Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-03-30
2002-09-17
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06451849
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to methods for prevention of cancers, certain non-cancer, hormone dependent diseases and/or cardiovascular diseases in a person, based on administering of hydroxymatairesinol to said person. The invention also concerns a method for increasing the level of enterolactone or another metabolite of hydroxymatairesinol in a person's serum thereby causing prevention of a cancer or a certain non-cancer, hormone dependent disease in a person, based on administering of hydroxymatairesinol to said person. Furthermore, this invention relates to pharmaceutical preparations, food additives and food products comprising hydroxymatairesinol.
BACKGROUND OF THE INVENTION
The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated by reference.
Lignans are defined as a class of phenolic compounds possessing a 2,3-dibenzylbutane skeleton. They are formed by coupling of monomeric units called precursors such as cinnamic acid, caffeic, ferulic, coumaric, and gallic acids (Ayres and Loike, 1990). Lignans are widely distributed in plants. They can be found in different parts (roots, leafs, stem, seeds, fruits) but mainly in small amounts. In many sources (seeds, fruits) lignans are found as glycosidic conjugates associated with fiber component of plants. The most common dietary sources of mammalian lignan precursors are unrefined grain products. The highest concentrations in edible plants have been found in flaxseed, followed by unrefined grain products, particularly rye. Mammalian lignan production from different plant food are given in Table 1.
Considerable amounts of lignans are also found in coniferous trees. The type of lignans differs in different species and the amounts of lignans vary in different parts of the trees. The typical lignans in heart wood of spruce (
Picea abies
) are hydroxymatairesinol, (HMR), &agr;-conidendrin, conidendrinic acid, matairesinol, isolariciresinol, secoisolariciresinol, liovile, picearesinol, lariciresinol and pinoresinol (Ekman 1979). The far most abundant single component of lignans in spruce is HMR, about 60 percent of total lignans, which occurs mainly in unconjugated free form. Lignan concentration in thick roots is 2-3 percent. Abundance of lignans occur in the heart wood of branches (5-10 percent) and twists and especially in the knots, where the amount of lignans may be higher than 10 percent (Ekman, 1976 and 1979). These concentrations are about hundred-fold compared to ground flax powder known as lignan-rich material.
The chemical structure of hydroxymatairesinol is
Lignans can be isolated e.g. from compression-wood fiber. These fibers originate from compression wood of stems and knots (oversize chip fraction) worsen the quality of paper (Ekman 1976).
Plant lignans such as matairesinol and secoisolariciresinol, are converted by gut microflora to mammalian lignans, enterolactone and enterodiol, correspondingly (Axelson et al. 1982). They undergo an enterohepatic circulation and are excreted in the urine as glucuronide conjugates (Axelson and Setchell, 1981). As an experimental evidence for the chemopreventive actions of lignans, supplementation of a high-fat diet with lignan-rich flaxseed flour (5% or 10%) or flaxseed lignans (secoisolariciresinol-diglycoside, SDG) prevented the development of antiestrogen-sensitive DMBA-induced breast cancer in the rat (Serraino and Thompson 1991 and 1992; Thompson et al. 1996a and 1996b). They reduced the epithelial cell proliferation, nuclear aberrations, the growth of tumors, and the development of new tumors. High lignan intake may also protect against experimental prostate and colon cancers. Dietary rye (containing lignans), prevented at early stages the growth of transplanted Dunning R3327 prostatic adenocarcinomas in rats (Zhang et al. 1997; Landström et al. 1998). The percentage of animals bearing palpable tumors, the tumor volume, and the growth rate were significantly lower. Further, flaxseed or SDG supplementation inhibited the formation of chemically induced aberrant crypts in rat colon (Serraino and Thompson 1992; Jenab and Thompson 1996). The antitumor action may therefore be due to weak estrogen-antiestrogen-like properties and/or other mechanisms, which are not well understood.
Urinary excretion and serum concentrations of enterolactone are low in women diagnosed with breast cancer (Ingram et al. 1997; Heltén et al. 1998) suggesting that lignans are chemopreventive. Mammalian lignans (enterolactone and enterodiol) have been hypothesized to modulate hormone-related cancers, such as breast cancer, because of their structural similarities to the estrogens. Enterolactone had weak estrogenic potency in MCF-7 cells (Mousavi and Adlercreutz 1992), but had no estrogenic response in mouse uterine weight (Setchell et al. 1981). As a sign of estrogenic-like activity, SDG feeding during pregnancy and lactation to rats increased the uterine weight at weaning but the effect was not evident at later stages (Tou et al. 1998). Possible antitumor effects have also been associated with their antiestrogenic actions (Waters and Knowler, 1982). The inhibition of aromatase by mammalian lignan, enterolactone, would suggest a mechanism by which consumption of lignan-rich plant food might contribute to reduction of estrogen-dependent diseases, such as breast cancer (Adlercreutz et al. 1993, Wang et al. 1994). The potential antioxidant activity of lignans could also represent a mechanism associated with the preventive action of lignans in the development of cancers. Further, mammalian lignans have shown to inhibit the conversion of testosterone to 5&agr;-dihydrotestosterone (DHT), the potent intracellular androgen, at the concentrations which are achievable in humans (Evans et al. 1995). The reduction in DHT concentration would modify the risk of prostate cancer (PC) and benign prostatic hyperplasia (BPH).
It is possible that lignans as precursors of enterolactone could also alleviate lower urinary tract symptoms (LUTS) and gynecomastia. On the basis of the results obtained in the animal model, we have suggested that estrogens play an essential role in the development of the muscular dysfunction involved in urethral dyssynergia seen as bladder neck dyssynergia or external sphincter pseudodyssynergia (Streng et al. unpublished observations). Such neuromuscular changes are at least partially reversed by an aromatase inhibitor (MPV-2213ad) indicating the role of estrogens. Further, gynecomastia, which is induced by exposure to estrogens or in the presence of increased ratio of estrogen to androgens. Gynecomastia can be successfully treated with an aromatase inhibitor. The capability of lignans to inhibit 5&agr;-reductase and/or aromatase combined with their potential antioxidant activity may represent mechanisms associated with the preventive action of lignans in the development of hormone-related diseases in male organism.
No data is available on the possible effects of lignans in humans. The current theories about lignan action in humans have been derived from studies on the effects of diets supplemented with flaxseed products (and thus lignans). Flaxseed in human female diet caused changes in menstrual cycle (Phipps et al. 1993). The subjects, all normally cycling women, showed a longer mean length of luteal phase and higher progesterone/17&bgr;-estradiol ration in serum during the luteal phase when they took 10 g of flax seed powder/day in addition to their habitual diets (Phipps et al. 1993). No significant differences between flax and control cycles or concentrations of either estrone or 17&bgr;-estradiol were found. Neither there were any significant differences between flax and control groups for concentrations of serum estrogens in postmenopausal women (Brzezinski et al. 1997). Flaxseed supplementation increased SHBG (protein which binds estradiol with high capacity) concentration in serum. This is a typical estrogenic effect in the liver tissu
Ahotupa Markku
Eckerman Chester
Kangas Lauri
Mäkelä Sari
Saarinen Niina
Goldberg Jerome D.
Hormos Nutraceutical Oy Ltd.
Lydon James C.
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