Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1991-09-13
1992-08-11
Griffin, Ronald W.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
514879, 4241951, 536 5, 536127, 536128, A61K 31751, A01N 3100, G01N 3100
Patent
active
051378787
DESCRIPTION:
DESCRIPTION
DETAILED DESCRIPTION OF THE INVENTION
Our invention is further illustrated by means of the following non-limiting examples:
EXAMPLE 1
Isolation of Rb.sub.1
About 1 g of crude ginsenosides obtained by the procedure described by Shoji in "Advances in Chinese Medicinal Materials Research" was dissolved in 10 ml of methanol. The resultant solution was mixed with 10 g of silica gel (Merck 0.040-0.063 mm particle size, 230-400 mesh ASTM). The silica gel was air dried for about 1 hour and then placed in a column for vacuum chromatography, as described by Coll et al, Aust. J. Chem., 30, 1305 (1977), prepacked with 80 g of silica gel. Elution with a solution of chloroform and methanol (85:15) gave a fraction from which 75mg of >98% pure Rb.sub.1 was obtained. An additional 120 mg of Rb.sub.1, purity about 60%, was recovered from other fractions of the eluate.
EXAMPLE 2
Preparation of Ginsenosides Enriched in Rb.sub.1
600 mg of the crude mixture of ginsenosides obtained by the procedure of Shoji was dissolved in 10 ml water. The aqueous solution was washed with ethyl acetate (2.times.40 ml) and then extracted with a solution of ethyl acetate and 1-butanol (4:1; 4 .times.40 ml) followed by extraction with a 1:1 solution of ethyl acetate-1-butanol (2.times.40 ml) and then 1-butanol presaturated with water (2.times.40 ml). The last three extracts were combined and concentrated to give 140 mg of ginsenosides containing about 60% of Rb.sub.1. Use of that enriched mixture as the starting material in Example 1 gave essentially pure Rb.sub.1.
The following examples illustrate that Rb.sub.1 and Rg.sub.1 directly and selectively increase acetylcholine function in the brain and are useful in the treatment of Alzheimer-type senile dementia.
EXAMPLE 3
Pinched off nerve endings (synaptosomes) from whole rat brain were first incubated in the presence of the precursor .sup.3 H-choline, which is converted intracellularly to .sup.3 H-ACh. The release of ACh from synaptosomes was quantitated under low [K]and high [K]conditions intended to simulate physiological stimulation. The addition of Rb.sub.1 increased the release of .sup.3 H-ACh as shown in FIG. 1.
EXAMPLE 4
Using a different protocol, synaptosomes, which had been previously incubated with .sup.3 H-choline, as in the first series of experiments, were continually perfused with HEPES-buffered Krebs solution. The release of ACh was effected by subjecting the synaptosomes to electrical field stimulation, which more closely mimics physiological stimulation. In FIG. 2 and 3, the left panel shows the release pattern in the absence of any added drug, and the right panel shows the release pattern in the presence of 10 .sup.-6 M drug during the last 25 minutes of perfusion. The results obtained by calculating the ratio of the amounts of ACh released during the two periods of electrical stimulation (the areas under the curves, S2/S1) indicate that both Rb.sub.1 and Rg.sub.1 increase the electrically stimulated release. In addition, Rg.sub.1 stimulates the resting release of .sup.3 H-ACh, as indicated, by the increase in the resting afflux of .sup.3 H-ACh when the drug was first added. While the net amount of .sup.3 H-ACh released in each run can vary, depending on the amount of protein on the filter and aging of the synaptosomes, the S2/S1 ratio remains quite constant from run to run using a given chamber. Therefore, in each experiment the same chamber was used for both control and test-drug runs.
The stimulation of ACh release is also associated with an increase in the specific uptake of the precursor .sup.3 H choline as shown in FIGS. 4 and 5. Although the magnitude of stimulation of choline uptake is not as great as the magnitude of stimulation of ACh release, it is a consistent and significant effect, and can still quantitatively account for the increase in release. This suggests a general stimulation of brain cholinergic function. Further, preliminary experiments show that of three cholinergic brain regions examined, cortex, stratum, and hippocampus, stimulation
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Benishin Christina G.
Liu Hsing J.
Pang Peter K. T.
Wang Lawrence C. H.
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