Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2001-08-01
2004-05-25
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S558000
Reexamination Certificate
active
06740679
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The invention relates to a nutritional or dietetic composition or supplement.
BACKGROUND OF THE INVENTION
Fatty acid oxidation plays a major role in the production of energy, and is essential during periods of fasting. Serious disorders in fatty acid metabolism can arise which range from skeletal and/or cardiac muscle weakness to episodes of metabolic apnea to death resembling sudden infant death syndrome. These disorders manifest with severe cardiomyopathy, hypoglycemia, myopathy, microvesicular fat deposition in affected organs, and/or fulminant hepatic failure. Patients suffering from inborn genetic errors in fatty acid metabolism often experience fatal or repeated severely debilitating episodes upon failure to generate energy via fatty acid metabolism. Premature infants require a maintenance of a high blood sugar level. Often, their routine diet does not provide sufficient amounts of carbohydrate energy sources and their fat metabolism enzymes are not efficient at birth. Elderly patients also experience difficulty in the regulation of blood sugar levels due to a decreased appetite and inefficient metabolism.
Saturated fatty acids are represented by the following structure:
where R represents an alkyl group. Naturally occurring fatty acids derived from higher plant and animal lipids include both saturated and unsaturated even-numbered carbon chains. The most abundant naturally occurring saturated fatty acids are palmitic acid (16 carbons; C
16
) and stearic acid (18 carbons; C
18
). Shorter-chain fatty acids (12-14 carbons; C
12
to C
14
) and longer-chain fatty acids (up to 28 carbons; C
28
) naturally occur in small quantities. Fatty acids of less than 10 carbons are rarely present in animal lipids, with the exception of milk fat comprising about 32% oleic acid (unsaturated C
18
), about 15% palmitic acid (C
16
), about 20% myristic acid (C
14
), about 15% stearic acid (C
18
), about 6% lauric acid (C
12
), and about 10% fatty acids of 4-10 carbons (C
4
-C
10
).
Fatty acids are generally categorized by the length of the carbon chain attached to the carboxyl group: short-chain for 4 to 6 carbons (C
4
-C
6
), medium-chain for 8 to 14 carbons (C
8
-C
14
), long-chain for 16 to 18 carbons (C
16
-C
18
), and very long-chains for 20 to 28 carbons (C
20
-C
28
).
The process by which fatty acids are metabolized involves mitochondrial &bgr;-oxidation in the mitochondria of the cell. As illustrated in
FIG. 1
, fatty acid oxidation of a long-chain fatty acid such as palmitic acid begins transport of the fatty acid through the plasma membrane via a plasma membrane carnitine transporter. As the fatty acid passes through the outer mitochondrial membrane, the fatty acid is converted in the presence of Coenzyme A (CoASH) and acyl-CoA synthetase into a fatty acid ester of Coenzyme A (fatty acyl-CoA) at the expense of ATP. The fatty acyl-CoA is converted into fatty acylcarnitine in the presence of carnitine and carnitine palmitoyltransferase I (CPT I). The fatty acylcarnitine then passes the inner membrane of the mitochondria, a step which is catalyzed by the carnitine/acylcarnitine translocase enzyme. Once inside the mitochondria, the fatty acylcarnitine is then converted back into fatty acyl-CoA in the presence of carnitine palmitoyltransferase II (CPT II). In the oxidation cycle within the mitochondria, the fatty acyl-CoA is dehydrogenated by removal of a pair of hydrogen atoms from the &agr; and &bgr; carbon atoms via a chain-specific acyl-CoA dehydrogenase to yield the &agr;,&bgr;-unsaturated acyl-CoA, or 2-trans-enoyl-CoA. The appropriate acyl-CoA dehydrogenase is determined by the carbon chain length of the fatty acyl-CoA, i.e., long-chain acyl-CoA dehydrogenase (LCAD; C
12
to C
18
), medium-chain acyl-CoA dehydrogenase (MCAD; C
4
to C
12
), short-chain acyl-CoA dehydrogenase (SCAD; C
4
to C
6
), or very long-chain acyl-CoA dehydrogenase (VLCAD; C
14
to C
20
). The &agr;,&bgr;-unsaturated acyl-CoA is then enzymatically hydrated via 2-enoyl-CoA hydratase to form L-3-hydroxyacyl-CoA, which in turn is dehydrogenated in an AND-linked reaction catalyzed by a chain-specific L-3-hydroxyacyl-CoA dehydrogenase to form &bgr;-ketoacyl-CoA. The appropriate L-3-hydroxyacyl-CoA dehydrogenase is determined by the carbon chain length of the L-3-hydroxyacyl-CoA, i.e., long-chain L-3-hydroxyacyl-CoA dehydrogenase(LCHAD; C
12
to C
18
) or short-chain L-3-hydroxyacyl-CoA dehydrogenase(SCHAD; C
4
to C
16
with decreasing activity with increasing chain length). The &bgr;-ketoacyl CoA ester undergoes enzymatic cleavage by attack of the thiol group of a second molecule of CoA in the presence of 3-ketoacyl-CoA thiolase, to form fatty acyl-CoA and acetyl-CoA derived from the &agr; carboxyl and the &bgr; carbon atoms of the original fatty acid chain. The other product, a long-chain saturated fatty acyl-CoA having two fewer carbon atoms than the starting fatty acid, now becomes the substrate for another round of reactions, beginning with the first dehydrogenation step, until a second two-carbon fragment is removed as acetyl-CoA. At each passage through this spiral process, the fatty acid chain loses a two-carbon fragment as acetyl-CoA and two pairs of hydrogen atoms to specific acceptors.
Each step of the fatty acid oxidation process is catalyzed by enzymes with overlapping carbon chain-length specificities. Inherited disorders of fatty acid oxidation have been identified in association with the loss of catalytic action by these enzymes. These include defects of plasma membrane carnitine transport; CPT I and II; carnitine/acylcarnitine translocase; very-long-chain, medium-chain, and short-chain acyl-CoA dehydrogenases (i.e., VLCAD, MCAD, and SCAD, respectively); 2,4-dienoyl-CoA reductase; long-chain 3-hydroxyacyl-CoA dehydrogenase acyl-CoA (LCHAD), and mitochondrial trifunctional protein (MTP) deficiency. To date, treatment for medium chain dehydrogenase (MCAD) deficiency has been found. However, the remaining defects often are fatal to patients within the first year of life, and no known effective treatment has been made available. In particular, patients suffering from severe carnitine/acylcarnitine translocase deficiency routinely die, there are no known survivors, and no known treatment has been found.
Attempts to treat these disorders have centered around providing food sources which circumvent the loss of catalytic action by the defective enzyme. For example, the long-chain fatty acid metabolic deficiency caused by a defective carnitine/acylcarnitine translocase enzyme (referred hereinafter as “translocase deficiency”) often leads to death in the neonatal period. Providing carnitine, a high carbohydrate diet, and medium-chain triglycerides to one translocase-deficient patient failed to overcome the fatty acid metabolic deficiency. It was believed that the metabolism of medium-chain fatty acids would not require the carnitine/acylcarnitine translocase enzyme, since medium-chain fatty acids are expected to freely enter the mitochondria. Thus, infant formulas were developed comprising even-carbon number medium-chain triglycerides (MCT) (e.g., 84% C
8
, 8% C
6
and 8% C
10
) which were expected to by-pass the translocase defect. Fatalities continue to occur despite treatment attempts with these formulas.
With the exception of pelargonic acid (saturated fatty acid with 9 carbons; C
9
), odd-carbon number fatty acids are rare in higher plant and animal lipids. Certain synthetic odd-carbon number triglycerides have been tested for use in food products as potential fatty acid sources and in the manufacture of food products. The oxidation rates of odd-chain fatty acids from C
7
and C
9
triglycerides have been examined in vitro in isolated piglet hepatocytes. (Odle, et al. 1991. “tilization of medium-chain triglycerides by neonatal piglets: chain length of even- and odd-carbon fatty acids and apparent digestion/absorption and hepatic metabolism,”
J Nutr
121:605-614; Lin, X, et al. 1996. “Acetate represents a major product of heptanoate and octanoate beta-oxidation in h
Baylor University Medical Center
Sidley Austin Brown & Wood LLP
Weddington Kevin E.
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