Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Bacteria or actinomycetales
Reexamination Certificate
2000-02-08
2004-04-06
Marx, Irene (Department: 1651)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Bacteria or actinomycetales
C424S725000, C424S093300, C514S456000
Reexamination Certificate
active
06716424
ABSTRACT:
TECHNICAL FIELD
The present invention relates to an isoflavone-containing composition and more particularly to a novel composition either comprising a daidzein-containing substance and a strain of microorganism capable of metabolizing daidzein to equol or comprising equol obtained by causing said strain of microorganism to act upon said daidzein-containing substance, which composition is useful for the prevention and alleviation of unidentified clinical syndrome and conditions associated with the menopause in middle-aged to elderly women.
BACKGROUND ART
The documented collaborative research of National Cancer Center of Japan and Helsinki University (Finland) attributes the low incidence of gender-specific neoplastic diseases such as carcinoma of the prostate in men and carcinoma of the breast or ovary in women among the Japanese as compared with the European and American people to the greater intake by the Japanese of soybean-derived foods containing various isoflavonoids and the consequent well-coordinated balance of hormones (H. Adlercreutz, et al., (1992) Lancet, 339, 1233; H. Adlercreutz, et al., (1992) Lancet, 342, 1209-1210).
Recently, there has been a mounting interest in the fact that isoflavonoids have estrogen (female hormone)-like activity (A. Molteni, et al.,(1995) J. Nutr., 125, 751S-756S), and it has been reported that these compounds are effective in osteoporosis which develops after the menopause when estrogen secretions have subsided or ceased (D. Agnusdei, et al., (1995) Bone and Mineral, 19 (Supple), S43-S48) as well as in menopausal syndrome (D. D. Baird, et al., (1995) J. Clin. Endocrinol, Metab., 80, 1685-1690; A. L. Murkies, et al., (1995) Maturitas., 21, 195-198).
According to the result of a survey undertaken by Margaret Lock (M. Lock, et al., (1988) Maturitas., 10, 317-332), the incidence of menopausal syndrome among the Japanese women is extremely low as compared with the Canadian counterparts. Based on the report, H. Adlercreutz and coworkers conjecture that the Japanese women ingest large amounts of processed soybean foods such as tofu, miso, soy sauce, etc. and, hence, the plant estrogens (isoflavonoids) occurring in those foods are responsible for the low incidence of menopausal syndrome. Comparing the urinary excretions (24-hour urine) which are known to reflect the amount of absorption of isoflavonoids actually ingested, the same authors further report that compared with the Western women, the urinary excretions in the Japanese women are tens of times as high (C. Herman, et al., (1995), J. Nutr., 125, 757S-770S).
It is, thus, considered that the intake of isoflavonoids such as daidzein, genistein, daidzin, genistin, etc. is effective for the alleviation and prevention of postmenopausal osteoporosis and menopausal syndrome. Particularly, the postmenopausal life expectancy in women has reportedly increased to more than 30 years owing to the recent trend toward longevity and the alleviation and prevention of various diseases and symptoms which may develop after the menopause have important meanings in that they would lead to improvements in quality of life (QOL).
However, the above report, i.e. the survey report on the amount of intake of isoflavonoids and the urinary excretions of isoflavonoids in the middle-aged to elderly women in Japan reflects the results generated in a limited rural area and no substantive information is available. Moreover, the correlation between the frequency of menopausal syndrome and the amount of intake of isoflavonoids has not been squarely analyzed and revealed.
Therefore, the object of the present invention is to provide a novel composition which is effective for the prevention and alleviation of the so-called unidentified clinical syndrome in middle-aged to elderly women, inclusive of menopausal syndrome, for which no effective means of prevention or alleviation has been available.
To accomplish the above object, the inventors first conducted a dietary survey, determination of urinary excretions of isoflavonoids, and a questionnaire survey about menopausal syndrome (unidentified clinical syndrome) in perimenopausal women in a broad geographical area including urban communities.
According to the results of the above investigation conducted in 116 women aged between 40 and 60 who belonged to Fukuoka Dietitian Association, the average amounts of intake of isoflavonoids were 9 mg/day for daidzein and 13 mg/day for genistein. The average urinary excretions of isoflavonoids were 19.6 &mgr;mol/day for daidzein and 10.0 &mgr;mol/day for genistein, and the average excretions of equol, a metabolite of daidzein, was 11.9 &mgr;mol/day (mean of subjects in whom it was detected). Incidentally, although daidzein and genistein were detected in all the subjects, equol was detected only in 46 (51.6%) of the 95 subjects.
Furthermore, women with paramenia and those within 5 years of the menopause being taken together as menopausal subjects, a questionnaire survey was conducted using 17 items which are in routine use in the diagnosis of menopausal syndrome [17 items as a modification of Kupperman menopausal index (Kupperman H. S., et al., (1953), J. Clin. Endocrinol. Metabol., 13, 688-703), i.e. 1. hot flushes, 2. perspiration, 3. local sensation of cold, 4. shortness of breath, 5. numbness of limbs, 6. hypesthesia, 7. difficulty in falling asleep, 8. fitful sleep, 9. irritability, 10. nervousness, 11. melancholy, 12. vertigo, nausea, 13. weakness(fatigue), 14. stiff shoulders, pain in joints, muscular pain, 15. headache, 16. palpitation, 17. tingling sensation] and the simplified menopausal index (SMI) was calculated. With subjects with SMI values not less than 20 being taken as a group of high climacteric symptoms and those with SMI values not greater than 19 as a group of low climacteric symptoms, the amount of intake of isoflavonoids and the urinary excretion of isoflavonoids were respectively compared between the groups.
As a result, whereas no intergroup difference was found in the amount of intake of daidzein, the amount of intake of genistein tended to be lower in the group of high climacteric symptoms at p=0.0643. With regard to the urinary excretions of isoflavonoids, no intergroup difference was found whether for daidzein or for genistein but the excretions of equal were significantly low (p<0.01) in the group of high climacteric symptoms.
From the above results, the inventors found that unidentified clinical symptoms in menopausal women are more closely related to the amount of intake of genistein and the urinary excretion of equal, among various isoflavonoids.
In the past the relationship of the amounts of intake and urinary excretion of isoflavonoids as a whole to their physiological effect has been discussed without regard to specific kinds of isoflavonoids such as daidzein and genistein but the results of the survey conducted by the inventors in the Japanese middle-aged and elderly women made it clear that not only the amounts of intake and urinary excretion of isoflavonoids in general but also the amount of intake of genistein and the urinary excretion of equol, particularly the rate of metabolic conversion of daidzein to equol, are closely related to unidentified clinical climacteric symptoms in menopausal women.
In another study undertaken by the inventors in healthy adult volunteers (25-33 years of age), it was found that the urinary excretions of isoflavonoids (daidzein and genistein) after single ingestion of soy milk, a representative isoflavonoid-containing food, are increased in a dose-related fashion but in subjects who showed no urinary excretion of equol, equol was not detected in the urine even when the amount of intake of soy milk was increased two-fold, indicating the existence of individual difference in the metabolic pathway from daidzein to equol.
It is known that equol, which is a metabolite of daidzein, is not detected in isoflavonoid-containing foods such as processed soybean products nor is it taken into the body from foods in ordinary diets (K. Reinli, et al., (1996), Nutr. Ca
Imaizumi Kiyoko
Kumemura Megumi
Masaki Kyosuke
Shimizu Seiichi
Uchiyama Shigeto
Marx Irene
Otsuka Pharmaceutical Co. Ltd.
Sughrue & Mion, PLLC
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