Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Food or edible as carrier for pharmaceutical
Reexamination Certificate
2001-11-01
2003-01-07
Dees, José G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Food or edible as carrier for pharmaceutical
C424S400000, C514S002600
Reexamination Certificate
active
06503530
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention provides a method of avoiding rapid development of extreme hyperammonemia and metabolic acidosis in undiagnosed metabolically abnormal infants having an inherited metabolic disorder.
Inborn errors of metabolism occur when there is a block in a pathway in a metabolic sequence. The block results in a rapid accumulation of normal intermediary products in abnormally large amounts and also of products of usually little used metabolic pathways. This biochemical abnormality is when characterized by hyperammonemia and/or ketoacidosis in neonatal-onset metabolic disorder. Restricting the intake of the essential substance from which the toxic metabolite is derived can treat the accumulated toxic effects of these intermediary metabolites. This minimizes the accumulation of intermediates that damage organs, particularly the nervous system, and affects the extent of mental retardation.
Conventional management of infants diagnosed with certain inborn errors of amino acid or nitrogen metabolism requires the restriction of the specific amino acid(s) to the minimum amount required for normal growth and development. The amount of the restricted amino acid provided by the diet must be sufficient to meet the metabolic requirements dependent on it, but it must not permit an excess accumulation in the body fluids of the amino acid or its derivatives, or of nitrogen.
However, until the infant has been diagnosed with a metabolic disorder by newborn screening, or unless the infant is suspected of having such a disease due to a previously affected sibling, the early stage of the disease is often overlooked. During this period, referred to as the asymptomatic period, sometimes the accumulation of metabolites is extremely fast and extensive and the underlying metabolic deterioration rapidly progresses toward an abrupt onset of “intoxication-like” clinical distress. As a result the severity of metabolic insult at the discovery of disorder is often too advanced for adequate management and results in serious permanent damage of central nervous system and mental retardation.
General clinical presentation of acute metabolic disorder is essentially similar despite biochemical differences. Infantile type acute hyperammonemia and metabolic acidosis due to inborn errors of metabolism usually develop within a week of life, sometimes two to three days after birth. The infant, almost always, the product of a full-term normal pregnancy with no known prenatal or perinatal risk factors, and normal labor and delivery, appears to be normal for at least 24 hours. The onset of the illness within the first few days after birth is often fulminant with lethargy, hypotonia, vomiting, hypothermia, and hyperventilation. Without timely intervention, the infant progresses rapidly to coma and early death.
Conventional treatment of metabolic diseases caused by inborn errors of metabolism typically includes some form of dietary management, usually by consumption of a formula composed of the minimum amount essential for normal growth of one or more amino acids believed to be the basis of the disease
FDA regulations specify minimum and, in some cases, maximum nutrient level requirements for infant formulas, based on recommendations by the American Academy of Pediatrics Committee on Nutrition. Human milk has long been recognized as the feeding standard for term infant feeding. Human milk comprises between about 1.3 to about 1.6 g protein per 100 kcal milk having 20 kcal/oz. Protein concentrations as low as 1.1 g protein per 100 ml of formula having 20 kcal/oz. (or 1.6 g protein per 100 kcal of formula) have provided normal growth and serum indicators of protein nutritional status. See Picone et al;
J. Pediatr Gastroenterol Nutr,
1989; 9:351-360. The minimum amount of protein recommended by the Committee on Nutrition, American Academy of Pediatrics is 1.8 g protein per 100 kcal (or 1.2 g protein per 100 ml) formula having 20 kcal/oz.
Typical commercial formulas of 20 kcal/oz have 2.1 to 2.3 g protein per 100 kcal. See, Tables 4-5, Normal Childhood Nutrition & Its Disorders, Current Pediatric Diagnosis & Treatment, 7
th
ed. (1982), p. 99 and Tables E1 and E2, Pediatric Nutrition Handbook, 4
th
ed (1998), p. 655.
Table I, below, illustrates the excessive amount of protein content of several commercial formulas:
TABLE I
Cal/oz
Protein
Protein
(kcal/oz)
g/100 ml
g/100 kcal
Enfamil, Mead Johnson
20
1.42
2.1
Similac, Ross
20
1.45
2.2
SMA, Wyeth
20
1.5
2.3
Nutramigen, Mead Johnson
20
1.9
2.8
Isomil, Ross
20
1.7
2.5
ProSobee, Mead Johnson
20
2.0
3.0
Portagen, Mead Johnson
20
2.2
3.5
Progestimil, Mead Johnson
20
1.9
2.8
Formula for use in the nutritional support of various inherited metabolic disorders restricts the amino acids that are responsible for the accumulation of toxic intermediary metabolites, but typically maintains the FDA recommended amount of protein. For example, U.S. Pat. No. 5,550,146 (Acosta et al.) discloses a generic powder base rich in fats, carbohydrates, vitamins, minerals and trace elements which can be readily admixed with specific amino acids to yield several different therapeutic products for use in nutritional support of various inherited metabolic diseases.
A serious problem encountered with conventional treatment is that it is typically delayed until the infant is diagnosed with such a disease. By the time the disorder is discovered, the severity of metabolic insult is often too advanced for adequate management and, in most cases, results in serious permanent damage of the central nervous system, mental retardation, coma or death.
Thus, it is highly desirable to provide a method of postponing the onset and/or substantially reducing the severity of metabolic intoxication in metabolically abnormal infants prior to diagnosis is desirable.
SUMMARY OF THE INVENTION
The method of the present invention overcomes the problems encountered in the prior art by restricting the protein intake of the general population of full-term newborns, which include normal and undiagnosed, metabolically abnormal newborns, to minimum level required for normal growth at least during the first two weeks of life until newborn screening for inherited metabolic disorders is complete.
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N. Raiha et al.Milk Protein Intake in the Term Infant, 75 ACTA Paedriatr Scand 887-892 (1986).
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Kang Chunghee Kimberly
Kang David S.
Brinks Hofer Gilson & Lione
Dees Jos,e G.
George Konata M.
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