Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-04-25
2003-02-04
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S556000, C514S561000, C514S562000
Reexamination Certificate
active
06514973
ABSTRACT:
The invention relates to compositions for the treatment and prevention of transmethylation disorders, preferably neurological and pathopsychological diseases.
It has been documented that neurological symptoms are associated with abnormally high levels of homocysteine in the blood (hyperhomocysteinemia or homocysteinuria). Investigations indicate that hyperhomocysteinemia contributes to microcephaly, mental retardation severe psychomotor retardation, convulsions, apneic spells, and even death. In several patients with methylenetetrahydrofolate reductase deficiency, which is one of the reasons for homocysteine accumulation, demyelination of the brain and subacute combined degeneration of the spinal cord was reported. Results of several studies have also shown that defective methylenetetrahydrofolate reductase and elevated homocysteine level are risk factors for neural tube defects such as spina bifida and anencephaly. Furthermore, elevated homocysteine levels have been found in amniotic fluid of pregnant women having fetuses with neural tube defects. The existence of a linear connection between the homocysteine level of mother and fetus has been reported.
In the human body, homocysteine is formed from methionine. In a simplified description methionine is condensed with adenosine triphosphate to produce S-adenosylmethionine and the latter is converted to S-adenosylhomocysteine. S-Adenosylhomocysteine is rapidly metabolised to homocysteine which is an important branch-point metabolite. It can be regenerated back to methionine, it can be converted to S-adenosylhomocysteine or it can enter the trans-sulfuration-pathway by reaction to cystathionine.
In the past, it has been the aim of several studies to treat hyperhomocysteinemia, i.e. to lower the elevated homocysteine levels. It is known that betaine and choline, which is converted to betaine by oxidation, may act as methylating agents. For example, the enzyme-catalyzed reaction between betaine and homocysteine in the human organism leads to the formation of methionine and dimethylglycine and the treatment with betaine is known to be efficient in lowering homocysteine concentrations. Other attempts included the supplementation of vitamins like vitamin B
6
, vitamin B
12
or usual multivitamins, vitamin B
6
in combination with a methionine restriction, methylcobalamine, folic acid, folic acid together with vitamins B
6
and B
12
, folate, and occasionally folate in combination with vitamin B
6
, vitamin B
12
, choline or betaine (M. R. Malinow, J. Nutr. 126 (1996) 1238-1243).
However, the effectiveness of the previously applied compositions was not satisfactory. The treatment approach has not been linked to the complexity of the transmethylation metabolism.
The invention had the object of providing new compositions for the treatment and prevention of transmethylation disorders, preferably neurological and pathopsychological diseases, which improve the treatment significantly.
It has now been found that this object can be achieved with compositions which comprise one or more active ingredients and, optionally, one or more natural substances, solid, liquid and/or semiliquid excipients or auxiliaries, characterized in that the active ingredients consist of
a) a component A consisting of one or more phosphatidylserines,
b) a component B consisting of one or more methyl transporters, and
c) a component C consisting of one or more compounds selected from methyl and methylene donors,
provided that phosphatidylserines and compounds with methyl transporting properties do not form part of component C.
The new compositions according to the invention also affect the whole area of cardiovascular dysfunctions.
The invention furthermore relates to compositions for the treatment and prevention of diseases associated with hyperhomocysteinemia.
Phosphatidylserines, which are donors of one carbon groups, are naturally occurring phospholipid components of cellular membranes. These biomembranes are involved in a number of vital processes, such as nerve cell differentiation, activation and renewal, nerve transmitter production, ion transport etc. Phosphatidyiserines are found in all cells and organs of the body, but they are most concentrated in nerve cells of the brain and are essential for several brain functions, e.g. for the conduction of nerve impulses and the production, storage and release of neurotransmitters.
It has been documented that the oral supplementation with 200 to 300 mg of phosphatidylserines per day for 2 to 6 months improves brain metabolism and benefits cognitive functions such as memory, thinking, learning, and the ability to concentrate especially in aging people and in patients with certain neurological and pathopsychological conditions. The effectiveness of phosphatidylserines in the treatment of senile dementia, Parkinson's disease epilepsy, depression, and age-associated memory impairment has also been demonstrated in several studies.
Posphatidylserines appear to make pro-homeostatic contributions and provide metabolic support to a wide range of brain functions. It has been assumed that phosphatidylserines are able to stimulate glucose metabolism in the brain and also increase the number of neurotransmitter receptor sites.
Phosphatidylserines are not abundant in common foods, but they have a good availability by oral route and are suitable as dietary supplement. They appear in the blood at about 30 minutes after oral administration and are able to cross the blood-brain barrier. Phosphatidylserines reach the brain within minutes after being absorbed.
As mentioned above, it has been documented that many neurological symptoms are associated with hyperhomocysteinemia. According to the invention it has now been found that an elevated homocysteine level is a sign of the inadequate methyl pool involving both methyl donors and methyl transporters. Therefore, the homocysteine level in the human body may be used as an indicator of the state of the transmethylation metabolism in certain cases.
In the human body, one-carbon or C
1
groups exist in several oxidation states. These groups include methyl groups, methylene groups, methylidyne groups, carbonyl groups, formyl groups, hydroxymethyl groups, and carboxyl groups. Practically, these groups can be divided into groups at the oxidation level of methanol, formaldehyde, and formate Exemplary sources of the methyl group (methanol oxidation level) are methionine, adenosylmethionine, methylated glycines, and choline. The sources of methylene group (formaldehyde oxidation level) are serine and glycine. One of the sources of the group at the formate oxidation level is e.g. histidine. All of these one-carbon groups form the so-called one-carbon pool and participate in many important reactions. As the methyl group is biochemically the most ubiquitous, the one-carbon pool is often referred to as the methyl pool.
The metabolic events of methyl groups are usually specified as transmethylation, whereas the involved molecules are called transmethylators. Depending upon their function during the metabolic events, the transmethylators are classified as methyl donors, methyl transporters, and methyl acceptors. Methyl donors are e.g. methionine, S-adenosylmethionine, choline, methylglycine (sarcosine), dimethylglycine, and trimethylglycine (betaine). Methyl transporters are e.g. tetrahydrofolates which are derived from folic acid and methylcobalamine and adenosylcobalamine, which are coenzymes derived from vitamin B
12
. Methyl acceptors include all nucleic acids, proteins, most of them enzyme proteins, phospholipids (components of biomembranes), and many biological amines, which serve as neurotransmitters in many cases.
The properly functioning methylation of these four classes of acceptor molecules is of importance for their biochemical activity. The methylation of the nucleic acids assures their structure stability and their accurate genetic performance. The methylation of the enzyme proteins ensures their specificity and efficiency and prevents the accumulation of intermediary metabolites. The
Buchholz Herwig
Meduski Jerzy D.
Jarvis William R. A.
Merck Patent Geseilschaft Mit Beschrankter Haftung
Millen White Zelano & Branigan
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