Immunostimulatory and metastasis inhibiting fermented...

Chemistry: molecular biology and microbiology – Micro-organism – per se ; compositions thereof; proces of... – Fungi

Reexamination Certificate

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C435S243000

Reexamination Certificate

active

06355474

ABSTRACT:

The invention relates to an immunostimulatory and metastasis inhibiting fermented and dried vegetal material. pharmaceutical compositions containing thereof, to the process for the preparation of the material and the use of the dried vegetal material as a dietary supplement and in the production of immunostimulaton, and especially metastasis inhibiting pharmaceutical compositions.
One of the main objectives of the treatment of tumours is the inhibition of metastases. The primary tumour caused by the malignant growth of the cells spreads via metastases to the neighbouring cells and organs and causes in the latter secondary tumours, which cannot be removed surgically and may also become resistant to chemotherapy.
Researchers concentrate more and more on the development of immunomodulatory materials and materials of natural—mainly of vegetable—origin have been studied intensively.
It is a well known fact that compounds with a quinone structure play an important biological role. Several quinone derivatives are to be found in plants, like ubiquinones, plastoquinones, menaquinones, which play a role in photosynthesis, but also in the cell respiratory system of vertebra, thus also humans and in the coagulation of blood etc. Several benzoquinone derivatives are also used for medicinal purposes. Adriamycin, daunorubicin and mitomycin C. are quinone derivatives with a cytostatic effect. While other benzo- and hydroquinones have an antimicrobal effect and are the active components of antibiotics suitable for treatments of bacterial infections like Tetran-B. Metacyclin and Doxycyclin.
The Literature reports that 2.6-dimethoxy-p-benzoquinone (2.6-DMBQ) and 2-methoxy-p-benzoquinone (2-MBQ) have a fungicidal and bacteriostatic effect, and that 2.6-DMBQ and 2-MBQ are also cytotoxic for malignant tumour cells. [Int. J. Quant. chem.: Quant. Biol. Symp. 7. 217-222 (1980), 9. 27-30 (1982) and 12. 257-261 (1985); Phytochemistry 27. 225 (1971) and J. Agric. Food Chem. 39. 266 (1991)]. It has been shown that a mixture of 2.6-dimethoxy-p-benzoquinone and ascorbic acid inhibits the groh of Ehrlich ascites tumour cells in mice. [Proc. Natl. Acad. Sci. USA 81. 2088-2091 (1984) and 82. 1439-1442 (1985)]. 2.6-dimethoxy-p-benzoquinone and 2-methoxy-p-benzoquinone have been found and isolated in several plants [Magy. Kem. Folyoirat 102/7. 320-325 (1996)]. These two compounds can be found in the largest quantities in glucoside form in wheat (Tricitum vulgaris), to be more exact in wheat germ. The compounds were isolated in the fifties from wheat germs fermented with yeast and identified for the purpose of examination of quality deterioration of bread to which wheat germ has been added. [Hevl. Him. Acta 33., 433 (1950); J. Chem. Soc. London 1952, 4821-4823].
According to the literature in wheat germ the quantity of 2-MBQ is about 0.05 weight %. that of 2.6-DMBQ about 0.01 weight % (as glucoside). The presence of quinones as glucosides is explained by the fact that quinones, especially) methoxy-substituted p-benzoquinones are reactive while their hydroquinone-glucosides are more stable and inert.
During our experiments relating to the stud, of the fermentation of wheat germ we concluded that the dry extract deriving from the fermented liquid produced while fermenting wheat germ with baker's yeast (Saccharomices cerevisiae) has a surprising immunostimulatory and metastasis inhibiting effect, and it can be applied successfully as the active agent of immunostimulatory and metastasis inhibiting pharmaceutical compositions.
This finding is surprising, because although the literature reports [Proc. Natl. Acad. Sci. USA 80. 129 (1983)] that a mixture of 2.6-DMBQ and ascorbic acid inhibits the growth of Ehrlich ascites tumour cells (these are eminently suitable for quantitative analysis of the growth of tumours and for the study of their biochemical functions) the extract described in the invention (which contains besides unidentifiable components 2.6-DMBQ and 2-MBQ) proved to be practically ineffective on these primary and generally all tumour cells, even when combined with ascorbic acid. It proved only very effective in the treatment of metastases. The aspects of the treatment of primary tumours and the metastases developing from the former are basically different, so it was not self-evident for the researcher that a plant extract containing components which are known to be effective in the treatment of primary tumours and not yet fully identifiable as to its chemical composition should have an immunostimulatory and metastasis inhibiting effect. [Cancer. Principles and Practice of Oncology, Vol 1.4
th
edition. J. B. Lippincott Company. Philadelphia, 1993.]
Thus the present invention concerns an immunostimulatory and metastasis inhibiting fermented and dried vegetal material which is obtainable by fermenting wheat germ with baker's yeast in an aqueous medium filtering the fermented liquid cell-free and drying it.
The present invention also relates to an immunostimulatory and metastasis inhibiting pharmaceutical composition the active agent of which contains the fermented, dried vegetal material described in the invention.
The present invention also concerns the use of the above mentioned fermented and dried vegetal material in the production of immunostimulatory and metastasis inhibiting pharmaceutical compositions.
The present invention also concerns the processes of treating mammals for the stimulation of the immune system and inhibition of metastases with the pharmaceutical composition described in the invention.
The invention further concerns a dietary supplement comprising the fermented, dried vegetal material described in the invention and maltodextrin.
According to the invention the fermented, dried societal material has been identified and examined on the basis of its 2.6-DMBQ content. We would like to note here that full identification of the chemical composition of the extract was not possible with the available methods, so all data concern the 2.6-DMBQ contents as a basis.
It proved suitable to use for the production of the fermented, dried vegetal material described in the present invention wheat germ—which is a by-product of flour milling and available in large quantities—around to flour quality, either in its original state or defatted. The use of defatted wheat germ has no specific advantages. Fermentation was done with baker's yeast (Saccharomyces cerevisiae). This type of yeast is commercially available. The period of fermentation seas about 10-24 hours, preferably 15-20 hours or about 18 hours. The temperature of the fermentation is about 25-35° C. preferably about 30° C. The weight ratio of the wheat germ and the yeast is 4:1-2:1, preferably about 3:1, the weight ratio of the dry matter and water is 1:6-1:12, preferably about 1:9.
The fermentation—on a laboratory scale—can be e.g. effected by adding in a glass fermentor to the freshly ground wheat germ the yeast suspension in water, and by stirring or shaking the mixture. The fermented liquid gets foamy.
After fermentation the mixture is centrifuged for 5-15 minutes at 2000-4500/min, preferably about 3000/min. The supernatant is boiled, cooled and dried in an appropriate manner, e. g. by lyophilisation or spray-drying.
The product, a reddish-brown powder is the material according to the invention. It is expedient to keep the material until further use cooled, and because of its hygroscopic character in sealed containers. The 2.6-DMBQ contents of the resulting dry material is about 0.4 mg/g.
In a large scale fermentation (e.g. 4 cubic meters) it is suitable to apply continuous areating, e.g. 0.5 l air/l of fermented liquid/minute, and slow stirring. The period of fermentation is about 18 hours. In order to inhibit foaming the usual additives can be applied—it is preferable to use sunflower oil. At the end of the fermentation process areating and stirring are discontinued and the fermented liquid is separated from the wheat germ—yeast suspension in the usual manner, for exam

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