Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-06-02
2002-01-22
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S899000
Reexamination Certificate
active
06340703
ABSTRACT:
This invention relates to compositions, therapeutic uses and methods of treatment or prevention of menopausal symptoms and osteoporosis.
Menopausal symptoms and osteoporosis are significant scourges in the female population, generally affecting many women in later life.
Menopausal symptoms are very well known and are described, for example, by Greene, J. G. and Cooke, D. J. (1980)
British Journal of Psychiatry
Volume 136, 486-491 (incorporated herein by reference). Hot flushes are one of the principal menopausal symptoms which are uncomfortable and irritating. Greene and Cooke have developed a score in order to measure menopausal symptoms in women. This score is approved by the U.S. Department of Health and widely used in the medical community. The indicators of menopausal symptoms according to Greene and Cooke comprise hot flushes, sweating at night, heart beating quickly or strongly, feelings of tension or nervousness, difficulty in sleeping, excitability, attacks of panic, difficulties in concentrating, feelings of tiredness or lack of energy, unhappiness or depression, crying spells, irritability, feelings of dizziness or faintness, pressure or tightness in head or body, parts of the body feeling numb or tingling, dry vagina and/or dry mouth, headaches, muscle and joint pains, loss of feeling in hands or feet, breathing difficulties, and loss of interest in sex.
The peri-menopausal stage of life in women is associated with a fall in blood levels of the three major estrogens—estradiol, estrone and estriol—which occurs naturally in women usually between 45-55 years of age. The primary or acute menopause symptoms which effect menopausal women include hot flushes and night sweats. These are associated with often dramatically increased blood perfusion of the skin producing discomfort and sweating.
The precise mechanism of these symptoms is unknown but generally is thought to represent disturbance to normal homeostatic mechanisms controlling vasomotor activity and thermoregulation.
The fact that treatment and/or prevention with replacement estrogens usually relieves the symptoms (so-called estrogen replacement therapies) establishes the link between these symptoms and an estrogen deficiency. The menopausal stage of life is associated with a wide range of other acute symptoms as described above and these symptoms are generally estrogen-responsive.
Osteoporosis is believed to affect one third to one half of all post-menopausal women. In the United States it has been reported that annually 500,000 bone fractures occur as a result of osteoporosis. It is further reported that nearly one third of women over 65 will suffer at least one bone fracture resulting from osteoporotic bone weakening. Increased calcium intake and other approaches are suggested to have some effect. However, the widespread effects of osteoporosis indicates effective approaches for prevention/treatment have not yet arisen.
It has previously been thought that reduction in endogenous estrogen levels which occurs prior to menopause causes or contributes to the symptoms of menopause, as well as post-menopausal osteoporosis.
Isoflavones, being plant chemicals which occur largely in members of Leguminosae, display a range of biological functions which have suggested they may be useful in treating a host of medical conditions.
A small sub-group of isoflavones (comprising daidzein, genistein, biochanin, and formononetin and) is distinguished by their ability to bind to estrogen receptors on animal (including human) cells. This is due to the close similarity of the steric structure of the diphenolic rings of isoflavones with the steroidal ring structure of estrogens such as estradiol, estrone and estriol. Although having substantially lower binding affinity to the receptor compared to steroidal estrogens, estrogenic isoflavones are weakly estrogenic. This group of five isoflavones have the most basic diphenolic structure possible in contrast to the relatively more complex structures of other isoflavonoid compounds. This simplicity of structure and its close proximity in shape to the steroidal ring structure of estrogenic hormones is believed to grant these compounds their estrogenicity. This group also exhibits a range of biological functions in animal cells which appear to be independent of the estrogen receptor and these include anti-oxidant, diuretic, anti-spasmolytic and anti-cancer effects. These interesting functions with their potential therapeutic benefits has brought this particular group of isoflavones to the attention of medical researchers in recent years.
In the plant, the isoflavones can occur in a variety of forms—(i) in the basic form, (ii) in a malonyl form, and (iii) in an acetyl form; the isoflavones are biologically active in each of these forms. The naturally-occurring state for each of these forms is as a glycoside, being bound to a sugar moiety such as glucose to produce a water-soluble form. In this form, the isoflavone has enhanced stability to degradative factors such as heat, oxidation and ultraviolet irradiation. This water-soluble form also permits transport of the isoflavone both around the plant and intra-cellularly. At the intracellular site of biochemical function of the isoflavone, an intra-cellular glucoside enzyme cleaves the sugar moiety, leaving the more biologically active, but water-insoluble, aglucone form.
When ingested in the diet, the isoflavones undergo varying degrees of metabolism within the gut, within the gut wall, and within the liver before entering the parenteral bloodstream to exert their biological effects. The first metabolic process is the hydrolysis of the glucosidic form to the aglucone form. This occurs as a result both of low pH from gastric acid and of the action of &bgr;-glycosidase enzyme activity within bowel bacteria.
Some of the aglucone isoflavones are absorbed intact and in passing through the gut wall are believed to be glucuronated or sulphonated as per steroidal compounds. The bulk of isoflavones are fermented within colonic bacteria. One of the fermentation processes is to demethylate isoflavones (eg. formononetin gives daidzein and biochanin gives genistein on demethylation). In another series of fermentation steps, daidzein and genistein are converted to a range of end-products including equol, dehydroequol, O-desmethylangolensin (ODMA), 6-hydroxy-ODMA, 2-dehydro-ODMA, dihydrodaidzein, tetra-hydrodaidzein and dihydrogenistein. The liver is capable of further demethylation of isoflavones such as formononetin and biochanin to the more basic daidzein and genistein structures. The isoflavones and their metabolites and derivatives circulate freely within the body and are excreted primarily in the urine with smaller amounts in the faeces.
The possibility that dietary estrogenic isoflavones may have some therapeutic benefit in acute menopausal symptoms was suggested by the observation that Japanese women who typically have much higher dietary levels of isoflavones (mostly derived from soya) compared to women in Western countries have a reportedly lower incidence of acute menopausal syndrome symptoms such as hot flushes. This has led to somewhat speculative claims of therapeutic benefit of the isoflavones from the group daidzein, formononetin, biochanin and genistein in the treatment and/or prevention of acute menopausal syndrome symptoms (U.S. Pat. No. 5,498,631 -Gorbach et al).
Gorbach analysed urinary isoflavone excretion in Japanese subjects who consumed a traditional Japanese low-fat diet. The presence of estrogenic isoflavones in the urine of the women, men and children studied suggested to Gorbach that the isoflavones produced a therapeutic effect. The obvious flaws in this study, namely that in a diet with high isoflavone intake significant urinary out-put of isoflavones would be expected, and the huge number of biochemically active species in any diet make it impossible to ascribe biological effects to any particular component or components indicate that Gorbach's claims do not stand scrutiny. The fact that a community with a particular heal
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Novogen, Inc.
Webman Edward J.
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