Claims
- 1. A method for alleviating the symptoms of Alzheimer type senile dementia, which comprises administering to a mammal affected with Alzheimer-type senile dementia an amount of ginsenoside Rb.sub.1 or of ginsenoside Rg.sub.1, effective to increase the availability of acetylcholine in the cortical and hippocampal regions in the brain of the mammal.
- 2. A method according to claim 1, wherein the Rb.sub.1 or Rg.sub.1, is administered to the mammal in a daily dosage of 100-1000 mg.
- 3. A method according to claim 2, wherein the daily dosage is administered in portions 3 or 4 times per day.
- 4. A method according to claim 1, wherein the Rb.sub.1 or Rg.sub.1, is administered together with a metabolic precursor for acetylcholine.
- 5. A method according to claim 4, wherein the metabolic precursor is lecithin or choline.
- 6. A method according to claim 1, wherein the Rb.sub.1 or Rg.sub.1, is administered together with a cholinesterase inhibitor.
- 7. A method according to claim 6, wherein the cholinesterase inhibitor is physostigmine, pyridostigmine or paraoxon.
- 8. A method according to claim 1, wherein the Rb.sub.1 or Rg.sub.1 is administered together with a metabolic precursor for acetycholine and an acetylcholinesterase inhibitor.
- 9. A composition for alleviating the symptoms of Alzheimer-type senile dementia comprising 25-100 mg of Rb.sub.1 or Rg.sub.1 and a metabolic precursor for acetylcholine.
- 10. A composition for alleviating the symptoms of Alzheimer-type senile dementia comprising 25-100 mg of Rb.sub.1 or Rg.sub.1 and a cholinesterase inhibitor.
- 11. A composition for alleviating the symptoms of Alzheimer-type senile dementia comprising 25-100 mg of Rb.sub.1 or Rg.sub.1, a metabolic precursor for acetylcholine and a cholinesterase inhibitor.
BACKGROUND OF THE INVENTION
This application is a continuation-in-part of application Ser. No. 07/297,012, filed Jan. 13, 1989, now U.S. Pat. No. 4,966,893.
The present invention is directed to compositions, and methods for alleviating the symptoms of senile dementia of the Alzheimer's type. In one specific aspect, the present invention is directed to an improved process for the isolation and purification of a ginsenoside useful in practicing that method.
Senile dementia of the Alzheimer's type (SDAT) is widely recognized as a problem of increasing proportions in North America as well as around the world. The disease is associated with progressive physical and mental impairment to the point where the patient requires total care, and becomes a tremendous social and economic burden. Progress of the disease is believed to be related to degeneration of certain nerve tracts in the central nervous system, resulting in the loss of associated functions. Pathological studies indicate that brains of SDAT patients have loss of several neurotransmitter systems, related to different functions, but the system which is implicated the most is the cholinergic system. Studies show that several important cholinergic tracts innervating the cortical and hippocampal regions degenerate. Although this particular degeneration may not account for all of the symptoms of SDAT, it may account for the cognitive and memory deficits, which are some of the most difficult symptoms for patients and their families to deal with.
The pharmacological approaches which have been proposed for the managements of SDAT symptoms may be classified in two ways. The first is drugs which improve the function of existing neurons, especially to increase cholinergic nerve function. The second is drugs which decrease degeneration/increase regeneration of nerves.
Two types of drugs have been used in clinical trials to improve central cholinergic functions. The first is compounds which increase the availability of the existing endogenous neurotransmitter, acetylcholine (ACh); and the second is compounds which are exogenous, and mimic the effects of the endogenous transmitter at the receptor. However, these compounds exhibit side effects which limit their use.
It is generally believed that compounds which will increase the availability of the endogenous neurotransmitter are more desirable. Substances in this category are cholinesterase inhibitors, such as physostigmine and pyridostigmine, which decrease the breakdown of ACh, thus prolonging its functional lifetime at the crucial location, the synaptic cleft, and choline and lecithin, which increase the availability of the precursor for synthesis. Thus far, other compounds have not been described which directly increase the availability of the endogenous neurotransmitter ACh by any other mechanisms, except by blockade of inhibitory presynaptic receptors (with e.g. atropine or clonidine), or by non-specific depolarization of nerves (e.g. veratridine).
Ginseng is the name given to the dried roots of the ginseng plants (genus Panax) and, more particularly, to extracts of those roots. The roots and their extracts contain a variety of substances including saponins and sapogenins.
Ginseng has been extensively used, mostly in Asia, as a tonic to promote health and well being, and as a medicine in the treatment of various disease conditions. The beneficial attributes of ginseng are attributed to its saponin content, a mixture of glucosides referred to collectively as gensenosides.
U.S. Pat. No. 4,157,894 to Bombardelli discloses the isolation of saponins from ginseng roots and the use of a purified concentrate in the geriatric field for elderly patients having difficulty in digesting less concentrated preparations. Bombardelli also discloses the structures of saponins Rb.sub.1, Rb.sub.2, Rc, Rd, Re, Rf and Rg.
U.S. Pat. No. 4,702,949 to Liu discloses a composition comprising 5-15% ginsenoside, 30-50% tetramethylpyrazine, 30-50% astragalan, and 5-15% atractylol in the treatment of cerebral vascular insufficiency and resultant paraplegia, hemiplegia and impaired neurofunction.
U.S. Pat. Nos. 4,157,894; 4,317,816; 4,446,130; 4,647,460; 4,684,628; 4,687,761; and 4,755,504 disclose the use of ginseng or ginseng extracts, alone, or in combination with other substances for various medically related purposes.
A procedure for the isolation of a crude mixture of ginsenosides from ginseng is described by J. Shoji, "Advances in Chinese Medicinal Materials Research", World Scientific Publishing Company, Singapore, pages 455-469 (1985). Material prepared by this established procedure is commercially available.
The preparation of ginseng extract s is also disclosed by Bombardelli and by Liu, discussed above, and in the other U.S. patents listed above. Rb.sub.1 and Rg.sub.1 have the structural formula: ##STR1## In Rb.sub.1, R.sub.1 is D-glucose B(1.fwdarw.6)D-glucose, R.sub.2 is D-glucose B(1.fwdarw.2)D-glucose and R.sub.3 is H. In Rg.sub.1, R.sub.1 is D-glucose, R.sub.2 is H, and R.sub.3 is O-D-glucose.
Existing procedures for the isolation and purification of ginsenoside Rb.sub.1 include standard column chromatography, thin-layer chromatography, and high performance chromatography. These methods are laborious for the isolation of the compound in large quantities and often yield a low purity product.
A primary object of the present invention is to provide compositions and methods for the treatment of senile dementia of the Alzheimer's type.
Another object of the invention is to provide an improved process for the isolation and purification of a ginsenoside used in that method for treating senile dementia.
We have discovered that ginsenosides Rb.sub.1 and Rg.sub.1 directly and selectively increase acetylcholine function in the brain and, accordingly, are useful in alleviating the symptoms of senile dementia. Those ginsenosides may be administered together with metabolic precursors for ACh synthesis and/or with cholinesterase inhibitors.
In one specific aspect, the present invention is a method for alleviating the symptoms of Alzeimer-type senile dementia, which comprises administering to a mammal affected with Alzheimer-type senile dementia an amount of ginsenoside Rb.sub.1 or of ginsenoside Rg.sub.1 effective to increase the availability of acetylcholine in the cortical and hippocampal regions in the brain of the mammal.
In a second specific aspect, the present invention is a process for the isolation of ginsenoside Rb.sub.1 which comprises the steps:
A mixture of ginsenosides enriched in Rb.sub.1 particularly useful as the starting material in the process of the present invention may be obtained by:
The vacuum chromatographic process described above yields ginsenoside Rb.sub.1 of good quality and can be adapted to the preparation of larger amounts of that ginsenoside. Exceptionally high purity Rb.sub.1 can be obtained by using a mixture of ginsenosides enriched in Rb.sub.1 as the starting material in the process.
In a third specific aspect, the preset invention is a composition for alleviating the symptoms of Alzheimer-type senile dementia comprising:
PCT Information
| Filing Document |
Filing Date |
Country |
Kind |
102e Date |
371c Date |
| PCT/US90/00121 |
1/12/1990 |
|
|
9/13/1991 |
9/13/1991 |
| Publishing Document |
Publishing Date |
Country |
Kind |
| WO90/08315 |
7/26/1990 |
|
|
US Referenced Citations (15)
Continuation in Parts (1)
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Number |
Date |
Country |
| Parent |
297021 |
Jan 1989 |
|
Patent Grant
5137878
