastrointestinal disorders that require examination of the bile for accurate diagnosis. See Example 6.

Methods and compositions for facilitating cannulation of the common bile duct (CBD) and/or the pancreatic duct (PD), including cannulation of the minor papilla, of a patient during a gastrointestinal procedure, particularly endoscopic retrograde cholangiopancreatography (ERCP), comprising administering to the patient at least one agent that is selected from the group consisting of fats, fatty acids, long- chain triglycerides, oils, particularly corn oil, and magnesium sulfate are also provided. In other embodiments, methods for facilitating cannulation of the common bile duct (CBD) and/or the pancreatic duct (PD) of a patient during a gastrointestinal procedure comprise administering to the patient at least one agent that stimulates cholecystokinin (CCK) secretion. Any agent that stimulates CCK secretion may be used in the practice of these embodiments. While not intending to be limited to a particular mechanism, administration of an agent of the invention (i.e., a fat, fatty acid, long-chain triglyceride, oil, particularly corn oil, magnesium sulfate, or an agent that stimulates CCK secretion) may promote increased bile secretion into the duodenum of the patient and/or promote relaxation of the sphincter of Oddi, thereby facilitating cannulation by promoting opening of the orifice that leads to the CBD and the PD. The methods of the invention for facilitating cannulation find use in diagnosing and/or treating such conditions as gall stones (cholelithiasis), common duct stones (choledocholithiasis), microlithiasis, cholestasis, bile duct obstruction, bile duct stricture, bile duct leak, pancreatic or biliary cancer, any cancer with liver metastasis, pancreatitis, and sphincter of Oddi dysfunction (SOD). Administering an agent of the invention (i.e., a fat, fatty acid, long-chain triglyceride, oil, particularly corn oil, magnesium sulfate, or an agent that stimulates CCK secretion) in accordance with the methods disclosed herein comprises, for example, oral administration, tube feeding, or topical application to the major or minor papilla in the duodenum. The agent may be administered to the patient alone or in combination with any liquid, beverage, or food product. In some embodiments, the agent (e.g., a fat or fatty acid, including long-chain triglycerides, for example, corn oil) is mixed with a beverage to produce a liquid fatty meal that is suitable for oral administration or tube feeding. In a preferred embodiment, the agent comprises corn oil prepared as a fatty meal. In other embodiments, the agent (e.g., magnesium sulfate) is mixed with saline to produce a liquid meal that is suitable for oral administration or tube feeding. Any agent may be combined with any beverage for use in the present methods. Agents of the invention (i.e., a fat, fatty acid, long-chain triglyceride, oil, particularly corn oil, magnesium sulfate, or an agent that stimulates CCK secretion) are typically administered from about 15 minutes to about 4 hours, more particularly from about 30 minutes to about 2 hours, before the gastrointestinal procedure. In one embodiment, an agent is administered from about 30 minutes to about 1 hour before the gastrointestinal procedure. A person skilled in the art will appreciate that the time for administration of the agent may be modified to achieve the desired result. In some embodiments, the agent is magnesium sulfate, which is administered, for example, orally, topically, or by tube feeding, in an amount from about 1 gram to about 10 grams, including about 1 gram, 2 grams, 3 grams, 4 grams, 5 grams, 6 grams, 7 grams, 8 grams, 9 grams, 10 grams, and other such values within the range of about 1 gram to about 10 grams. In another embodiment, the agent is a fat/fatty acid, including a long-chain triglyceride, for example corn oil, which is administered, for example, orally or by tube feeding, in an amount from about 5 grams to about 100 grams, including about 5 grams, about 10 grams, 15 grams, 20 grams, 25 grams, 30 grams, 35 grams, 40 grams, 45 grams, 50 grams, 55 grams, 60 grams, 65 grams, 70 grams, 75 grams, 80 grams, 85 grams, 90 grams, 95 grams, 100 grams, and other such values within the range of about 5 grams to about 100 grams. hi particular embodiments of the invention, the gastrointestinal procedure of interest requires cannulation of the CBD or the PD. Methods and compositions for facilitating cannulation of the CBD or PD during gastrointestinal procedures are further provided. Such procedures requiring cannulation include, for example, ERCP. ERCP is a procedure to x-ray the pancreatic duct, hepatic duct, common bile duct, duodenal papilla, and the gallbladder, hi this procedure, a thin, lighted tube (endoscope) is passed through the mouth and down into the first part of the small intestine (duodenum). A smaller tube (catheter) is then inserted through the endoscope into the bile and pancreatic ducts. A contrast is injected through the catheter into the ducts, and an x-ray is taken. As discussed above, ERCP is an important procedure in diagnosing and treating a variety of pancreatic and biliary diseases. hi certain embodiments, the methods and compositions of the invention facilitate cannulation of the CBD, more particularly deep cannulation of the CBD. hi other embodiments, cannulation of the PD is facilitated. By "cannulation" is intended insertion of a small tube or catheter into the CBD or PD. As used herein, "facilitating cannulation" includes reducing the time needed to cannulate the CBD or PD of a patient, as well as reducing the cannulation failure rate. "Cannulation failure rate" refers to the number of patients in a population of patients that are unable to be successfully cannulated. The methods and compositions disclosed herein for facilitating cannulation of the CBD or PD find further use in training of gastrointestinal medicine residents and fellows. Methods for treating a patient for a gastrointestinal disorder, particularly liver diseases, more particularly cholestasis, comprising administering to the patient a therapeutically effective amount of at least one agent that is selected from the group consisting of fats, fatty acids, long-chain triglycerides, oils, particularly corn oil, and magnesium sulfate are further provided, hi certain aspects of the invention, the methods for treating a patient for a gastrointestinal disorder, particularly liver diseases, more particularly cholestasis, comprise administering to the patient a therapeutically effective amount of at least one agent that stimulates CCK secretion. "Treatment" is herein defined as the administration of an agent (i.e., a fat, fatty acid, long-chain triglyceride, oil, particularly corn oil, magnesium sulfate, or an agent that stimulates CCK secretion) to a patient, where the patient has a gastrointestinal disorder, where the purpose is to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect the condition or the symptoms of the gastrointestinal disorder. In certain embodiments, the gastrointestinal disease is cholestasis, more particularly cholestatsis induced by total parenteral nutrition (TPN). Cholestatsis is a liver disease in which there is a blockage of the flow of bile that results in the accumulation of bile in the liver. While not intending to be limited to a particular mechanism of action, administration of an agent of the invention, particularly magnesium sulfate or corn oil, may function in the treatment of TPN- induced liver diseases such as cholestasis by causing gallbladder contraction and increased bile secretion in the patient. For purposes of the treatment of cholestasis, agents are typically administered orally or by tube feeding. The agent is generally administered to a patient suffering from cholestasis one or more times per day until the condition resolves. The agent may also be administered to the patient once a week, two times per week, three times per week, four times or more per week until the condition resolves. The agent may be administered as a single dose or as multiple doses. The timing and frequency of administration of the agent can be varied so long as the beneficial effects of the agent are achieved. By "therapeutically effective dose," "therapeutically effective amount," or

"effective amount" is intended an amount of the agent that brings about a positive therapeutic response with respect to treatment of a patient for a gastrointestinal disorder, particularly cholestasis. Li particular embodiments, a therapeutically effective dose of magnesium sulfate for the treatment of cholestasis is in the range from about 1 gram to about 10 grams, more particularly from about 4 grams to about 6 grams, when administered orally or by tube feeding. In other embodiments, a therapeutically effective dose of corn oil for the treatment of cholestasis is in the range from about 5 grams to about 100 grams, more particularly from about 30 grams to about 50 grams, when administered to the patient orally or by tube feeding. Determination of therapeutically effective amounts is well within the capability of those skilled in the art.

As used herein, "positive therapeutic response" refers to, for example, improving the condition of at least one of the symptoms of the gastrointestinal disorder, preventing the worsening of at least one symptom or the gastrointestinal disorder, or preventing or limiting the progression of the gastrointestinal disorder. In the case of cholestasis, therapeutic response can be assessed by, for example, monitoring for an improvement in liver function tests, such as serum total bilirubin and alkaline phosphatase levels. Those skilled in gastrointestinal medicine can readily determine appropriate tests for monitoring therapeutic response of a treatment for a gastrointestinal disorder. See Example 7.

The methods disclosed herein find use in the diagnosis and treatment of gastrointestinal disorders in any patient. The term "patient" refers without limitation to any human subject, including children, teenagers, adults, and the elderly.

The following examples are presented by way of illustration, not by way of limitation:

EXPERIMENTAL

Example 1: Oral Administration of Liquid Fatty Meal Prior to ERCP Methods Patient selection and randomization:

All patients referred for ERCP over a nine-month period were evaluated for eligibility. Eligible patients signed a written consent for the study. Exclusion criteria included the following:

1. Patients younger than 21 years old or older than 80 years old.

2. Pregnant patients.

3. Patients with preexisting stent in CBD or PD. 4. Patients with history of endoscopic or surgical sphincterotomy.

5. Patients with Billroth II surgery.

6. Patients who were not competent.

7. Patients who had ERCP within one week prior to the study.

8. Patients who need a biliary manometry study.

The method of Random Permuted Blocks of Fixed Length was used for patient allocation. See Matthews (2000) in An Introduction to Randomized Controlled Trials, ed. Matthews (Arnold, London, England). Each fixed length had 4 patients with 2 in each group. Each patient in the study group received a liquid fatty meal orally about 30 minutes before the procedure. Each patient in the control group received the same volume of a non-fat meal (control meal), as described below. The staff members at the research center were the only ones not blinded to the study.

Liquid fatty meal: Forty grams of fat is the adequate amount for stimulation of CCK secretion, with effect occurring shortly after oral administration. See, for example, Hopman et al (1984) Am. J. Clin. Nutr. 39:356-359; Isaacs et al. (1987) Digest. Dis. & ScL 32:481-486; Mclaughlin et al. (1999) Gastroenterol. 116: 46-53; Jonkers et al. (2000) Digest. Dis. & ScL 45 : 1719- 1726. Also, to determine how much fat and when the fat should be administered in this study, an abdominal ultrasound study was performed on volunteers to determine the maximal effect of a fatty meal on human gallbladder contraction. It appeared that 40 grams of corn oil is adequate for inducing gallbladder contraction, and the maximal effect occurred between 30 minutes to 60 minutes after oral intake of the oil. Therefore, 40 grams of corn oil was administered to each patient in the study group.

The recipe and protocol for preparing the liquid fatty meal and the control meal were as follows:

1. Weigh 40 grams of corn oil (study group) or deionized water (control group).

2. Weigh 90 grams of deionized water.

3. Measure 1 level tsp of Pineapple-Orange Crystal Light powder.

4. Mix water and Crystal Light powder together until homogenous.

5. Add the 40 grams of oil or water, blend until smooth with the hand blender.

Endoscopists: Two pancreaticobiliary endoscopists took part in the study. In order to avoid the situation of one endoscopist being assigned by chance to the study group and the other to the control group, the two endoscopists took turns performing the ERCP for two-week intervals.

ERCP fellows: This study was performed in a tertiary medical center where training of fellows to perform ERCP is required. For each procedure, a trainee (one of the ERCP fellows) was the first endoscopist. In the preliminary study, each fellow was given 10 minutes to successfully cannulate the patient (i.e., the time from starting cannulation of the common bile duct of the pancreatic duct, not from the time of esophageal cannulation). If deep CBD cannulation was not achieved in this time period, an attending physician took over the scope and continued the procedure. This resulted in a much longer cannulation time. In this study, each fellow was permitted to have the first 10 minutes of the procedure (counting from the time of esophageal intubation).

Appearance of the major papilla: Photos of the major papilla for each patient were taken.

Cannulation time: The deep CBD cannulation time is the time from starting cannulation to the time when the catheter successfully cannulates deep inside the CBD, and therapeutic procedures, therefore, can be performed if they are needed. The PD cannulation time is the time from starting cannulation to the time when a pancreatogram is achieved.

Fluoroscopy time (FT): The machine in the ERCP room automatically recorded the FT during an ERCP procedure. The following formula was used to calculate the FT during deep CBD cannulation:

FT during deep CBD cannulation = (FT at the time of completed deep CBD cannulation - FT at the beginning of cannulation)

Cannulation failure: Two criteria were used for determination of a cannulation failure: 1) when the major papilla could not be localized or could not be visualized at the right position; and 2) when cannulation time exceeded one hour.

Patient follow-up: All patients were followed up for three days post the ERCP procedure. Post-procedural symptoms including abdominal pain, nausea, vomiting, and bleeding were recorded.

Statistical considerations and analysis: The sample size calculation for the study was based on the difference in mean deep CBD cannulation times for the two groups. If the difference was greater than 5 minutes, and the Standard deviation for each group was 8, then 30 patients in each group will yield approximately 80% statistical power to detect the difference using a two-sided 0.05 level of significance. After the study was completed, the Student T Test was used to compare the mean cannulation times and the FTs between the two groups. Rosner, ed. (2000) Fundamentals of

Biostatistics (5th ed; Duxbury Press, Pacific Grove, California). The Wilcoxon rank- sum test was also used to test the difference of the cannulation times and the FTs between the two to avoid the possible influence of any large data skew in the two groups. Fisher's exact test was used to test the differences in cannulation rates for different categories between the two groups. See Rosner, ed. (2000), supra. All statistical tests were two-sided, and a p-value of <0.05 was considered statistically significant.

Results A total of 161 patients were assessed for eligibility. Seventy-six patients met one of the exclusion criteria. One patient refused the study. Eighty- four patients were randomized into a study group and a control group by staff members at the GCRC. The procedure was not completed in 6 patients. The study of the remaining 78 patients was completed (Figure 1). The age, gender, the indications for ERCP, and the procedures performed in each group were similar.

The appearance of the fatty meal was similar to the control meal. The meal was placed in a Styrofoam cup with a lid in the kitchen at the hospital. The study team could not see what a patient had.

In the study group, bile was seen near the major papilla in 82% of the patients. In those patients, an opened orifice of the common bile duct/pancreatic duct was observed easily. In the control group, bile was seen near the major papilla in 28% of the patients. In most of the patients in this group, the orifice of the common bile duct/pancreatic duct was not easily identified (photographs not shown).

The CBD could not be cannulated in 2 patients from the study group and 3 patients from the control group. Deep CBD cannulation could not be achieved in 3 patients from the study group and 3 patients from the control group. There were no statistical differences among the CBD cannulation failure rates between the two groups. The PD was cannulated in all patients except one in the control group.

The liquid fatty meal decreased the mean deep CBD cannulation time from 14.7 to 8.0 minutes (P=O.005), and the median deep cannulation time from 11.5 to 8.0 minutes (P=0.008) (Table IA). The fatty meal did not affect the PD cannulation time. In both groups, the mean PD cannulation times were about 3 minutes.

The mean FTs during the deep CBD cannulation were 3.3 minutes and 6.1 minutes for the study group and the control group respectively (P=O.040). The median FTs during the deep CBD cannulation were 2.5 minutes and 3.9 minutes for the study group and the control group respectively (P=0.013) (Table IB).

Table 1. Effect of the Liquid Fatty Meal on Deep CBD Cannulation Time (A) and FT (B) (Minutes)

A.

Figure imgf000018_0001

*SD: Standard deviation

The two senior endoscopists performed ERCP on almost an equal number of patients in the study group and the control group. The outcomes from those two endoscopists were similar and showed the same pattern as mentioned above. No clinical parameters to test Otis were used. No patients in this study experienced any significant abdominal pain, nausea, vomiting, or bleeding post the study.

Discussion Traditionally, all patients are required to fast overnight or at least eat no solid food for 6 hours and no liquids for 4 hours before an endoscopic procedure, especially before an upper gastrointestinal endoscopic procedure. See, for example, Faigel et al. (2003) Gastrointest. Endosc. 57:446-450. In order to avoid aspiration, this is a valid precaution that should continue to be practiced. However, this traditional practice makes the ERCP procedure more difficult to perform. As a result of fasting, the patient's sphincter of Oddi is closed tightly, and bile secretion into the duodenal lumen is much less than that of a postprandial state, especially less than after a fatty meal (Weisbrodt (2001) Gastrointestinal Physiology (6th ed.; Mosby, New York)). To the inventor's knowledge, this is the first report of administration of a liquid fatty meal to facilitate cannulation at ERCP.

In some patients, the orifice of the CBD/PD can't be identified easily. Blind cannulation of the major papilla may achieve successful cannulation in experienced hands. However, this may not be true for all cases. Prolonged blind cannulation may cause edema, trauma, bleeding at the major papilla, and possible spasm of the sphincter of Oddi and may result in more morbidity to the patient. The fatty meal made the orifice of the CBD/PD much easier to identify and, therefore, avoided blind cannulation and made the procedure more efficient in those patients. hi the control group, the cannulation time varied greatly. About 25% of deep CBD cannulation took longer than 20 minutes to complete. In the study group, less than 5% of deep CBD cannulation took longer than 20 minutes to complete. This observation provides more evidence that the liquid fatty meal facilitates the deep CBD cannulation at ERCP in those difficult cases.

Radiation exposure during ERCP is always a concern for patients and ERCP staff (Heyd et al. (1996) Gastrointest. Endosc. 44:287-292; Cohen et al. (1997) Surg. Endosc. 11:615-617; Larkin et al. (2001) Gastrointest. Endosc. 53:161-164; BuIs et al. (2002) Br. J. Radiol. 75:435-443; and Tsalafoutas et al. (2003) Rad. Protect. Dosimetry 106:241-246). The radiation doses of the patient and ERCP staff depend mostly on FT. See Heyd et al. (1996), supra. The liquid fatty meal decreased FT by 2.8 minutes on average in each ERCP procedure. The radiation dose of one-minute of fluoroscopy is approximately 15 mGy at skin entrance (Bushberg (2002) Essential Physics of Medical Images (2nd ed.; Lippincott Williams & Wilkins, Philadelphia, PA)). As a comparison, the radiation dose of a typical chest x-ray (including posterior-anterior and lateral) is 0.4 to 0.5 mGy at skin entrance (Bushberg (2002), supra.). In other words, reduction of 2.8 minutes of FT in each ERCP is equal to reducing the radiation dose by an amount equivalent to 84 to 105 chest x-rays. For a physician who performs 10 ERCPs a month, the liquid fatty meal reduces FT by approximately 336 minutes for the physician as well as the associated staff in one year. This is equal to the radiation dose of 11250 to 12600 chest x-rays. Although the ERCP staff wears protection during the procedure, this amount of radiation dose can't be ignored.

The mechanism underlying this observation is likely related to stimulation of CCK secretion (Figure 2). Among different fats, long-chain triglyceride (LCT) is the most potent stimulator of CCK secretion in the human body. See Hopman et al.

(19M) Am. J. Clin. Nutr. 39:356359; Isaacs et al. (1987) Digest. Dis. άc Sci. 32:481- 486; Mclaughlin et al. (1999) Gastroenterol. 116:46-53; and Jonkers et al. (2000) Digest. Dis. & ScL 45:1719-1726. The liquid fatty meal used in this study contained 100% LCT. See, for example, USDA. Search the USDA national nutrient database for standard reference at http://www.nal.usda. gov/fnic/foodcomp/search. CCK increases gallbladder contraction and bile excretion into the lumen of the duodenum and relaxes the tone of the sphincter of Oddi (Walsh (1987) in Physiology of the Gastrointestinal Tract, ed. Johnson (Raven Press, New York)). However, one study showed that CCK had no effect on cannulation at ERCP when CCK was administered intravenously during the procedure (Thompson et al. (1986) Endoscopy 18:251). Apparently, fat ingestion can result in a more complicated physiological process in the body than that of a simple application of exogenous CCK. See Weisbrodt (2001) Gastrointestinal Physiology (6th ed.; Mosby, New York).

The liquid fatty meal had no effect on the successful CBD cannulation rate of ERCP in this study. In some cases, the patient's intestinal anatomy prevented the endoscopy being placed at the right position for cannulation. The liquid fatty meal could not solve the anatomical problem. Therefore, it may be a true phenomenon that the liquid fatty meal had no effect on CBD cannulation failure rate. On the other hand, it may be possible that the number of patients in this study is relatively too small to see the difference in cannulation failure rate.

The possibility of this observation occurring by chance is very small, if not zero. First, theoretically, fat is the most potent natural stimulator for bile secretion and relaxation of the sphincter of Oddi. See Weisbrodt (2001) Gastrointestinal Physiology (6th ed.; Mosby, New York); and Walsh (1987) in Physiology of the Gastrointestinal Tract, ed. Johnson (Raven Press, New York). Secondly, this was a randomized, double-blinded study that basically avoids all bias from the study staff. When designing this study, an additional group was considered for use as another control. This group would have no meal before the procedure. However, this might be difficult for a double-blind study. When a patient does not drink a meal before the procedure, the study personnel would know. Therefore, before this study, a comparison between the non-fat meal and no meal was made in an open, non-blinded way. A non-fat meal slightly decreased the deep CBD cannulation time when compared to that of no meal. Therefore, the order from easiest cannulation to the most difficult cannulation group should be: the fatty meal group, the non-fat meal group, and the no meal group.

Pancreatitis is a major complication of ERCP (Freeman (2003) Gastrointestinal Endoscopy Clinics of North America 13:775-789. By decreasing the cannulation time, the fatty meal may decrease this complication. However, to confirm this, a much larger study is needed.

Based on this study, the liquid fatty meal is an inexpensive, readily available, natural substance for patients to have, and safe when used before ERCP. Although most ERCP procedures are not difficult to perform, some cases may be so. There is no way to predict the degree of difficulty of cannulation in advance of an ERCP procedure. Therefore, a liquid fatty meal should be routinely administered before an ERCP procedure to decrease cannulation time and radiation exposure.

Example 2: Topical Administration of Magnesium Sulfate Prior to ERCP A randomized double-blinded study was performed. In this study, 1.6 grams of magnesium sulfate in 10 ml normal saline or the same volume of normal saline was directly applied to the major papilla when the endoscope was ready for cannulation. The cannulation times, as defined below, were recorded for each patient. All patients referred for ERCP over a ten-month period were evaluated for eligibility. Eligible patients signed a written consent for the study. Exclusion criteria were as described above in Example 1, and the study profile is shown in Figure 3.

The following terminology is used herein: 1) initial CBD (ICBD) cannulation time: the time from the initiation of cannulation to the time of obtaining an initial cholangiogram; 2) deep CBD (DCBD) cannulation time: the time from the initiation of cannulation to the time when the catheter was deep inside the CBD, whereby, therapeutic interventions could be performed, hi some cases, ICBD and DCBD cannulation times may be the same. Magnesium sulfate greatly facilitated DCBD cannulation in ERCP by significantly decreasing the DCBD time (Table 2). Both the ICBD and DCBD cannulation times in the study group were shorter than those in the control group, but statistically the difference between the ICBD cannulation times was not significant. Possibly the effect of topical administration of magnesium sulfate was delayed, and only became appreciable several minutes or longer after administration.

There were no statistical differences among the ICBD and DCBD cannulation rates between the magnesium group and the control group (data not shown). Also, there were no effects on PD cannulation (data not shown).

Table 2. Effect of Magnesium Sulfate on CBD Cannulation Time

Group Initial cannulation time Deep cannulation time

(Minutes, M+SD) (Minutes, M+SD)

Magnesium 9.16+5.6 15.61+7.79 Control 12.59+12.51 34.15+17.88

P value >0.05 <0.05

The degree of difficulty/success of DCBD cannulation can be classified in three categories: 1) failure to achieve DCBD cannulation, in which cannulation was attempted for longer than 1 hour without successful DCBD cannulation; 2) difficulty achieving DCBD cannualtion, where DCBD cannulation was achieved after attempting 30 minutes or longer; and 3) ease/relative ease in DCBD cannulation, where DCBD cannulation was achieved within 30 minutes. Magnesium sulfate had no effect on category number 1, but significantly improved the cannulation time in category number 2 (Table 3).

Table 3. Effect of Magnesium Sulfate on Deep CBD Cannulation

Degree of difficulty Magnesium (T= 18)# Control (T=21) * P value#

N (%) N (%) Failed cannulation

(1 to 2 hours) 4 (22) 5 (24)

>0.05

Difficult cannulation (>30 minutes) 0 (0) 7 (33)

<0.05

Easy/ Relatively easy cannulation (<30 minutes) 14 (78) 9 (43) <0.05

* T, total number of patients who had attempted deep CBD cannulation.

# P value: comparison percentage between magnesium and control groups.

The variation of the CBD cannulation times in the control group was large.

The initial CBD cannulation time varies from 0.5 minutes to 53 minutes, and the deep CBD cannulation time varies from 2 minutes to 68.5 minutes. Potentially CBD cannulation in ERCP in a subset of patients may be very easy; in another it may be extremely difficult. In a subset of patients with difficult CBD cannulation, magnesium sulfate facilitates DCBD cannulation. If patients with difficult (lengthy) cannulation could be identified pre-procedure, then the use of magnesium sulfate to facilitate the cannulation would be a novel way to aid the procedure by shortening the procedure time. In the subset of patients with relatively easy cannulation, use of magnesium sulfate may be not necessary. However, there is no way to predict the degree of difficulty of cannulation in advance. Magnesium sulfate is inexpensive and safe. Therefore, based on this study, magnesium sulfate should be routinely used in ERCP to facilitate CBD cannulation. Example 3: Effect of Magnesium Sulfate Administration on

Human Gallbladder Contraction

A double-blinded study was performed to identify the maximal effect of magnesium sulfate on human gallbladder contraction. The physician who performed the ultrasound examination was blinded to the study. Six healthy volunteers were studied. Each volunteer participated in the study for two days. On day one, patients were given magnesium sulfate; on the second day, patients were administered normal saline. Both days, each volunteer had 5 abdominal ultrasound examinations after overnight fasting. One ultrasound examination was performed immediately before drinking 3 grams of magnesium sulfate in 8 oz. of saline or an equivalent volume of normal saline alone, and then additional ultrasounds were performed 30 minutes, 1 hour, 2 hours and 4 hours after magnesium sulfate administration. The method for calculation of gallbladder volume was adopted from others. See Paulezki, et al. (1996) J. Clin. Ultrasound. 24:277-285; and Hashimoto et al. (1999) Am. J. Gastroenterol. 94:3492-3496. The mean gallbladder volumes were calculated at each time, and comparisons were made between magnesium sulfate and normal saline. The data showed that magnesium sulfate significantly reduced the gallbladder volume, and the maximal effect appeared at 1 to 2 hours (Table 4).

Table 4. Comparison Between the Mean Pre-meal Volume and Mean Post-meal Volume in the Magnesium Sulfate Group

Figure imgf000024_0001

The results of the ultrasound study provided information regarding when and how much magnesium sulfate should be administered to facilitate cannulation of the CBD/PD in ERCP. The effect of magnesium sulfate on human gallbladder contraction and on cannulation in ERCP should be related to each other. Thus, it is reasonable to use the results from this ultrasound study as a guide for performing additional studies using magnesium sulfate to facilitate cannulation in ERCP. Furthermore, studies investigating the effect of higher doses of magnesium sulfate (e.g., 5 grams) on human gallbladder contraction are underway.

Example 4: Oral Administration of Magnesium Sulfate Prior to ERCP General Description of the Study

A randomized, double-blinded study is performed. Patients enrolled in this study are randomly distributed into either one of the study groups or one of the control groups. Magnesium sulfate or saline is prepared by a pharmacologist, the only person not blinded to the study. Three grams of magnesium sulfate is used as the optimal dosage for this study, based on data from the previous ultrasound study. 1 to 2 hours is used as the optimal time for administration of magnesium sulfate, again, based on the ultrasound study, which showed that the maximal effect of magnesium sulfate on human gallbladder contraction occurred 1 to 2 hours after it was given. Four groups of patients are in the study:

Group 1 : oral administration of 3 grams of magnesium sulfate (in 4 oz of normal saline) 1 to 2 hours before the procedure;

Group 2: topical application of 3 grams of magnesium sulfate (in 10 ml of normal saline) directly to the major papilla; Group 3: oral administration of 4 oz. of normal saline 1 to 2 hours before the procedure;

Group 4: topical application of 10 ml of normal saline directly to the major papilla.

Patient Selection

Patients are selected based on the criteria described herein above in Example 1. All enrolled patients are asked to sign an informed, written consent before ERCP. Patients are randomly divided into a study group or a control group.

ERCP Procedure

A study nurse is present in the ERCP room for the entire procedure. The study nurse records all parameters outlined in Table 5. Table 5. ERCP Recording Sheet

Patient information (please stamp this sheet using the patient's hospital card)

Procedure Date: Attending Physician:

Fellow:

Time of drinking of magnesium sulfate or normal saline: Time of intubation (procedure starting time):

Time of attempting cannulation: X-ray time: Time of achieved PD cannulation: X-ray time:

Time of achieved ICBD cannulation: X-ray time:

Time of achieved DCBD cannulation: X-ray time:

Procedure completed time: X-ray time:

Total procedure time: Total X-ray time:

Please attach an ERCP report with this sheet and file together in the office.

The study is performed at a medical school where fellows are trained, hi order not to interfere with the fellows' training and, at the same time, allow the study to be performed, a fellow is permitted to start the procedure and have 10 minutes to achieve cannulation. If deep CBD cannulation is not achieved in 10 minutes, an attending physician takes over and continues the cannulation.

In this study, the x-ray time used during cannulation is measured. The minutes of x-ray used during the procedure are displayed by the x-ray machine and are then recorded.

Complications and Follow Up

Pancreatitis is the major complication of ERCP. Abdominal pain is the main symptom of pancreatitis, whereas diarrhea is the major complication of magnesium sulfate. These two symptoms, abdominal pain and diarrhea, are recorded for all patients in this study up to three days post ERCP.

The study staff follow-up on all participating patients for three days after the procedure, since most of the immediate complications will occur shortly after the procedure. Statistical Considerations

The main parameters in the study are the cannulation times and the number of successful cannulations in each group. In addition, the amount of x-ray used in different groups is compared. In the previous study (Example 2), a significant difference in the deep CBD cannulation times between the topical magnesium sulfate group and the control group was observed. The difference in deep CBD cannulation times in the two groups was almost 20 minutes. 25 patients in each group should be sufficient for carrying out statistical analysis. 100 total patients are used in this study.

Example 5: Reduced Procedure Costs Resulting From Oral Administration of Liquid Fatty Meal Prior to ERCP

A study of 160 patients undergoing ERCP was performed essentially as described in Example 1. The necessity of using a guide wire and additional catheters to achieve cannulation was determined. Using guide wires and additional catheters increases the cost of ERCP, as the cost of each is approximately $120.

A guide wire was required in 2 out of the 81 patients receiving the fatty meal in order to achieve cannulation. hi contrast, at least one guide wire and/or more than one catheter were required to achieve successful cannulation in 19 out of the 79 patients in the control group (i.e., no fatty meal). These data suggest that costs associated with performing ERCP can be reduced by administration of the liquid fatty meal prior to the procedure.

Example 6: Administration of Magnesium Sulfate or Long-Chain Triglycerides

Prior to EGD for Diagnosis of Micro lithasis Patients with non-ulcer dyspepsia (NUD) referred for esophagogastroduodenoscopy (EGD) are enrolled in this study and are randomized into three groups to assess the use of magnesium sulfate and long-chain triglycerides in facilitating diagnosis of microlithasis as an etiology for NUD. The treatment groups are outlined in Table 6. Table 6: Study Groups for Administration of Magnesium Sulfate or Long-Chain Triglycerides Prior to EGD for Diagnosis of Microlithasis

Figure imgf000028_0001

Patient Selection

A total of 300 patients are selected for the study from patients (18 to 80 years of age) that present with NUD for EGD examination. 100 patients are randomly assigned to each treatment group. Patients with a known allergy to magnesium sulfate and those who have active diarrhea are not eligible to participate.

Administration of Treatment

The magnesium sulfate, long-chain triglycerides, and saline are prepared by a study nurse and administered to the patient as described above. EGD is then performed in accordance with standard procedures known in the medical arts. When the scope is in the duodenum, bile aspiration is performed.

Bile Measurements and Analysis

The collected bile volume is measured and compared among each group of patients. The bile is further examined under polarized microscopy for crystals (microlithasis). Data collection occurs as the procedure progresses or as soon as possible after the procedure is completed.

Follow-up

Study staff follow-up with participating patients daily for two days after the procedure. Any complications, particularly self-limited diarrhea, are recorded.

Statistical Analysis Data from the study is analyzed in accordance with accepted statistical methods known in the art.

Example 7: Administration of Magnesium Sulfate or Long-Chain Triglycerides

For Treatment of Cholestasis

Patients on total parenteral nutrition (TPN) that have been diagnosed with cholestasis are selected for this study and are randomized into four treatment groups to assess the therapeutic effect of magnesium sulfate on cholestasis. The treatment groups are described in Table 7.

Table 7: Study Groups for Administration of Magnesium Sulfate or Long-Chain Triglycerides For Treatment of Cholestasis

Figure imgf000029_0001

Patient Selection

A total of 100 TPN patients between the ages of 18 and 80 that suffer from cholestatis are selected for the study Diagnosis of cholestasis is confirmed before enrollment in the study by a process such as, for example, reviewing the patient's baseline liver tests (e.g., serum total bilirubin and alkaline phosphatase levels) and imaging studies (e.g., abdominal CT scan and ultrasound). 25 patients are randomly assigned to each treatment group. Patients who have a known allergy to magnesium sulfate, have active diarrhea, have abdominal surgery within one week of the study, or have a bowel obstruction are not eligible to participate. Administration of Treatment and Measurement of Liver Function

The magnesium sulfate, long-chain triglycerides, and water are prepared by a study nurse and administered to the patient orally or by tube feeding as described above. Liver function is assessed daily by measuring serum total bilirubin and alkaline phosphatase levels. Results of liver function tests before, during, and after the study are compared. Abdominal ultrasounds are performed on each patient before and immediately after the study to assess any stones or sludge in the gallbladder, as well as other changes resulting from the treatments.

The duration of the study is 4 weeks. If a patient's liver function is not improving after receiving 3 doses of magnesium sulfate, the study on that patient is ended. If a patient's liver function normalizes any time before the end of the 4-week study, the study on the patient is also ended.

Follow-up Study staff follow-up with participating patients daily for two days after the study. Any complications are recorded.

Statistical Analysis

Data from the study is analyzed in accordance with accepted statistical methods known in the art.

Claims

THAT WHICH IS CLAIMED:
1. A method for diagnosing a gastrointestinal disorder in a patient using a gastrointestinal procedure, said method comprising administering to said patient at least one agent that is selected from the group consisting of fats, fatty acids, long- chain triglycerides, oils, and magnesium sulfate.
2. The method of claim 1, wherein said gastrointestinal procedure is selected from the group consisting of endoscopic ultrasound (EUS), magnetic resonance imaging (MRI), magnetic resonance cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography (ERCP), endoscopic examination of pancreatic function, HIDA scan, esophagogastroduodenoscopy (EGD), and computerized axial tomography (CT scan).
3. The method of claim 2, wherein said gastrointestinal procedure is magnetic resonance imaging (MRI) or magnetic resonance cholangiopancreatography (MRCP).
4. The method of claim 3, wherein administration of said agent improves the quality of images of the gastrointestinal system of said patient obtained during the gastrointestinal procedure, and thereby facilitates diagnosis of said gastrointestinal disorder.
5. The method of claim 1, wherein said gastrointestinal disorder is selected from the group consisting of pancreatic divisum, chronic pancreatitis, bile duct stone, bile duct cancer, bile duct stricture, bile duct leak, pancreatic cancer, any cancer with liver metastasis, and microlithasis.
6. A method for facilitating cannulation of the common bile duct or the pancreatic duct of a patient during a gastrointestinal procedure, said method comprising administering to said patient at least one agent that is selected from the group consisting of fats, fatty acids, long-chain triglycerides, oils, and magnesium sulfate.
7. The method of claim 6, wherein said gastrointestinal procedure is endoscopic retrograde cholangiopancreatography (ERCP).
8. The method according to any one of claims 1-7, wherein said agent comprises magnesium sulfate.
9. The method according to any one of claims 1-7, wherein said agent comprises at least one fat.
10. The method of claim 9, wherein said fat comprises a long-chain triglyceride.
11. The method according to any one of claims 1-7, wherein said agent comprises at least one oil.
12. The method of claim 11, wherein said oil comprises corn oil.
13. The method according to any one of claims 8-12, wherein said agent is mixed with a beverage.
14. The method according to any one of claims 8-12, wherein said agent is mixed with saline.
15. The method according to any one of claims 9-121, wherein said agent is prepared as a fatty liquid meal.
16. The method according to any one of claims 1-7, wherein said agent is administered orally.
17. The method of claim 16, wherein said agent comprises about 1 gram to about 10 grams of magnesium sulfate.
18. The method of claim 16, wherein said agent comprises about 5 grams to about 100 grams of corn oil.
19. The method according to any one of claims 1-7, wherein said agent is administered by tube feeding.
20. The method of claim 6, wherein said agent is administered by topical application to the major papilla.
21. The method according to any one of claims 1-7, wherein said agent is administered about thirty minutes before the gastrointestinal procedure.
22. The method according to any one of claims 1-7, wherein said agent is administered at about fifteen minutes to about 4 hours before the gastrointestinal procedure.
23. The method according to any one of claims 1-7, wherein said agent promotes relaxation of the sphincter of Oddi.
24. The method according to any one of claims 1-7, wherein said agent promotes increased bile secretion in said patient.
25. The method according to any one of claims 1-7, wherein said agent promotes increased pancreatic juice secretion in said patient.
26. The method of claim 6, wherein said method facilitates cannulation of the common bile duct.
27. The method of claim 26, wherein said method facilitates deep cannulation of the common bile duct.
28. The method of claim 6, wherein said method facilitates cannulation of the pancreatic duct.
29. The method of claim 6, wherein said method facilitates cannulation of the minor papilla in duodenum of said patient.
30. The method of claim 6, wherein facilitating cannulation comprises reducing cannulation time.
31. The method of claim 6, wherein facilitating cannulation comprises reducing cannulation failure rates.
32. The method of claim 6, wherein said method further facilitates collection of bile from said patient during said gastrointestinal procedure.
33. The method of claim 32, wherein said gastrointestinal procedure is selected from the group consisting of endoscopic retrograde cholangiopancreatography (ERCP) and esophagogastroduodenoscopy (EGD).
34. The method of claim 6, wherein said gastrointestinal procedure is used for diagnosis of pancreatic divisum, cholestasis, microlithiasis, cholelithiasis, choledocholithiasis, bile duct obstruction, bile duct stricture, bile duct leak, pancreatic cancer, chronic pancreatitis, biliary cancer, any cancers with liver metastasis, or sphincter of Oddi dysfunction.
35. The method of claim 6, wherein said gastrointestinal procedure is used for treatment of pancreatic divisum, cholestasis, microlithiasis, cholelithiasis, choledocholithiasis, bile duct obstruction, bile duct stricture, bile duct leak, pancreatic cancer, chronic pancreatitis, biliary cancer, any cancers with liver metastasis, or sphincter of Oddi dysfunction.
36. The method according to any one of claims 1-3, wherein said method permits improved visualization of the pancreas of said patient during said gastrointestinal procedure.
37. A method of treating a patient for cholestasis, said method comprising administering to said patient a therapeutically effective amount of at least one agent that is selected from the group consisting of fats, fatty acids, long-chain triglycerides, oils, and magnesium sulfate.
38. The method of claim 37, wherein said cholestasis is induced by total parenteral nutrition (TPN).
39. The method of claim 37, wherein said agent comprises magnesium sulfate or corn oil.
40. The method of claim 37, wherein said agent is administered orally or by tube feeding.
41. The method of claim of claim 37, wherein said therapeutically effective amount of said agent comprises about 1 gram to about 10 grams of magnesium sulfate.
42. The method of claim 37, wherein said therapeutically effective amount of said agent comprises about 5 grams to about 100 grams of corn oil.
43. The method of claim 37, wherein said agent is administered to said patient daily.
44. A method for diagnosing a gastrointestinal disorder in a patient using a gastrointestinal procedure, said method comprising administering to said patient at least one agent that stimulates cholescystokinin (CCK) secretion.
45. The method of claim 44, wherein said gastrointestinal procedure is selected from the group consisting of endoscopic ultrasound (EUS), magnetic resonance imaging (MRI), magnetic resonance cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography (ERCP), endoscopic examination of pancreatic function, HIDA scan, esophagogastroduodenoscopy (EGD), and computerized axial tomography (CT scan).
46. The method of claim 44, wherein said gastrointestinal disorder is selected from the group consisting of pancreatic divisum, chronic pancreatitis, bile duct stone, bile duct cancer, bile duct stricture, bile duct leak, pancreatic cancer, any cancer with liver metastasis, and microlithasis.
47. A method for facilitating cannulation of the common bile duct or the pancreatic duct of a patient during a gastrointestinal procedure, said method comprising administering to said patient at least one agent that stimulates cholescystokinin (CCK) secretion.
48. The method of claim 47, wherein said gastrointestinal procedure is endoscopic retrograde cholangiopancreatography (ERCP).
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012076723A1 (en) * 2010-12-10 2012-06-14 Mosaiques Diagnostics And Therapeutics Ag Method and marker for the diagnosis of a bile duct stricture and of a cholangiocellular carcinoma in bile
US10035009B2 (en) 2013-04-15 2018-07-31 The Board Of Trustees Of The Leland Stanford Junior University Systems and methods for treating pancreatic cancer

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012076723A1 (en) * 2010-12-10 2012-06-14 Mosaiques Diagnostics And Therapeutics Ag Method and marker for the diagnosis of a bile duct stricture and of a cholangiocellular carcinoma in bile
US10035009B2 (en) 2013-04-15 2018-07-31 The Board Of Trustees Of The Leland Stanford Junior University Systems and methods for treating pancreatic cancer

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