WO1998036734A1 - A novel nutritional therapy which minimizes plasma cholecystokinin (cck) levels - Google Patents
A novel nutritional therapy which minimizes plasma cholecystokinin (cck) levels Download PDFInfo
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- WO1998036734A1 WO1998036734A1 PCT/US1998/002890 US9802890W WO9836734A1 WO 1998036734 A1 WO1998036734 A1 WO 1998036734A1 US 9802890 W US9802890 W US 9802890W WO 9836734 A1 WO9836734 A1 WO 9836734A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0029—Parenteral nutrition; Parenteral nutrition compositions as drug carriers
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/115—Fatty acids or derivatives thereof; Fats or oils
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/17—Amino acids, peptides or proteins
- A23L33/18—Peptides; Protein hydrolysates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/01—Hydrolysed proteins; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/01—Hydrolysed proteins; Derivatives thereof
- A61K38/012—Hydrolysed proteins; Derivatives thereof from animals
- A61K38/018—Hydrolysed proteins; Derivatives thereof from animals from milk
Definitions
- pancreatitis is a serious disease in terms of symptoms, social welfare, morbidity, complications, and mortality. It is a disease with no efficacious therapies.
- pancreatitis is defined by a series of clinical symptoms (e.g. abdominal pain), functional impairments (e.g. steatorrhea and diabetes mellitus) and morphological findings (chronic inflammatory lesions) (Sarles et al. Scand. J. Gastroenterol. 24:641-42,1989).
- clinical symptoms e.g. abdominal pain
- functional impairments e.g. steatorrhea and diabetes mellitus
- morphological findings chronic inflammatory lesions
- chronic pancreatitis is defined by a series of clinical, functional, and morphological signs. Many doctors consider the diagnosis of chronic pancreatitis established when there is recurrent or chronic upper abdominal pain in the setting of abnormal pancreatic ducts or abnormal pancreatic exocrine function.
- pancreatitis causes significant pain in approximately 50% of patients. The pain may decrease with time, but requires regular medication with analgesics, including opiates. Approximately 50% of the patients develop steatorrhea and diabetes mellitus. Pancreatic pseudocysts are a common complication affecting approximately 20% of the patients.
- pancreatic inflammation and scarring affects nerves, the other that intraductal and intraparenchymal pancreatic pressure is increased (Madsen and Winkler Scand. J. Gastroenterol. 17:553-54, 1982; Ebbehoj et al. Scand. J. Gastroenterol. 25:1099-102, 1990).
- CCK Cholecystokinin
- CCK levels rise in the brain and produce the feeling of satiety.
- CCK levels are elevated in some patients suffering from chronic pancreatitis. Ingestion of food stimulates CCK release in the duodenum and by stimulation of the exocrine pancreas, exacerbates the inflammation and hence the pain of chronic pancreatitis. This is a rationale for (i) minimizing ingestion of food during "flares" of chronic pancreatitis, and (ii) periodically admitting patients to the hospital during severe flares for complete bowel rest or for hyperalimentation.
- an oral nutritional support which minimally increases plasma CCK levels should be effective in treating patients with chronic pancreatitis (as well as other disease states which show increased CCK plasma levels).
- an object of the invention is to control plasma cholecystokinin
- CCK CCK levels in a subject by administering to the gastrointestinal tract of the subject an emulsion which includes mixed length polypeptides and a medium chain triglyceride.
- Another object of the invention is to provide nutritional support to a subject by administering to the gastrointestinal tract of the subject an emulsion which includes mixed length polypeptides and a medium chain triglyceride, such that CCK plasma levels are stabilized.
- Another object of the invention is to provide a method of maintaining or repleting a nutritional status of a subject suffering from chronic pancreatitis by administering to the gastrointestinal tract of the subject an emulsion which includes mixed length polypeptides and a medium chain triglyceride, such that CCK plasma levels are stabilized.
- Another object of the invention is to provide a method of promoting weight gain in a subject without feeling of satiety by administering to the gastrointestinal tract of the subject an emulsion which includes mixed length polypeptides and a medium chain triglyceride, such that CCK plasma levels are stabilized.
- a still further object of the invention is to provide a method of treating pain in a subject suffering from chronic pancreatitis by administering to the gastrointestinal tract of the subject an emulsion which includes mixed length polypeptides and a medium chain triglyceride, such that CCK plasma levels are stabilized.
- the present invention features a method of controlling plasma cholecystokinin
- the method includes administering to the gastrointestinal tract of the subject an emulsion which includes mixed length polypeptides and a medium chain triglyceride.
- the emulsion which can be used in the method of the invention is Peptamen®.
- the nutritional status of the subject is maintained or repleted.
- the method of the invention is particularly useful for subjects who are suffering from chronic pancreatitis or anorexia caused by any condition, including anorexia nervosa.
- the method of the invention is used to stabilize CCK plasma levels.
- the CCK plasma levels are maintained in the range between about 0.5 pM and about 5.0 pM, more preferably between about 1.0 pM and about 3.5 pM, most preferably, between about 1.0 pM and about 2.5 pM.
- the mixed length polypeptides are in the form of a protein hydrolysate.
- the protein hydrolysate is preferably partially hydrolyzed in nature and includes a substantial fraction of variable chain length peptides, e.g., medium or short chain peptides, e.g., di- and tri-peptides, but has less than about 15% free amino acids, more preferably less than about 10% free amino acids.
- only the highest biological value proteins are hydrolyzed, e.g., whey, lactalbumin, casein, egg white, egg solids, soy, or delactosed milk solids.
- the protein source is lactose-free, and free amino acids are preferably avoided in the emulsion of the invention.
- the emulsion may also include a source of carbohydrates, for example a simple or complex carbohydrate, e.g., monosaccharides, disaccharides, or oligosaccharides. Corn starch is a preferred carbohydrate source.
- additives useful in the invention include a source of essential fatty acids, and vitamins and minerals.
- vitamins and minerals are added in accordance with, or approximately, the Recommended Dietary Allowance (RDA), now called the Reference Daily Intake (RDI).
- RDA Recommended Dietary Allowance
- RDI Reference Daily Intake
- the emulsion can also contain nutrients not recommended by the RDA, e.g., beta-carotene, carnitine, and taurine.
- the emulsion can also include an antioxidant.
- the emulsion may be administered orally or by tube administration.
- the invention features, a method of providing nutritional support to a subject.
- the method includes administering to the gastrointestinal tract of the subject an emulsion which includes mixed length polypeptides and a medium chain triglyceride.
- the emulsion provides the needed nutritional support while the CCK plasma levels are stabilized.
- the invention features methods of maintaining or repleting a nutritional status of a subject suffering from chronic pancreatitis or promoting weight gain in a subject without feeling of satiety. These methods include administering to the gastrointestinal tract of the subject an emulsion which includes mixed length polypeptides and a medium chain triglyceride, such that CCK plasma levels are stabilized.
- Treatment of pain in a subject suffering from chronic pancreatitis is also important.
- Figure 1 is a bar graph depicting differences in CCK plasma levels in six healthy individuals after feeding with Peptamen®, Ensure® or a 1/4 lb hamburger.
- Figure 2 is a graph depicting the CCK time course data (at 30, 60, 90, 120 and 180 minutes) after ingestion of one can of Peptamen®.
- Figure 3 is a bar graph depicting the effect of Peptamen® on the weight gain in mice with Cystic Fibrosis as compared to wild type mice on regular Purina mouse chow.
- the invention pertains to a method of controlling plasma CCK levels in a subject.
- the method includes administering to a subject an emulsion which includes mixed chain polypeptides and a medium chain triglyceride.
- the mixed chain polypeptides may be any suitable partially hydrolyzed protein or protein hydrolysate utilized in a nutritional formula such as soy protein hydrolysate, casein hydrolysate, whey protein hydrolysate, animal and vegetable protein hydrolysates, partially hydrolyzed whey, casein or soy proteins, and mixtures thereof.
- Soy or casein protein hydrolysates comprising a substantial proportion of variable chain length peptides, e.g., medium chain and short chain peptides, e.g., di- and tri-peptides, but having less than about 15% free amino acids, preferably less than about 10% free amino acids, are preferred.
- protein hydrolysate will have about 12% free amino acids.
- Mixed chain polypeptides can also be chemically synthesized using methods known in the art, e.g., conventional Merrifield solid phase f-Moc or t-Boc chemistry.
- the protein source should be lactose-free so it can be used for lactose intolerant patients.
- the biological value of the protein should be considered first, with the highest biological values being found in casein, whey, lactalbumin, egg albumin, and whole egg proteins.
- the cost should be considered, the lowest cost with the best biological value being the best combination.
- short chain peptides di- and tri- peptides
- free amino acids might be potential stimulators of the exocrine pancreas.
- mixtures of di- and tri- peptides and longer chain peptides are preferred, allowing for high biological proteins and maintaining a low cost.
- the medium chain triglycerides are primarily capric and caprylic acid residues.
- An MCT source is fractionated coconut oil which is a mixture of C6:0 (1 to 2%), C8:0 (65 to 75%), C10:0 (25 to 35%), and C12:0 (1 to 2%) medium-chain fatty acids (see, e.g., Bach and Babayan, Am. J. Clin. Nut.36:950-962, 1982).
- the source of carbohydrate may be any simple monosaccharides, disaccharides, oligosaccharides, or complex carbohydrates. Examples include fructose, maltodextrin, corn syrup and hydrolyzed corn starch.
- Carbohydrate sources which may be utilized in the emulsion of the invention include hydrolyzed or nonhydrolyzed starches. A corn starch is the preferred carbohydrate source in the emulsion.
- the antioxidant can be for example, alpha-tocopherol, tocopheryl acetate, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) or a mixture thereof.
- Particularly preferred antioxidants are alpha-tocopherol, tocopheryl acetate, ascorbic acid and ascorbyl palmitate.
- the source of essential fatty acids may comprise a mixture of safflower oil, and soy oil, or combinations that at least provide adequate amounts of essential fatty acids, e.g., linoleic or alpha linoleic acids (such as safflower oil or sunflower oil), as well as omega-3 or omega-9 fats.
- suitable fat sources include corn oil, coconut oil, sunflower oil, peanut oil, fish oil, canola oil and olive oil.
- safflower oil is preferred because it has the highest percentage of the essential fatty acid, linoleic acid. Three grams per liter of safflower oil has been shown to be nutritionally sufficient without any evidence of essential fatty acid deficiencies.
- Emulsifiers may be added for stability purposes to the emulsion, e.g., emulsifiers such as soybean phospholipids.
- Flavoring may also be added to the emulsion to make it more palatable. Flavoring can be in a form of flavored extracts, volatile oils, chocolate flavoring, peanut butter flavoring, cookie crumbs, vanilla or any commercially available flavoring.
- the emulsion may also contain a stabilizer such as ⁇ -carrageenan.
- ⁇ -carrageenan increases the viscosity of the formula without forming a gel structure, thus retarding the precipitation of insoluble calcium and phosphorous salts if included in the formula.
- Xanthan gum or other standard stabilizers may also be used as a stabilizer in the same fashion as ⁇ -carrageenan.
- the emulsion to be used in the methods of the invention is preferably provided in a ready-to-feed form, it may also be concentrated by increasing the percent total solids of the formula or made in powder form, both procedures being well known to those skilled in the art.
- the concentrate or powder are then reconstituted for feeding by adding water (tap or deionized-sterilized water).
- the emulsion may be used as a supplement or for total nutritional support.
- administering to the gastrointestinal tract of the subject refers to administration of the emulsion by tube-feeding or by having a subject drink the same.
- the caloric density of the emulsion is 1.0 kcal/ml.
- the term "subject,” refers to an individual suffering from a condition or a disorder in which it is beneficial to stabilize CCK levels after regular feedings.
- disorders include, but are not limited to, chronic pancreatitis and anorexia caused by any condition, including anorexia nervosa.
- CCK plasma levels are stabilized refers to maintaining CCK plasma levels in the range between about 0.5 pM and about 5.0 pM, more preferably between about 1.0 pM and about 3.5 pM, most preferably between about 1.0 pM and about 2.5 pM, after a feeding with the emulsion of the invention, e.g., Peptamen®.
- CCK plasma levels are stabilized if about 60 to 90 minutes after a feeding with the emulsion of the invention, the CCK plasma levels do not exceed about 3.5 pM, more preferably about 2.5 pM, and about 180 minutes after feeding CCK plasma levels return to a basal level, e.g., about 0.5 pM.
- Peptamen® Clintec Nutrition Company, Deerfield, Illinois.
- Peptamen® includes whey protein hydrolysate and MCT.
- the peptide distribution of Peptamen® is as follows:
- the nutrient composition of Peptamen® is as follows: NUTRIENT INFORMATION Serving Size One Can (500 mD
- VITAMIN D IU 100 25 400 100
- THIAMINE (B 1 ) mg 0.75 50 3 200 RIBOFLAVIN (B 2 ) mg 0.85 50 3.4 200 NIACIN mg 10 50 40 200
- Peptamen® minimally stimulates the exocrine pancreas as assessed by CCK levels. This demonstrates that Peptamen® is an important adjunct in the nutritional supplementation of patients with chronic pancreatitis.
- mice with the Cystic Fibrosis (CF) deleted gene were analyzed in mice with the Cystic Fibrosis (CF) deleted gene, as compared to age matched normal (wild type) mice on regular Purina mouse chow.
- the CF mice on average, weigh approximately 50% less than age matched wild type mice.
- the mice from both groups were fed ad lib.
- the mice were placed on their respective diets at 21 days of age (the standard time for weaning).
- the data ( Figure 3) is for 50 days on these respective diets, and it demonstrates that the weight gain in CF mice fed with Peptamen® is much greater (4.3 fold) compared to the weight gain in wild type mice fed with Purina mouse chow (2.2 fold).
- the data demonstrate that Peptamen® or an equivalent emulsion can maintain or replete a nutritional status of a subject.
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Abstract
A method of controlling plasma cholecystokinin (CCK) levels in a subject. The method includes administering to the gastrointestinal tract of the subject an emulsion which includes mixed length polypeptides and a medium chain triglyceride. This method is particularly useful for providing nutritional support to patients suffering from chronic pancreatitis or anorexia caused by any condition, including anorexia nervosa.
Description
A NOVEL NUTRITIONAL THERAPY WHICH MINIMIZES PLASMA CHOLECYSTOKININ (CCK) LEVELS
Background of the Invention
Chronic pancreatitis is a serious disease in terms of symptoms, social welfare, morbidity, complications, and mortality. It is a disease with no efficacious therapies.
No single, pathognomonic sign exists. Instead, chronic pancreatitis is defined by a series of clinical symptoms (e.g. abdominal pain), functional impairments (e.g. steatorrhea and diabetes mellitus) and morphological findings (chronic inflammatory lesions) (Sarles et al. Scand. J. Gastroenterol. 24:641-42,1989).
The true prevalence of the disease is not known, although estimates range from 0.04 to 5 percent. In the industrialized countries, alcohol consumption is the most important etiological factor, accounting for approximately two-thirds of all cases of chronic pancreatitis (Gyr et al. (eds) Pancreatitis, concepts and classification.
Amsterdam: Elsevier, 1984, pp:347-350; Sarles et al. Digestion 19:110-25, 1979). Smoking, diets high or low in fat and high in protein may also contribute to the development of the disease (Gyr et al. (eds) Pancreatitis, concepts and classification. Amsterdam: Elsevier, 1984, pp:347-350; Sarles et al. Digestion 19:110-25, 1979). The last third of chronic pancreatitis is classified as idiopathic with few cases caused by hyperparathyroidism or occurring in families (Gyr et al. (eds) Pancreatitis, concepts and classification. Amsterdam: Elsevier, 1984, pp:347-350; Sarles et al. Digestion 19:110- 25, 1979).
As mentioned above, chronic pancreatitis is defined by a series of clinical, functional, and morphological signs. Many doctors consider the diagnosis of chronic pancreatitis established when there is recurrent or chronic upper abdominal pain in the setting of abnormal pancreatic ducts or abnormal pancreatic exocrine function.
Chronic pancreatitis causes significant pain in approximately 50% of patients. The pain may decrease with time, but requires regular medication with analgesics, including opiates. Approximately 50% of the patients develop steatorrhea and diabetes mellitus. Pancreatic pseudocysts are a common complication affecting approximately 20% of the patients.
The pathogenesis of pain is uncertain. Pseudocysts may cause pain, but this complication is easily diagnosed and treated. Two main theories of the genuine pancreatic pain have been proposed. One is that the pancreatic inflammation and scarring affects nerves, the other that intraductal and intraparenchymal pancreatic
pressure is increased (Madsen and Winkler Scand. J. Gastroenterol. 17:553-54, 1982; Ebbehoj et al. Scand. J. Gastroenterol. 25:1099-102, 1990).
No curative treatment for chronic pancreatitis exists. Instead, treatment is aimed towards complications, such as pseudocysts and symptoms such as pain and steatorrhea. Treatment is often difficult, because of the complexity of the problems, involving not fully understood pathophysiology, poor compliance, and risk of addiction.
The international literature has presented many treatment regimens, which in selected series of patients seem effective, e.g., operative procedures for pain, pain reduction with enzyme substitution therapy, and improvement of steatorrhea by administration of pancreatic enzyme supplements.
To date, the management of flares has generally consisted of minimizing oral intake to "rest" the pancreas. This frequently leads to nutritional deficiencies in the setting of a catabolic state.
Thus, a need still exists to develop a nutritional therapy which minimally stimulates the exocrine pancreas, reduces the abdominal pain, and at the same time provides adequate nutritional support.
Cholecystokinin (CCK) is the principal hormone that stimulates the exocrine pancreas. In addition, following a meal, CCK levels rise in the brain and produce the feeling of satiety. CCK levels are elevated in some patients suffering from chronic pancreatitis. Ingestion of food stimulates CCK release in the duodenum and by stimulation of the exocrine pancreas, exacerbates the inflammation and hence the pain of chronic pancreatitis. This is a rationale for (i) minimizing ingestion of food during "flares" of chronic pancreatitis, and (ii) periodically admitting patients to the hospital during severe flares for complete bowel rest or for hyperalimentation. Thus, an oral nutritional support which minimally increases plasma CCK levels should be effective in treating patients with chronic pancreatitis (as well as other disease states which show increased CCK plasma levels). In addition, since case reports of antioxidant therapy have been shown to improve the pain of chronic pancreatitis, this approach may be of further benefit. Accordingly, an object of the invention is to control plasma cholecystokinin
(CCK) levels in a subject by administering to the gastrointestinal tract of the subject an emulsion which includes mixed length polypeptides and a medium chain triglyceride. Another object of the invention is to provide nutritional support to a subject by administering to the gastrointestinal tract of the subject an emulsion which includes mixed length polypeptides and a medium chain triglyceride, such that CCK plasma levels are stabilized.
Another object of the invention is to provide a method of maintaining or repleting a nutritional status of a subject suffering from chronic pancreatitis by administering to the gastrointestinal tract of the subject an emulsion which includes mixed length polypeptides and a medium chain triglyceride, such that CCK plasma levels are stabilized.
Another object of the invention is to provide a method of promoting weight gain in a subject without feeling of satiety by administering to the gastrointestinal tract of the subject an emulsion which includes mixed length polypeptides and a medium chain triglyceride, such that CCK plasma levels are stabilized. A still further object of the invention is to provide a method of treating pain in a subject suffering from chronic pancreatitis by administering to the gastrointestinal tract of the subject an emulsion which includes mixed length polypeptides and a medium chain triglyceride, such that CCK plasma levels are stabilized.
These and other objects and features of the invention will be apparent from the following description and from the claims.
Summary of the Invention
The present invention features a method of controlling plasma cholecystokinin
(CCK) levels in a subject. The method includes administering to the gastrointestinal tract of the subject an emulsion which includes mixed length polypeptides and a medium chain triglyceride. For example, the emulsion which can be used in the method of the invention is Peptamen®. In a preferred embodiment, the nutritional status of the subject is maintained or repleted. The method of the invention is particularly useful for subjects who are suffering from chronic pancreatitis or anorexia caused by any condition, including anorexia nervosa.
In a preferred embodiment, the method of the invention is used to stabilize CCK plasma levels. For example, the CCK plasma levels are maintained in the range between about 0.5 pM and about 5.0 pM, more preferably between about 1.0 pM and about 3.5 pM, most preferably, between about 1.0 pM and about 2.5 pM.
In another preferred embodiment, the mixed length polypeptides are in the form of a protein hydrolysate. The protein hydrolysate is preferably partially hydrolyzed in nature and includes a substantial fraction of variable chain length peptides, e.g., medium or short chain peptides, e.g., di- and tri-peptides, but has less than about 15% free amino acids, more preferably less than about 10% free amino acids. In a preferred
embodiment, only the highest biological value proteins are hydrolyzed, e.g., whey, lactalbumin, casein, egg white, egg solids, soy, or delactosed milk solids. In other preferred embodiments, the protein source is lactose-free, and free amino acids are preferably avoided in the emulsion of the invention. The emulsion may also include a source of carbohydrates, for example a simple or complex carbohydrate, e.g., monosaccharides, disaccharides, or oligosaccharides. Corn starch is a preferred carbohydrate source.
Other additives useful in the invention include a source of essential fatty acids, and vitamins and minerals. Preferably, vitamins and minerals are added in accordance with, or approximately, the Recommended Dietary Allowance (RDA), now called the Reference Daily Intake (RDI). The emulsion can also contain nutrients not recommended by the RDA, e.g., beta-carotene, carnitine, and taurine.
In addition to the components descried above, the emulsion can also include an antioxidant. The emulsion may be administered orally or by tube administration.
In another aspect, the invention features, a method of providing nutritional support to a subject. The method includes administering to the gastrointestinal tract of the subject an emulsion which includes mixed length polypeptides and a medium chain triglyceride. The emulsion provides the needed nutritional support while the CCK plasma levels are stabilized.
In yet another aspect, the invention features methods of maintaining or repleting a nutritional status of a subject suffering from chronic pancreatitis or promoting weight gain in a subject without feeling of satiety. These methods include administering to the gastrointestinal tract of the subject an emulsion which includes mixed length polypeptides and a medium chain triglyceride, such that CCK plasma levels are stabilized.
Treatment of pain in a subject suffering from chronic pancreatitis is also important.
The following description and non-limiting examples further elucidate the invention.
Brief Description of the Drawings
Figure 1 is a bar graph depicting differences in CCK plasma levels in six healthy individuals after feeding with Peptamen®, Ensure® or a 1/4 lb hamburger.
Figure 2 is a graph depicting the CCK time course data (at 30, 60, 90, 120 and 180 minutes) after ingestion of one can of Peptamen®.
Figure 3 is a bar graph depicting the effect of Peptamen® on the weight gain in mice with Cystic Fibrosis as compared to wild type mice on regular Purina mouse chow.
Detailed Description of the Invention
The invention pertains to a method of controlling plasma CCK levels in a subject. The method includes administering to a subject an emulsion which includes mixed chain polypeptides and a medium chain triglyceride.
The mixed chain polypeptides may be any suitable partially hydrolyzed protein or protein hydrolysate utilized in a nutritional formula such as soy protein hydrolysate, casein hydrolysate, whey protein hydrolysate, animal and vegetable protein hydrolysates, partially hydrolyzed whey, casein or soy proteins, and mixtures thereof. Soy or casein protein hydrolysates comprising a substantial proportion of variable chain length peptides, e.g., medium chain and short chain peptides, e.g., di- and tri-peptides, but having less than about 15% free amino acids, preferably less than about 10% free amino acids, are preferred. For example, protein hydrolysate will have about 12% free amino acids. Mixed chain polypeptides can also be chemically synthesized using methods known in the art, e.g., conventional Merrifield solid phase f-Moc or t-Boc chemistry. For greatest use, the protein source should be lactose-free so it can be used for lactose intolerant patients. When choosing a protein source, the biological value of the protein should be considered first, with the highest biological values being found in casein, whey, lactalbumin, egg albumin, and whole egg proteins. Next, the cost should be considered, the lowest cost with the best biological value being the best combination. There is evidence to suggest that short chain peptides (di- and tri- peptides) are preferentially absorbed. Furthermore, free amino acids might be potential stimulators of the exocrine
pancreas. Thus, mixtures of di- and tri- peptides and longer chain peptides are preferred, allowing for high biological proteins and maintaining a low cost.
The medium chain triglycerides (MCTs) are primarily capric and caprylic acid residues. An MCT source is fractionated coconut oil which is a mixture of C6:0 (1 to 2%), C8:0 (65 to 75%), C10:0 (25 to 35%), and C12:0 (1 to 2%) medium-chain fatty acids (see, e.g., Bach and Babayan, Am. J. Clin. Nut.36:950-962, 1982).
The source of carbohydrate may be any simple monosaccharides, disaccharides, oligosaccharides, or complex carbohydrates. Examples include fructose, maltodextrin, corn syrup and hydrolyzed corn starch. Carbohydrate sources which may be utilized in the emulsion of the invention include hydrolyzed or nonhydrolyzed starches. A corn starch is the preferred carbohydrate source in the emulsion.
The antioxidant, can be for example, alpha-tocopherol, tocopheryl acetate, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) or a mixture thereof. Particularly preferred antioxidants are alpha-tocopherol, tocopheryl acetate, ascorbic acid and ascorbyl palmitate.
The source of essential fatty acids may comprise a mixture of safflower oil, and soy oil, or combinations that at least provide adequate amounts of essential fatty acids, e.g., linoleic or alpha linoleic acids (such as safflower oil or sunflower oil), as well as omega-3 or omega-9 fats. Examples of other suitable fat sources include corn oil, coconut oil, sunflower oil, peanut oil, fish oil, canola oil and olive oil. However, the use of safflower oil is preferred because it has the highest percentage of the essential fatty acid, linoleic acid. Three grams per liter of safflower oil has been shown to be nutritionally sufficient without any evidence of essential fatty acid deficiencies.
Emulsifiers may be added for stability purposes to the emulsion, e.g., emulsifiers such as soybean phospholipids.
Flavoring may also be added to the emulsion to make it more palatable. Flavoring can be in a form of flavored extracts, volatile oils, chocolate flavoring, peanut butter flavoring, cookie crumbs, vanilla or any commercially available flavoring.
The emulsion may also contain a stabilizer such as λ-carrageenan. λ- carrageenan increases the viscosity of the formula without forming a gel structure, thus retarding the precipitation of insoluble calcium and phosphorous salts if included in the formula. Xanthan gum or other standard stabilizers may also be used as a stabilizer in the same fashion as λ-carrageenan.
While the emulsion to be used in the methods of the invention is preferably provided in a ready-to-feed form, it may also be concentrated by increasing the percent total solids of the formula or made in powder form, both procedures being well known
to those skilled in the art. The concentrate or powder are then reconstituted for feeding by adding water (tap or deionized-sterilized water). The emulsion may be used as a supplement or for total nutritional support.
Certain terms used herein are described below for clarity.
As used herein, the phrase "administering to the gastrointestinal tract of the subject," refers to administration of the emulsion by tube-feeding or by having a subject drink the same. Preferably, the caloric density of the emulsion is 1.0 kcal/ml.
As used herein, the term "subject," refers to an individual suffering from a condition or a disorder in which it is beneficial to stabilize CCK levels after regular feedings. Examples of such disorders include, but are not limited to, chronic pancreatitis and anorexia caused by any condition, including anorexia nervosa.
As used herein, the phrase "CCK plasma levels are stabilized," refers to maintaining CCK plasma levels in the range between about 0.5 pM and about 5.0 pM, more preferably between about 1.0 pM and about 3.5 pM, most preferably between about 1.0 pM and about 2.5 pM, after a feeding with the emulsion of the invention, e.g., Peptamen®. For example, CCK plasma levels are stabilized if about 60 to 90 minutes after a feeding with the emulsion of the invention, the CCK plasma levels do not exceed about 3.5 pM, more preferably about 2.5 pM, and about 180 minutes after feeding CCK plasma levels return to a basal level, e.g., about 0.5 pM.
Example 1
An example of an emulsion that can be used in the methods of the invention is Peptamen®, Clintec Nutrition Company, Deerfield, Illinois. Peptamen® includes whey protein hydrolysate and MCT. The peptide distribution of Peptamen® is as follows:
Average peptide size: 8 amino acid residues
The nutrient composition of Peptamen® is as follows:
NUTRIENT INFORMATION Serving Size One Can (500 mD
NUTRIENT PER 500 ml PER 2000 ml
COMPOSITION AMOUNT %U.S. RDA AMOUNT %U.S. RDA CALORIES kcal 500 ** 2000 ** PROTEIN 20.0 44 80 178 CARBOHYDRATE 63.5 ** 254 ** FAT* 8 19.5 ** 78 **
Vitamin Composition VITAMIN A IU 1875 37 7500 150
VITAMIN D IU 100 25 400 100
VITAMIN E IU 10 33 40 133
VITAMIN K meg 62.5 ** 250 **
VITAMIN C mg 50 83 200 333
THIAMINE (B1) mg 0.75 50 3 200 RIBOFLAVIN (B2) mg 0.85 50 3.4 200 NIACIN mg 10 50 40 200
VITAMIN B6 mg 1.5 75 6 300
FOLIC ACID meg 200 50 800 200
PANTOTHENIC ACID mg 5 50 20 200
VITAMIN Bp meg 3 50 12 200
BIOTIN meg 150 50 600 200
CHOLINE mg 225 ** 900 **
Example 2
The effect of Peptamen® on plasma CCK levels was analyzed in six normal healthy volunteers and compared to 1/4 lb hamburger (a maximal stimulus to the pancreas) as well as Ensure®, a standard enteral feed containing similar calories but in the form of non-hydrolyzed proteins and long chain triglycerides. Following an overnight fast for at least ten hours, on three consecutive days, baseline blood was drawn for measurements of basal CCK levels and individuals then given either one can of Peptamen® over two minutes, a 1/4 lb hamburger, or one can of Ensure. Phlebotomy was repeated one hour later to determine peak CCK levels. CCK concentration was determined by bioassay following extraction of CCK from plasma with a C18 Sep-pak. A dose response curve was then established using rat pancreatic acini with known
concentrations of CCK-8 and CCK concentration subsequently determined in the samples (Figure 1).
Mean basal CCK levels were 0.46 pM + 0.29. This increased to 10.75 pM + 0.45 one hour following ingestion of hamburger. Ensure produced a similar increase in CCK levels with a mean of 7.9 pM + 1.25. In contrast, the CCK concentration following Peptamen® ingestion was 1.43 pM ± 0.72 and was statistically different from the other two feeds (p< 0.0001).
A time course was performed with measurement of CCK levels at 30, 60, 90, 120 and 180 minutes post ingestion of one can of Peptamen® (Figure 2). This demonstrated a peak between 60 and 90 minutes.
Peptamen® minimally stimulates the exocrine pancreas as assessed by CCK levels. This demonstrates that Peptamen® is an important adjunct in the nutritional supplementation of patients with chronic pancreatitis.
Example 3
The effect of Peptamen® on the weight gain was analyzed in mice with the Cystic Fibrosis (CF) deleted gene, as compared to age matched normal (wild type) mice on regular Purina mouse chow. The CF mice, on average, weigh approximately 50% less than age matched wild type mice. The mice from both groups were fed ad lib. The mice were placed on their respective diets at 21 days of age (the standard time for weaning). The data (Figure 3) is for 50 days on these respective diets, and it demonstrates that the weight gain in CF mice fed with Peptamen® is much greater (4.3 fold) compared to the weight gain in wild type mice fed with Purina mouse chow (2.2 fold). Thus, the data demonstrate that Peptamen® or an equivalent emulsion can maintain or replete a nutritional status of a subject.
The foregoing examples are purely illustrative and are not intended to be the limitation of the invention. Those skilled in the art can determine other modifications on the diabetic supplement bar used herein. Such modifications are included within the following claims.
What is claimed is:
Claims
1. A method of controlling plasma cholecystokinin (CCK) levels in a subject comprising administering to the gastrointestinal tract of said subject an emulsion, said emulsion comprising mixed length polypeptides and a medium chain triglyceride.
2. The method of claim 1, wherein said mixed length polypeptides comprise a protein hydrolysate.
3. The method of claim 2, wherein said protein hydrolysate is selected from the group consisting of enzymatically hydrolyzed whey, lactalbumin, casein, egg white, egg solids, soy, and delactosed milk solids.
4. The method of claim 2, wherein said protein hydrolysate comprises less than about 15% of free amino acids.
5. The method of claim 1, wherein said emulsion further comprises a carbohydrate.
6. The method of claim 5, wherein said carbohydrate is selected from the group consisting of corn starch, dextrose and glucose.
7. The method of claim 1, wherein said emulsion further comprises a source of essential fatty acids.
8. The method of claim 1 , wherein said emulsion further comprises an antioxidant.
9. The method of claim 1, wherein said emulsion further comprises an emulsifier.
10. The method of claim 1 , wherein said emulsion further comprises a source of vitamins and minerals.
11. The method of claim 1 , wherein said administration to the gastrointestinal tract includes oral or tube administration.
12. The method of claim 1, wherein said CCK plasma levels are stabilized. - i l ¬
ls. The method of claim 1, wherein said subject is suffering from chronic pancreatitis or anorexia nervosa.
14. The method of claim 1 , wherein nutritional status of said subject is maintained or repleted.
15. The methods of claim 1, wherein said emulsion is Peptamen®.
16. A method of providing nutritional support to a subject comprising administering to the gastrointestinal tract of said subject an emulsion, said emulsion comprising mixed length polypeptides and a medium chain triglyceride, wherein CCK plasma levels are stabilized.
17. A method of maintaining or repleting a nutritional status of a subject suffering from chronic pancreatitis comprising administering to the gastrointestinal tract of said subject an emulsion, said emulsion comprising mixed length polypeptides and a medium chain triglyceride, wherein CCK plasma levels are stabilized.
18. A method of promoting weight gain in a subject without feeling of satiety, comprising administering to the gastrointestinal tract of said subject an emulsion, said emulsion comprising mixed length polypeptides and a medium chain triglyceride, wherein CCK plasma levels are stabilized.
19. A method of treating pain in a subject suffering from chronic pancreatitits, comprising administering to the gastrointestinal tract of said subject an emulsion, said emulsion comprising mixed length polypeptides and a medium chain triglyceride, wherein CCK plasma levels are stabilized.
20. The method of claim 19, wherein said emulsion further comprises an antioxidant.
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AU62793/98A AU6279398A (en) | 1997-02-21 | 1998-02-11 | A novel nutritional therapy which minimizes plasma cholecystokinin (cck) levels |
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US80400597A | 1997-02-21 | 1997-02-21 | |
US08/804,005 | 1997-02-21 |
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WO (1) | WO1998036734A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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EP1112006A2 (en) * | 1998-05-01 | 2001-07-04 | Abbott Laboratories | Elemental enteral nutritional product containing hydrolysed soy protein and partially hydrolysed caseinate |
WO2005042012A1 (en) * | 2003-10-29 | 2005-05-12 | Altus Pharmaceuticals Inc. | Non-pancreatic proteases for controlling plasma cholecystokinin (cck) concentration and for treating pain |
WO2007004878A2 (en) * | 2005-07-01 | 2007-01-11 | N.V. Nutricia | Infant nutrition with hydrolised proteins |
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Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1112006A2 (en) * | 1998-05-01 | 2001-07-04 | Abbott Laboratories | Elemental enteral nutritional product containing hydrolysed soy protein and partially hydrolysed caseinate |
WO2005042012A1 (en) * | 2003-10-29 | 2005-05-12 | Altus Pharmaceuticals Inc. | Non-pancreatic proteases for controlling plasma cholecystokinin (cck) concentration and for treating pain |
US7459155B2 (en) | 2003-10-29 | 2008-12-02 | Altus Pharmaceuticals Inc. | Treating abdominal pain due to pancreatitis with seaprose |
WO2007004878A2 (en) * | 2005-07-01 | 2007-01-11 | N.V. Nutricia | Infant nutrition with hydrolised proteins |
WO2007004878A3 (en) * | 2005-07-01 | 2007-03-29 | Nutricia Nv | Infant nutrition with hydrolised proteins |
US20090203592A1 (en) * | 2005-07-01 | 2009-08-13 | N.V. Nutricia | Infant nutrition with hydrolised proteins |
AU2006266546B2 (en) * | 2005-07-01 | 2012-01-12 | N.V. Nutricia | Infant nutrition with hydrolised proteins |
CN102894371A (en) * | 2005-07-01 | 2013-01-30 | 努特里希亚公司 | Infant nutrition with hydrolised proteins |
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