JP2003516946A - Compositions for improving the proliferative response during gastrointestinal adaptation and use in short bowel syndrome - Google Patents

Abstract

  (57) [Summary] A method for treating short bowel syndrome in a patient in need thereof, comprising administering to the patient an effective amount of a formulation containing arachidonic acid and docosahexaenoic acid.

Description

Detailed Description of the Invention

TECHNICAL FIELD The present invention relates to methods for treating patients with short bowel syndrome and formulations containing long chain polyunsaturated fatty acids (PUFAs) useful in such methods.

BACKGROUND OF THE INVENTION Short bowel syndrome is a term used to describe the condition of malabsorption of nutrients after extensive surgical resection of the small intestine (Vanderhoof, J.A.
JA), Gastroenterology, 113 (5): 1767-78 (1997)).
The extent to which malabsorption occurs depends not only on the quantitative amount of absorbed tissue removed from the small intestine, but also on the particular portion of the small intestine removed. For example, removal of the distal portion of the ileum may have worse consequences than removal of the proximal intestine because removal of the ileocecal valve allows for more free communication between the remaining small intestine and the large intestine. It seems unlikely that there would be a significant effect on the low capacity of the gastrointestinal flora to ferment complex carbohydrates, but the loss of a distinct microenvironment impairs the distinct absorption properties of the two domains (Nordgarakidonic. Acid Ludo, IH (Nordgarachidonic acidrd, IH) et al.
Scandinavian Journal of Gastroenterology
Journal of Gastroenterology), 30 (9): 897-904 (1995)).

After surgical resection of the small intestine, the remaining tissue undergoes a rapid proliferative response of resorbed surface area. The same factors associated with malabsorption are associated with the extent of proliferative response after excision, ie the extent and location of removed tissue. However, the proliferative response is also affected by the supply of enteral nutrition.

Numerous nutrients have been evaluated in an attempt to maximize the proliferative response after excision of the small intestine. Diets rich in growth hormones and glutamine and high-carbohydrate-low-fat diets have all been studied (eg, Byrne, TP, et al., Annals of Surgery, 222 (3): 254-5 (1995); Scolapio, JS, et al., Gastroenterology.
nterology), 113 (4): 1402-5 (1997); Sax, H., Journal ・
Of Parental and Entrepreneurial Nutrition (Journal of Pa
renteral and Enteral Nutrition), 26 (2): 123-8 (1998)). Formulas containing amino acids have been studied in an attempt to avoid hypersensitivity and digestion of intact proteins (Bines, JF et al., Journal.
Journal of Pediatric Gastroenterology & Nutrition, 26 (2): 123-8 (1998))
. Dietary restrictions on insoluble fiber, oxalate and lactose have also been proposed (Lykins, TS, et al., Journal of the American.
Journal of the American Dietetic Asso
Ciation), 98 (3): 309-15 (1998), evidence that small amounts of lactose are tolerated (Marteau, PM, et al., Nutrition, 13 (1): 1.
3-16 (1997))).

[0005] Fat digestion and absorption is particularly problematic when short bowel syndrome occurs in infancy, because fat digestive capacity is limited in the early stages of development (eg Heinemann, ED). (Heineman, ED) et al., Journal of Pediatric Surgery, 31 (4): 520-5 (1996). The use of medium chain triglycerides has been proposed as a means of bypassing the need to package fat into triglycerides in intestinal epithelial cells and relieving stress on fat absorption (Goulet, O., European. Journal of Medical Research (European Journal of Medical Research), 2 (2): 79-83 (
1997)). At the same time, the supply of essential fatty acids to patients with short bowel syndrome is an important nutritional objective.

It has been postulated that certain fatty acids may enhance residual gastrointestinal hyperplasia.
For example, Kollman, KA, et al., Journal of Pediatric Gastroenterol Nutrition (Journal of Pediatri).
C Gastroenterol Nutrition), 28: 41-5 (1999) systematically varied the origin of the fats and oils used to make up the four meals. Each diet was fixed to give 30% of calories from fat. Each diet provided 10% of the fat as soybean oil sufficient to meet the essential amino acid requirements. The rest of the fat was hydrogenated coconut oil, docosahexaenoic acid, which is an n-3 series long-chain polyunsaturated fatty acid having 22 carbon atoms, and arachidonic acid, which is an n-6 series long-chain fatty acid having 20 carbon atoms. 0 for a processing group
% Arachidonic acid and docosahexaenoic acid; one group ate 5% arachidonic acid and 3.3% docosahexaenoic acid; another group 15
% Arachidonic acid and 10% docosahexaenoic acid; the fourth group received 45% arachidonic acid and 30% docosahexaenoic acid. In this experiment, 80% of the intestine was removed from each animal. Two types of diet (without arachidonic acid and docosahexaenoic acid, but with a high content of safflower oil,
Additional experiments with 45% arachidonic acid and 30% docosahexaenoic acid) investigated the extent of excision. Excision range is 60%, 70%
Or 80%. In 80% excised animals, very high levels of arachidonic acid / docosahexaenoic acid resulted in less growth of the remaining duodenal DNA than was observed without arachidonic acid / docosahexaenoic acid, so diet-dependent growth There was a response. Measurements of mucosal mass, protein and sucrase activity were unchanged in the duodenum. In marked contrast, a diet high in arachidonic acid / docosahexaenoic acid resulted in significantly higher mucosal mass and protein in the ileum than a diet without arachidonic acid / docosahexaenoic acid. Also,
The difference did not reach statistical significance, but there was clearly more DNA when using a diet high in arachidonic acid / docosahexaenoic acid. These results indicate that certain arachidonic acid / docosahexaenoic acid-rich diets may have certain benefits.

When the extent of excision was studied for animals fed one of two extreme diets, a measure of response was found between animals fed safflower oil but with different excisions. There was no difference. However, in animals fed a high arachidonic acid / docosahexaenoic acid diet, there was a gradual response to duodenal DNA and sucrase activity, and ileal mucosal, DNA and protein. In each case, the proliferative response was greatest among the most resected animals.

These results show that to the extent that the rest of the intestinal growth is higher than with safflower oil,
Compared to comparable resected rats fed a diet increased by arachidonic acid + docosahexaenoic acid and containing 10% soybean oil or a small amount of PUFA (3.3% docosahexaenoic acid and 5% arachidonic acid). Arachidonic acid / docosahexaenoic acid supplementation may be most useful if not only was there a significantly enhanced mucosal volume when rats were given large amounts of PUFA, but also when the extent of intestinal resection was maximal It shows that there is a nature.

DISCLOSURE OF THE INVENTION The present invention is a method of treating short bowel syndrome in a patient in need thereof, comprising administering to this patient an effective amount of a formulation containing arachidonic acid and docosahexaenoic acid. Regarding the method. Furthermore, the present invention relates to formulations suitable for use in such methods.

The present invention relates to a method for treating short bowel syndrome by administering to a patient with short bowel syndrome a formulation containing arachidonic acid and docosahexaenoic acid. In the formulation of the present invention, the amount of arachidonic acid may be at least the same as or more than the amount of docosahexaenoic acid. Preferably, the amount of arachidonic acid to docosahexaenoic acid is in the range 2: 1 to 1: 1 and more preferably in the ratio 1.5: 1. The beverages of the invention preferably contain docosahexaenoic acid at least 1.5% by weight, more preferably at least 2.2% by weight, advantageously at least 3.32% by weight, calculated on the total fatty acid content of the beverage. Contained in the amount of. This amount is preferably 12%, calculated on the total fatty acid content of the beverage. The beverages of the invention preferably contain arachidonic acid at least 1.5% by weight, more preferably at least 3.32% by weight, advantageously at least 4.44% by weight, calculated on the total fatty acid content of the beverage. Contained in the amount of. This amount is preferably 18%, calculated on the total fatty acid content of the beverage.

The formulations of the present invention have been found to be particularly useful in the treatment of short bowel syndrome. The above proportions of arachidonic acid and docosahexaenoic acid still apply in formulations for treating infants with short bowel syndrome.

The present invention is not limited to a particular formulation, as long as it contains the appropriate amounts of arachidonic acid and docosahexaenoic acid. However, in its preferred form, the formulation of the present invention is a total nutritional beverage consisting of proteins, carbohydrates, vitamins and minerals, containing a specific blend of vegetable oils suitable to achieve a particular fatty acid pattern. The formulations of the present invention may be formulated as liquids or as powders intended to be reconstituted with a suitable amount of water before consumption. In this embodiment, the invention is formulated so that it can provide a need for total nutrition for infants with short bowel syndrome. Infancy and short bowel syndrome independently impose severe dietary requirements on the individual, but until now, as mentioned above, appropriate nutritional interventions to simultaneously satisfy the needs of infant and short bowel syndrome. Did not exist.

The fatty acids useful in the formulations of the present invention, arachidonic acid and docosahexaenoic acid, may preferably be prepared in the form of single cell oil. The level of docosahexaenoic acid in the formula of the present invention is the level of docosahexaenoic acid (total intake 3 g / day) (21 CFR184.XX) which the US Food and Drug Administration has declared to be generally accepted as safe for the general public. It may be the same or more.
However, the intended use of the formulas of the present invention is in the treatment of short bowel syndrome, so the restrictions associated with general food supply are not relevant as a safety concern. Treatment of short bowel syndrome has certain advantages of formulas, such as weight gain, a more rapid transition to complete enteral nutrition and a reduced incidence of lactic acidosis, but the risk of not using formula and physiologically active fatty acids. Requests that consideration should be given to theoretical concerns about.

As stated above, a preferred embodiment of the present invention is a nutritionally complete infant formula suitable for use in the method of the present invention for treating infant and child short bowel syndrome. Such a formula contains proteins, carbohydrates, lipids, and effective amounts of arachidonic acid and docosahexaenoic acid according to the present invention.

The term “infant formula” can be easily recognized by a person skilled in the art. When initially concentrated or in powder form, when diluted or reconstituted as is, a typical infant formula has about 60-110 grams / liter carbohydrate, 10-35 grams / liter protein, And 20 ~
Contains 50 grams / liter of lipid, as well as vitamins, minerals, fibers and emulsifiers. To such infant formula, suitable amounts of arachidonic acid and docosahexaenoic acid can be added according to the present invention.

An example of a suitable commercially available infant formula to which arachidonic acid and docosahexaenoic acid may be added is S-26 available from Wyeth Nutritionals International Inc. , S-26LBW and SMA infant formula.

Preferably, the formulas useful in the present invention do not contain lactose as a carbohydrate, but rather maltodextrin, as is typically the case with standard infant formulas. Maltodextrin may also be used with alternative forms of polymerized glucose (including starch) conventionally used in infant formulas, such as tapioca starch. In addition, some of the carbohydrates, as much as 20%, may be in the form of sucrose, which improves the taste of the formulation. This use of carbohydrates allows the formula to be consumed orally over a longer period after excision. However, the amount of carbohydrates contained in the final formulation to avoid excessive metabolic production of D-lactic acid must be carefully considered by the intestinal bacterium.

[0018]   The invention will now be illustrated with reference to the following specific examples. (Example)   Formulation examples of the infant formula suitable for use in the present invention are shown below.

[0019]   Formula A   Ingredient gram%   Water 48.5 82.5   Maltodextrin 7.1 10.6   Sodium and calcium caseinate 1.6 2.4   Whey Protein Concentrate 2.6 3.9   Vegetable oil 6.0 9.0   Minerals 0.25 0.37   Vitamins 0.02 0.03                                             66.0 100

The calorie distribution of Formula A is about 28.4% CHO; about 16.8% protein.
And fat about 54.8%; about 150 kcal / 100 cc.

Listed below are various fat blends that may be used to optimize the supply of high amounts of arachidonic acid and docosahexaenoic acid required for the formulations of the present invention. Fat blend 1
~ 3 contains various concentrations of arachidonic acid and docosahexaenoic acid in a formula that complies with the FDA's GRAS Declaration for Consumption of Docosahexaenoic Acid. These particular fat blends are best employed in the management of short bowel syndrome after a period of rapid growth in order to maintain the individual on a diet high in arachidonic acid / docosahexaenoic acid.

[0022]   Fat Blend # 1   Vegetable oil 92.5%   DHASCO (40% docosahexaenoic acid) 3.7 (1.5% docosahexa)                                                     (Enoic acid)   ARASCO (40% arachidonic acid) 3.8 (1.5% arachidonic acid)                                             100

This concentration of docosahexaenoic acid + arachidonic acid in a ratio of 1: 1 is 1666 k
Cal / d gives 3.0 g / d LCP.

[0024]   Fat Blend # 2   Vegetable oil 83.4%   DHASCO (40% docosahexaenoic acid) 8.3%   ARASCO (40% arachidonic acid) 8.3%                                             100

This level of 1: 1 ratio of DHASCO and ARASCO is 750 kc
Al / d gives 3.0 g / d LCP.

[0026]   Fat Blend # 3   Vegetable oil 83.4%   DHASCO (40% docosahexaenoic acid) 5.5%   ARASCO (40% arachidonic acid) 11.1%                                             100

This level of DHASCO and ARASCO is 3.0 at 750 kcal / d.
gives g / d LCP, but the ratio of arachidonic acid to docosahexaenoic acid is 2: 1
Is.

However, a preferred formulation for short bowel syndrome uses higher amounts of arachidonic acid and docosahexaenoic acid. In the preferred form of the invention, the level of arachidonic acid is 18% of fatty acids and the level of docosahexaenoic acid is 12% of fatty acids (Table 7).

[0029]   Fat blend # 4   10% vegetable oil   Hydrogenated palm oil 15%   DHASCO (40% docosahexaenoic acid) 30%   ARASCO (40% arachidonic acid) 45%                                             100

[0030]   The complete fatty acid composition of Fat Blend # 4 is shown below.   Fatty Acid Contribution to Preferred Fat Blends

[Table 1] Studies on the mechanism by which arachidonic acid and docosahexaenoic acid-rich diets enhance the proliferative response show that prostaglandin formation is important. Arachidonic acid metabolism may be studied by the use of agents that selectively block the pathway of arachidonic acid metabolism by inhibiting cyclooxygenase and lipoxygenase. In rats fed a diet that was excised and fat was provided primarily as arachidonic acid (45% of fatty acids) and docosahexaenoic acid (30% of fatty acids), the duodenal proliferative response was increased by treatment with inhibitors of lipoxygenase. did. The result of blocking this pathway of arachidonic acid metabolism is to increase the formation of prostaglandin products via the cyclooxygenase pathway. In the duodenum, mucosal mass, D
NA and protein content were increased respectively when compared to excised control rats.
In contrast, inhibition of cyclooxygenases (prostaglandins and pathways that produce, for example, thromboxane A ₂ ) results in altered mucosal mass, DNA, protein or sucrase activity compared to excised control rats. None (Table 1).

Table 1. Mucosal mass, DNA, protein and sucrase activity in rat duodenum Control-lipooxygenase-cyclooxygenase mucosal mass 108.0 + 2.5 125 + 3.6 107.0 + 4.4 (mg / cm) DNA 287.1 + 5.6 323.2 + 10.6 276.6 + 11.2 (mcg / cm) Tank 87.6 + 2.0 101.3 + 3.1 81.0 + 3.0 (mg / cm) Scraze 596.4 + 20.7 648.0 + 48.6 513.9 + 46.2 (μmol / cm ・ min)

Some similar results were observed in the ileum. Mucosal mass and protein content were actually reduced to a statistically significant extent by cyclooxygenase inhibitors (Table 2).

[0033]   Table 2. Mucosal mass, DNA, protein and sucrase activity in rat ileum                                     Processing                      Control-Lipooxygenase-Cyclooxygenase   Mucosal volume 95.9 + 3.6 105.0 + 4.2 73.9 + 4.4   (mg / cm)   DNA 252.0 + 9.7 257.1 + 15.7 223.8 + 16.2   (mcg / cm)   Tampa 65.9 + 2.1 69.5 + 3.3 55.4 + 3.5   (mg / cm)   Scraze 196.4 + 15.6 137.4 + 16.7 146.7 + 18.7   (μmol / cm ・ min)

A study completed by the present inventors with a series of dietary management of children with short bowel syndrome showed that a high-fat, low-carbohydrate, high-calorie enteral diet resulted in a more rapid withdrawal from total parenteral nutrition,
That is, it has been found that it allows a faster complete enteral nutritional supply and a lesser occurrence of bacterial overgrowth. Included in the study group were children who had traditionally been unable to tolerate a standard enteral nutritional supply consisting of amino acid or hydrolyzed protein formulas and showed improved weight gain after changing to a high fat formula. there were.

These data indicate that there is a biochemical link from experimental observations in rats to human short bowel syndrome. In fact, improved weight gain and decreased incidence of lactic acidosis in 5 individuals fed a high fat diet without AA or DHA may be explained by knowledge gained from rat mechanistic studies. If the proliferative response is dependent on prostaglandin formation via the cyclooxygenase pathway, then the clinical results would be entirely dependent on the proper use of high fat formulations containing high levels of the arachidonic acid precursor linoleic acid. The fat source used for the clinical response was essentially corn oil rich in linoleic acid.

Nevertheless, the formation of arachidonic acid from its precursor linoleic acid is rather inefficient compared to the dietary supply of arachidonic acid and the formation of gastrointestinal prostaglandins formed after feeding corn oil. There is no direct measurement of. The dependence of intestinal growth on prostaglandin production, shown in the rat data above, is
It is shown that the arachidonic acid-rich diet of the present invention is quantitatively superior to the conventional diet for short bowel syndrome.

The present invention may be embodied in other specific forms without departing from its spirit or essential attributes, and thus, as indicating the scope of the present invention, the above detailed description of the invention. Rather, reference should be made to the appended claims.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 43/00 112 A23L 2/00 F (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE, TR), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG) , KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP , KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, R O, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, UZ, VN, YU, ZA, ZW (72) Inventor Eric Lewis Lean United States 19355 Malvern, PA, USA Anthony Drive 1 (72) Inventor John Charles Wallingford 1167 F Term, Northam Road, Gladwin, Pennsylvania, USA 19035 4B017 LC03 LK09 LK13 4B018 LB08 MD10 MD11 MD36 ME14 4C076 AA11 BB01 CC16 CC40 DD66 FF15 FF16 4C206 AA01 AA02 DA05 MA02 MA04 MA05 MA72 NA14 ZA66 ZC12 ZC54

Claims (19)

[Claims] 1. A method of treating short bowel syndrome in a patient in need thereof, comprising administering to said patient an effective amount of a formulation containing arachidonic acid and docosahexaenoic acid. 2. The formulation comprises arachidonic acid and docosahexaenoic acid 2: 1.
The method according to claim 1, which is contained in a ratio of 1: 1. 3. The formulation comprises arachidonic acid and docosahexaenoic acid at 1.5.
The method according to claim 2, wherein the content is 1: 1. 4. The method of claim 1, wherein the formulation is a nutritionally complete beverage. 5. The method of claim 4, wherein the nutritionally complete beverage is infant formula. 6. A nutritionally complete beverage suitable for treating short bowel syndrome containing arachidonic acid and docosaexaenoic acid. 7. A nutritionally complete beverage according to claim 6, further comprising maltodextrin. 8. A nutritionally complete beverage according to claim 7, which is completely devoid of lactose. 9. The ratio of arachidonic acid to docosahexaenoic acid is from 2: 1 to 1: 1.
The nutritionally complete beverage of claim 6, which is 1. 10. The ratio of arachidonic acid to docosahexaenoic acid is 1.5: 1.
A nutritionally complete beverage according to claim 9. 11. A nutritionally complete beverage according to claim 6 which is an infant formula. 12. A method of treating short bowel syndrome in an infant, comprising administering to the infant an infant formula containing arachidonic acid and docosaexaenoic acid. 13. The method of claim 12, wherein the infant formula contains arachidonic acid and docosahexaenoic acid in a ratio of 2: 1 to 1: 1. 14. The method of claim 13, wherein the infant formula contains arachidonic acid and docosahexaenoic acid in a ratio of 1.5: 1. 15. The method of claim 12, wherein the supply of high levels of dietary arachidonic acid and docosahexaenoic acid regulates prostaglandin production and increases metabolites of the growth-promoting cyclooxygenase pathway. 16. The nutrition according to claim 6, wherein docosahexaenoic acid and arachidonic acid are each present in an amount of at least 1.5% by weight, calculated on the total fatty acid content of the beverage. A drink that is scientifically complete. 17. A nutritional claim according to claim 16 containing at least 2.2% by weight of docosahexaenoic acid and at least 3.32% by weight of arachidonic acid, the amount being calculated based on the total fatty acid content of the beverage. A complete beverage. 18. A nutritional claim according to claim 17 containing at least 3.32% by weight of docosahexaenoic acid and at least 4.44% by weight of arachidonic acid (the amount being calculated on the basis of the total fatty acid content of the beverage). A complete beverage. 19. A nutritionally complete beverage according to claim 17 containing at least 12% by weight docosahexaenoic acid and at least 18% by weight arachidonic acid, the amount being calculated based on the total fatty acid content of the beverage. .