Inhibition of neonatal hyperbilirubinemia in breast fed infants

Details Inhibition of neonatal hyperbilirubinemia in breast fed infants Inhibition of neonatal hyperbilirubinemia in breast fed infants

2001-09-28

2003-09-30

Spear, James M. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Food or edible as carrier for pharmaceutical

C424S400000, C424S489000, C426S072000, C426S074000, C426S656000, C426S801000

Reexamination Certificate

active

06627213

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to methods useful in reducing serum bilirubin and thus the incidence and severity of infant jaundice. More particularly, it relates to the use of casein (or a salt thereof such as sodium caseinate), whey, and/or certain hydrolyzed casein formulations to supplement, while not interfering with, breast feeding.
Pediatricians recommend breast feeding as the most preferred way to feed most human neonates. However, breast feeding has been associated with increased levels of neonatal jaundice. Neonatal jaundice is mostly likely to occur during the first month (especially the first week) after a baby has been born.
Bilirubin is a red bile pigment formed during the catabolism of certain compounds such as hemoglobin. Human infants produce more bilirubin per unit of body weight than do adults because of greater red blood cell mass and shorter red blood cell life span. Bilirubin is poorly soluble in water and requires conjugation for excretion from the body.
Bilirubin is conjugated with glucuronic acid within the endoplasmic reticulum of the hepatocyte. Bilirubin conjugates in the intestine can act as a substrate for either bacterial or endogenous tissue &bgr;-glucuronidase. This enzyme hydrolyzes glucuronic acid from bilirubin glucuronide. The resulting unconjugated bilirubin produced is more rapidly absorbed from the intestine. This intestinal absorption of free bilirubin results in increased serum bilirubin levels in some neonates, which has been associated with infant jaundice.
There have been suggestions that adding aspartic acid and/or malic acid to the diet is a possible therapy for neonatal jaundice, due to inhibition of &bgr;-glucuronidase. See our laboratory's PCT publication WO 01/13743. The disclosure of this publication and of all other publications referred to herein are incorporated by reference as if fully set forth herein. While including exogenous aspartic and/or malic acid in a breast feeding baby's diet reduces the incidence of infant jaundice, it is desirable to further optimize the inhibition and treatment of such jaundice.
It is known that infants fed certain complex infant formulas having carbohydrates, fats, vitamins, sodium caseinate, and/or casein hydrolysate have lower levels of infant jaundice. See G. Gourley, et al., 103 Gastroenterology 660-667 (1992); G. Gourley, et al., 25 J. Ped. Gast. & Nutr. 267-272 (1997); and G. Gourley, 44 Advances in Pediatrics 173-229, Chapter 6 (1997). However, because many infant formulas are designed as complete substitutes for breast feeding, they can interfere with the willingness of a baby to breast feed. Thus, a mother will likely lose the benefits of breast feeding when the jaundice problem arises if a standard infant formula solution is prescribed.
While cow milk also contains casein and whey, and has been fed to some infants, any attempt to substitute cow milk for human breast milk for a neonate would have similar adverse implications for restarting breast feeding. Moreover, there are also other concerns regarding the use of cow milk by very young neonates.
Thus, it can be seen that a need exists for the development of improved infant supplements which are effective in avoiding and reducing the severity of infant jaundice, and yet do not significantly interfere with breast feeding.
SUMMARY OF THE INVENTION
The present invention provides methods of administering a dietary supplement to a human infant. One administers to the human infant on a given day human breast milk, and on that same day administers to the human infant a supplement which is essentially free of carbohydrate (and preferably also essentially free of fat) comprising an additive selected from the group consisting of casein, salts of casein, whey, and a hydrolysate of casein.
In preferred forms the infant is less than one month old (even more preferably less than two weeks old) at the time of the administration. The supplement can be provided before the infant exhibits symptoms of jaundice (as a prophylactic), or it can be provided as a therapeutic treatment to reduce bilirubin levels. The most preferred additive is a sodium caseinate/whey mixture.
In another aspect the invention provides a method of reducing serum bilirubin levels in a human infant. One administers to the human infant on a given day human breast milk, and on that same day administers to the human infant a supplement which is essentially free of carbohydrate (and preferably also essentially free of fat) comprising an additive selected from the group consisting of casein, salts of casein, whey, and a hydrolysate of casein. Using this method, the serum bilirubin level of the infant is reduced.
Another form of the invention provides a supplement dose for use on a single day with a breast feeding baby. The supplement dose is essentially free of carbohydrate and less than 50 ml (preferably 30 ml or less) in volume. The dose contains between 0.1 gm and 10 gm of a material selected from the group consisting of casein, salts of casein (such as sodium caseinate), whey, and casein hydrolysates, and a liquid carrier. The liquid carrier can be water, or an aqueous solution containing appropriate ions such as potassium and sodium, or in another suitable liquid.
Yet another form of the invention provides a supplement dose for use on a single day with a breast feeding human baby. The supplement dose is dry and essentially free of carbohydrate, and contains between 0.1 gm and 10 gm of a material selected from the group consisting of casein, salts of casein, whey, and casein hydrolysates. The supplement dose is packaged with instructions for mixing at least a portion of the dose in breast milk.
The present invention provides supplement doses of the above kind which are effective in reducing the incidence and severity of infant jaundice (yet are small enough to avoid interfering with breast feeding), supplement doses of the above kind which help reduce serum bilirubin levels, and methods for using such doses.
These and still other advantages of the present invention will be apparent from the description which follows. The following description is merely of the preferred embodiments. The claims should therefore be looked to in order to understand the full scope of the invention.


REFERENCES:
patent: 4753926 (1988-06-01), Lucas et al.
patent: 5068184 (1991-11-01), Knuth et al.
patent: 5212235 (1993-05-01), Nestaas et al.
patent: 059775 (1982-09-01), None
patent: WO 94/14458 (1994-07-01), None
patent: WO 01/13743 (2001-03-01), None
Pp. 6, 7, 9, 10, 896, 897, 1008 and 1009 of the 1989 publication Deutsche Forschunganstalt Fur Lebensmittelschemie (ED.): Food Compositions and Nutrition Tables, Wissenschaftliche Verlagsgesellschaft MBH Stuttgart XP000213764 (in English).
G. Eisenbrand et al. (ED.): “Rompp Lexikon Lembensmittelchemie” 1995, Georg Thieme Verlag, Stuttgard, New York XP002153765 p. 10 and translation.
I. Matsuda et al., “Effects Of Aspartic Acid And Orotic Acid Upon Serum Bilirubin Level In Newborn Infants”, 90 Tohoku J. Exp. Med. 133-136 (1966) and e-mail communication of May 11, 2000 with author.
A. Saito et al., “The Effect Of Aspartic Acid On . . . Bilirubin”, 27 Shohni-ka-Shinryo 124-128 (1964) and partial crude translation.
D. Gray et al., “Effects Of Aspartic Acid, Orotic Acid, And Glucose On Serum Bilirubin Concentrations In Infants Born Before Term”, 46 Arch. Dis. Child. 123-124 (1971).
G. Gourley, et al., “The Effect Of Diet Of Feces And Jaundice During The First 3 Weeks Of Life”, 103 Gastroenterology 660-667 (1992).
G. Gourley, et al., “Inhibition Of Beta-Glucuronidase By Casein Hydrolysate Formula”, 25 J. Ped. Gast. & Nutr. 267-272 (1997).
G. Gourley, “Bilirubin Metabolism And Kernicterus”, 44 Advances in Pediatrics 173-229, Chapter 6 (1997).
G. Gourley et al., “Neonatal Jaundice And Diet”, 153 Arch Pediatr Adolesc. 184-188 (1999).
S. Vaisman et al. Pharmacologic Treatment Of Neonatal Hyperbilirubinemia, Clinics In Perinatology, Symposium On Drug Therapy In the Neonate, vol. 2, No. 1, 37-57 (1975).
V. Hurgoiu et al., Aspartofortul

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