Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-07-22
2002-04-30
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S450000, C514S452000, C514S460000, C514S473000, C514S546000, C514S547000, C514S509000, C424S438000, C424S439000, C424S442000
Reexamination Certificate
active
06380244
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention is generally in the field of nutritional and therapeutic compositions for the modulation of ketone levels in humans and other mammals.
There are a number of conditions in human and animals in which it is desirable to increase the levels of ketone bodies in the human or animal body. Examples include seizure control, treatment of certain metabolic disorders, reduction of protein catabolism, appetite suppression during weight loss, and parenteral nutrition.
A number of treatments exist for seizure control in epileptic patients. Anti-seizure medications are popular; however, they are not always effective and can cause undesirable side-effects. A ketogenic diet has been used since the turn of the century, but lost favor with the development of anti-seizure medications. The ketogenic diet recently has attracted new interest for the treatment of certain forms of epilepsy, as well as other medical conditions. The diet, which typically is carefully controlled and doctor supervised, is very high in fat calories and low in carbohydrates. The diet forces the body to metabolize fats instead of carbohydrates for energy, thereby elevating the level of acetoacetate and D-3-hydroxybutyrate in the blood. These compounds are referred to as “ketone bodies,” thus the term “ketogenic” is used to describe the diet.
While the exact mechanism of action of the ketogenic diet is not well understood, it is believed that the elevated blood levels of ketone bodies have sedative effects which help to prevent seizures. In order to be effective for this purpose, however, the patient must strictly observe the diet. Vitamin and mineral supplements are included in the diet to make it nutritionally complete, since the diet is very high in fat, low in proteins, and requires the near elimination of carbohydrates. Each patient's diet is mathematically calculated based on the age, size, and activity level of the patient. Patients normally follow the diet for one to two years, at which time the patient is slowly weaned onto a normal diet. The diet has been found to be particularly effective with epileptic children. Major drawbacks are that the diet is not very palatable and that patient compliance demands complete commitment on the part of the patient and his or her family. Moreover, the diet's high fat content can increase the risk of vascular diseases, such as atherosclerosis.
Special diets are also used when a person urgently needs to lose weight for health reasons, for example prior to surgery or due to complications from obesity. In this situation, the doctor may prescribe a diet greatly restricting the person's caloric intake. With the caloric intake reduced, the body is forced to metabolize storage reserves for energy. The body can derive energy from fat and skeletal tissue, such as muscle and proteins. It is preferable, however, that fat tissue be used rather than protein, since the breakdown of proteins (i.e. “catabolism”) can undesirably result in muscular atrophy, immuno-suppression, and reduced wound healing. Supplementation of the diet with hydroxybutyric acid has been shown to reduce protein catabolism in subjects on low energy diets (Pawan & Semple,
Lancet
8:15 (1983)). It also has been reported that 3-hydroxybutyrate beneficially suppresses the appetite.
Total parenteral nutrition (“TPN”) is used to provide nutrients to patients who are unable to ingest food orally, such as in the case of intestinal failure. Common causes of this condition include inflammatory disorders of the gastrointestinal tract (e.g., Crohn's disease), radiation enteritis, and short bowel resulting from surgical resection of necrotic or diseased bowel. Approximately 22,000 outpatients and 150,000 inpatients currently receive TPN in the United States alone (
PR Newswire: Orphan Medical Announcement
, Jun. 9, 1995). Patients receive the nutrients, which typically are concentrated fat emulsions, directly into their veins. The nutrient compositions are described, for example, in U.S. Pat. No. 4,563,354 to Chang et al.; EP 0321428 A1; U.S. Pat. No. 5,093,044 to Wretlind et al.; PCT WO 88/08301; PCT WO 90/02548; PCT WO 90/02549; and PCT WO 90/11753. Parenteral treatment with fat emulsions, however, can have serious side effects, such as catheter obstruction, hyperlipemia, thrombopathy, fat overload syndrome, and fat embolism (Desrochers, et al.,
J. Nutr. Biochem
. 6:111-18 (1995)). It would therefore be tremendously beneficial to develop high energy, water soluble nutrients which can be used for long-term intravenous feeding.
In principle, the ketone bodies R-3-hydroxybutyrate and acetoacetate, which are natural constituents of human sera, could be used for intravenous feeding in lieu of fat emulsions. These compounds are good fuels for peripheral tissues, except during prolonged starvation and diabetic ketoacidosis, and are ultimately oxidized to carbon dioxide. Unfortunately, administration of these compounds in their acid form can cause vein irritation, and infusion of the compounds as sodium salts can result in a dangerous sodium overload (Desrochers, et al.,
J. Nutr. Biochem
., 6:1 11-18 (1995)). To overcome these problems, researchers have explored the administration of R-3-hydroxybutyrate with other basic amino acid salts (Beylot et al.,
Crit. Care Med
. 22:1091-98 (1994); Lammerant, et al.,
J. Mol. Cell. Cardiol
. 17:421-33 (1985)). Such treatments, however, may interfere with the transport of amino acids across the blood-brain barrier and/or harm patients with hepatic or renal pathologies (Desrochers, et al.,
J. Nutr. Biochem
. 6:111-18 (1995)). Others have described the use of sodium salts of 3-hydroxybutyric acid oligomers as nutrients, in order to decrease the ratio of salt to ketone body (Japanese Patent No. 94,321,778 to Hiraide, et al.).
Another approach utilizing a ketone body as a nutrient focuses on the synthesis of a glycerol monoester of acetoacetate, which is hydrolyzed in plasma and tissues to glycerol and acetoacetate (Birkhahn & Border,
Am. J. Clin. Nutr
. 3:436-41 (1978); Birkhahn, et al.,
J. Nutr
. 109:1168-74 (1979)). This composition was first to provide administration of large amounts of a ketone body without a large sodium load.
Researchers also have explored using precursors to the ketone bodies. For example, R, S-1,3-butanediol is a water soluble precursor, which is metabolized in the liver to R, S-3-hydroxybutyrate (Desrochers, et al.,
J. Nutr. Biochem
. 6:111-18 (1995)). However, the diol is unsuitable for use as an intravenous nutrient because it has a low caloric density per osmol, and because its oxidation in the liver markedly increases the [NADH]/[NAD
+
] ratio, which can induce alcoholic hypoglycemia. One effort to address these problems has focused on using an acetoacetate ester of R, S-1,3-butanediol, so that acetoacetate liberated by esterases can trap the reducing equivalents generated in the liver by the oxidation of the diol (Desrochers, et al.,
J. Nutr. Biochem
. 6:111-18 (1995)).
Modulating ketone body levels also is useful in the production of animals for the meat industry. U.S. Pat. Nos. 4,329,359 and 4,423,072 to Stahly disclose feeding dihydroxyalkanols and triglycerides to pregnant sows to improve the metabolic stability of newborn pigs. These compositions function to increase the ketone body levels in the sow. The ketone bodies then are transferred across the placenta, providing a supplemental energy source to the developing fetus.
PCT WO 98/41200 and PCT WO 98/41201 by British Technology Group Ltd disclose the use of acetoacetate in combination with poly D-&bgr;-hydroxybutyrate or esters or oligomers thereof, and/or a metabolic precursor or salt thereof in nutritional or therapeutic compositions to elevate the levels of ketone bodies in the blood for increasing cardiac efficiency, treatment of diabetes and insulin resistant states, and treatment of effects of neurodegenerative disorders and epilepsy. Although these applications provide mechanisms by which the ketone levels can
Martin David P.
Peoples Oliver P.
Williams Simon F.
Zhong Luhua
Holland & Knight LLP
Krass Frederick
Metabolix Inc.
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