Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-11-05
2004-06-15
Owens, Amelia (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S401000, C549S403000, C424S725000
Reexamination Certificate
active
06750248
ABSTRACT:
FIELD OF THE INVENTION
The current invention concerns methods of preparing an estrogenic preparation and isolating an estrogenic compound from a plant, such as an Epimedium plant, and uses thereof for selectively modulating the function of estrogen receptors.
BACKGROUND OF THE INVENTION
There is an ever-increasing interest in herbal or natural-source remedies or medications. Many individuals would rather use such products than conventional pharmaceutical preparations. Additionally, medicinal substances derived from natural products can provide commercial or industrial opportunities for local populations in areas where medicinal plants grow or are cultivated. Moreover, compounds identified as the active ingredients in natural products form an important basis for pharmaceutical research.
Estrogens are steroid hormones that regulate physiological processes such as the growth, differentiation, and functioning of many target tissues by regulating the expression of genes under control of estrogen-responsive elements. Tissues that express estrogen receptors include tissues of the female and male reproductive systems such as the mammary gland, uterus, vagina, ovary, testes, epididymis, and prostate (For reviews see: Pettersson, et al., 2001; Conneely, 2001). Estrogens have been increasingly shown to have important regulatory roles in the central nervous system and cardiovascular system and in physiological processes such as the maintenance of bone, lipid and fat metabolism, and atherosclerosis formation. Of the several physiological estrogens in women, 17-beta-estradiol (hereinafter referred to as “estradiol”) is the most potent.
“Phytoestrogens” are a broad group of plant-derived compounds of non-steroidal structure that can behave as estrogen mimics (For reviews: Kurzer, et al., 1997; Zava, et al., 1998; Setchell, 1998; Tham, et al., 1998). A typical feature of the chemical structure of phytoestrogens is the presence of a phenolic ring that, with few exceptions, is a prerequisite for binding to the estrogen receptor. Phytoestrogenic substances have been demonstrated to have estrogenic or anti-estrogenic activity and epidemiological data suggests that these substances may be useful for treatment of a variety of health problems that are correlated with estrogenic deficiency, including: premature ovarian failure; menopausal syndromes; osteoporosis; menstrual irregularities; pre-menstrual syndrome; cardiovascular disease; atherosclerosis, coronary artery disease and strokes; and cancer. These potential health benefits are consistent with epidemiological evidence that rates of heart disease, hormone-dependent cancers, osteoporotic fractures and menopausal symptoms are more favorable among populations that consume plant-based diets, especially among cultures with diets rich in soy products.
The biological effects of estrogens are mediated via estrogen receptors (ER), of which there are at least two types, i.e. ER-alpha and ER-beta (Pettersson, et al., 2001; Conneely, 2001). Estrogens are retained in target cells by the estrogen receptors (ERs). The ERs belong to the steroid-receptor superfamily of nuclear transcription factors, whose members include receptors for progesterone (PR), glucocorticoids (GR) and androgens (AR). The ERs, in common with other members of the steroid-receptor superfamily, are organized into domains that are responsible for specific functions. The N-terminal transactivation domain has a ligand-independent activation function. The DNA-binding domain (DBD) enables the receptor to bind to its cognate target site consisting of an inverted repeat of two half-sites with the consensus motif AGGTCA (or closely related sequences) spaced by 3 basepairs and referred to as an estrogen response element (ERE). The DBDs of ER-alpha and ER-beta share approximately 97% sequence homology but significant differences in amino-acid sequences are found in the N-terminal, and ligand-binding domains. Both ER-alpha and ER-beta bind to EREs in promoter regions of target cells. In addition ERs can regulate AP-1 enhancer elements, by acting on the transcription factors Fos and. Jun. The ligand-binding domain (LBD) also harbors a nuclear localization signal as well as sequences necessary for dimerization and transcriptional activation. Upon estrogen binding, ER undergoes a conformational change allowing the receptor to interact with chromatin and to modulate transcription of target genes. Modulation of gene expression leads to changes in the level of expression of corresponding proteins, which in turn bring about the myriad physiological activities associated with estrogens.
Although both ER-alpha and ER-beta bind specifically to the same estrogen response element (ERE), there are important differences in their actions in cellular systems and in their response to agonists and antagonists (Enmark, et al., 1998, Barkhem, et al., 1998). ER-beta requires approximately five- to ten-fold higher concentrations of estradiol than ER-alpha for maximum transactivation activity to occur and ER-beta is only approximately 30% as efficient as ER-alpha in a variety of reporter gene systems. The anti-estrogen tamoxifen is a mixed agonist/antagonist for ER-alpha but is a pure antagonist for ER-beta. ER-alpha and ER-beta can form functional DNA-binding heterodimeric complexes, and in these complexes ER-beta appears to be the dominant partner, given that activity is repressed at low concentrations of estradiol and in the presence of tamoxifen. Notably, ER-alpha and ER-beta have opposite effects at AP-1 and SP-1 sites (Paech, et al., 1997), in the presence of both agonists and antagonists. ER-alpha and ER-beta also bind to the same ligands with different affinity. In addition, after binding to estrogens and anti-estrogens, ER-alpha and ER-beta use different enhancer elements such as estrogen responsive element and AP1 sites in promoter regions of genes. Taken together, these studies suggest that ER-alpha and ER-beta may activate different downstream effects.
There are substantial differences in the distribution of ER-alpha and ER-beta in estrogen responsive tissues. ER-beta is expressed in many human tissues including the central nervous system, the cardiovascular system, the immune system, the urogenital tract, the gastrointestinal tract, the kidneys and the lungs (Omoto, et al., 2001). In contrast ER-alpha seems to predominate in reproductive tissues such as the uterus and breast, although smaller amounts of ER-beta are also present in these tissues. It is possible that ER-beta is the more widely expressed estrogen receptor in the body.
In tissues where both ER-alpha and ER-beta are co-expressed, it has been found in many cases that ER-beta opposes the actions of ER-alpha.
Phytochemicals and Phytoestrogens
Phytoestrogens may have partial estrogenic and anti-estrogenic activity due to their competition with endogenous estradiol for estrogen receptors (For reviews: Kurzer, et al., 1997; Zava, et al., 1998; Setchell, 1998; Tham, et al., 1998). The majority of phytoestrogens found in plants (including herbs and legumes) can be categorized into two primary classes: flavonoids and lignans. These substances have a structural similarity to the estrogens, estradiol and diethylstilbesterol, especially in relation to their —OH groups.
Flavonoids represent a family of phytochemicals with disparate functions, including: deterring herbivores, acting as antibacterial/antifungal agents and stimulating the formation of symbiotic relationships with nitrogen-fixing bacteria. The family of flavonoids is often subclassified on the basis of structural features into: flavones, isoflavones or coumestans. Isoflavones make up the most common form of phytoestrogens. Typically, phytoestrogens exhibit weak estrogenic activity, i.e. on the order of 100- to 1000-fold weaker activity compared to estradiol, but since these compounds may be present in the body in concentrations of 100-fold higher than endogenous estrogens, they may be present in the body at levels sufficient to compete with endogenous estrogen or compensate for estrogen deficien
Yap Sook Peng
Yong Eu Leong
National University of Singapore
Owens Amelia
LandOfFree
Methods for preparing an estrogenic preparation and isolated... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Methods for preparing an estrogenic preparation and isolated..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Methods for preparing an estrogenic preparation and isolated... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3346380