Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1998-01-26
2001-03-27
Peselev, Elli (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S249000, C514S345000, C514S814000
Reexamination Certificate
active
06207651
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the field of nutrition. Specifically, the invention is comprised of new oral vitamin preparations combining vitamin B
12
(B
12
, cobalamin) and folic acid (folate), and vitamin B
12
, folate, and pyridoxine (B
6
) for use in patients with elevated serum metabolite levels of homocysteine (HC), cystathionine (CT), methylmalonic acid (MMA), or 2-methylcitric acid (2-MCA). The elevation of these metabolites has been shown to be indicative of tissue deficiencies of B
12
and/or folate and/or B
6
, and related to increased risk of neuropsychiatric, vascular, renal and hematologic diseases. One embodiment of the present invention uses a non-prescription formulation comprising between 0.3-10.0 mg B
12
and 0.1-0.4 mg folate, with the preferred embodiment using 2.0 mg B
12
and 0.4 mg folate. Another embodiment of the non-prescription formulation uses 0.3-10 mg B
12
, 0.1-0.4 mg folate, and 5-75 mg B
6
, with the preferred embodiment using 2.0 mg B
12
, 0.4 mg folate, and 25 mg B
6
. Another embodiment of the present invention uses a prescription strength formulation comprising between 0.3-10.0 mg B
12
and 0.4-1.0 mg folate, with the preferred embodiment using 2 mg B
12
and 1.0 mg folate. In a further embodiment of the present invention, a prescription strength formulation is used comprising 0.3-10 mg B
12
, 0.4-1.0 mg folate, and 5-75 mg B
6
, with the preferred embodiment using 2 mg B
12
, 1.0 mg folate, and 25 mg B
6
. The formulations of the present invention eliminate the costly and time-consuming steps of distinguishing between vitamin deficiencies once a deficiency is found by measurement of serum metabolite levels. The present invention is of particular benefit to the populations at risk for tissue deficiencies of B
12
, folate, and B
6
, such as people over the age of 65, and populations that have or are at risk for neuropsychiatric, vascular, renal and hematologic diseases.
BACKGROUND
Vitamins B
12
, folate, and B
6
are required cofactors in metabolic pathways involving methionine, homocysteine, cystathionine, and cysteine. B
12
in the form of 5′-deoxyadenosylcobalamin is an essential cofactor in the enzymatic conversion of methylmalonylCoA to succinylCoA. The remethylation of homocysteine (HC) to methionine catalyzed by methionine synthase requires folate (methyltetrahydrofolate) and B
12
in the form of methylcobalamin. HC is condensed with serine to form cystathionine (CT) in a reaction catalyzed by cystathionine &bgr;-synthase which requires B
6
(pyridoxal phosphate). CT is hydrolyzed in another B
6
-dependent reaction to cysteine and &agr;-ketobutyrate.
It is important to diagnose and treat B
12
, folate, and B
6
deficiencies because these deficiencies can lead to life-threatening hematologic abnormalities which are completely reversible by proper treatment. B
12
deficiency is a multisystem disorder with extremely varied clinical presentation which has been thought to occur in 0.4% of the population, e.g., about 1 million people in the United States. Symptoms of B
12
deficiency include significant anemia, displayed for example in decreased hematocrit (e.g., <25%) or hemoglobin (e.g., ≦8 g%), with macrocytic red blood cells (i.e., mean cell volume generally greater than 100 fl), or neurologic symptoms of peripheral neuropathy and/or ataxia. See, for example, Babior and Bunn (1983) in
Harrison's Principles of Internal Medicine
, (Petersdorf et al., eds.), McGraw-Hill Book Co., New York; Lee and Gardner (1984) in
Textbook of Family Practice.
3rd Ed. (Rakel, ed.), Saunders & Co., Philadelphia). The hematological abnormalities seen are due to intracellular folate deficiency since folate is required for a number of essential enzymatic reactions involved in DNA and RNA synthesis and since the form of folate in serum (5-methyltetrahydrofolate) must be metabolized to tetrahydrofolate by the B
12
-dependent enzyme methionine synthase before it can be utilized by the RNA- and DNA-related enzymes. While it has been well recognized that individuals with B
12
deficiency could display neurologic disorders in the absence of anemia, such situations were believed to be exceptional and rare. See, Beck (1985) in
Cecil Textbook of Medicine,
17th Ed., (Wyngaarden and Smith, eds.), W. B. Saunders, Philadelphia, pp. 893-900; Babior and Bunn (1987) in
Harrison's Principles of Internal Medicine,
11th Ed., (Braunwald et al., eds.) McGraw-Hill, New York, pp. 1498-1504; Walton (1985) in
Brain's Diseases of the Nervous System,
9th Ed., Oxford University Press, Oxford, UK. The neurologic symptoms of B
12
deficiency were considered to be late manifestations of the disease most typically occurring after the onset of anemia or, if they occurred first, were soon to be followed by the onset of anemia. See, Woltmann (1919) Am. J. Med. Sci. 157: 400-409; Victor and Lear (1956) Am. J. Med. 20: 896-911.
However, it has recently been shown that the textbook description of severe megaloblastic anemia and combined systems disease of the nervous system is the rarest presentation of B
12
deficiency at the present time (Stabler et al. (1990) Blood 76: 871-881; Carmel (1988) Arch. Int. Med. 148: 1712-1714; Allen (1991) in
Cecil Textbook of Medicine,
19th Ed., (Wyngaarden and Smith, et al. eds.), W. B. Saunders, Philadelphia, pp. 846-854.). Therefore, contrary to previous teachings, patients that may benefit from B
12
therapy may have minimal to no hematologic changes while manifesting a wide variety of neurologic and psychiatric abnormalities (Lindenbaum et al. (1988) N. Engl. J. Med. 318: 1720-1728; Greenfield and O'Flynn (1933) Lancet 2: 62-63). This is particularly true for populations at risk for B
12
deficiency, such as the elderly population (Pennypacker et al. (1992) J. Am. Geriatric Soc. 40: (in press).
The incidence of folate deficiency in the population is unknown, but has been thought to occur commonly in individuals with various degrees of alcoholism. The hematologic abnormalities seen with folate deficiency, such as macrocytic anemia, are indistinguishable from those seen with B
12
deficiency. Folate is required for a number of essential enzymatic reactions involved in DNA and RNA synthesis, and is particularly important in rapidly dividing cells like those in the bone marrow.
B
6
is required for the first step in heme synthesis and serves a major role in transamination reactions of amino acid metabolism, in decarboxylations, and in the synthesis of the neuroactive amines histamine, tyramine, serotonin, and &ggr;-aminobutyric acid (GABA). Clinical manifestations include microcytic hypochromic anemia, characteristic skin changes of dermatitis and acrodynia, muscular weakness, and a variety of neuropsychiatric abnormalities including hyperirritability, epileptiform confusions, depression and confusion (Newberne and Conner (1989) in Clinical Biochemistry of Domestic Animals, Academic Press, San Diego, pp. 796-834).
Vitamin deficiencies are generally determined by measurement of serum levels. Normal serum B
12
levels are 200-900 pg/ml, with levels of less than 100 pg/ml being said to indicate clinically significant deficiency (Beck (1985) supra) However, serum B
12
levels are a relatively insensitive determinant of B
12
deficiency in that only 50% of patients with clinically confirmed B
12
deficiency have levels less than 100 pg/ml, 40% are 100-200 pg/ml, and at least 5-10% have values in the 200-300 pg/ml range. Diagnosis is further complicated by the fact that 2.5% of normal subjects (6,250,000 people in the U.S.) have low serum B
12
levels (Allen (1991) supra), with no evidence of B
12
deficiency and are unlikely to benefit from B
12
therapy (Schilling et al. (1983) Clin. Chem. 29: 582; Stabler (1990) supra).
Normal serum folate levels are 2.5-20 ng/ml, with levels less than 2.5 ng/ml indicating the possibility of clinically significant deficiency. Like B
12
serum levels, however, serum folate levels are a relatively insensitive measure in that only 50-75% of patients with folate deficiency
Allen Robert H.
Stabler Sally P.
Gibson Dunn & Crutcher, LLP
Metabolite Laboratories
Peselev Elli
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