Drug – bio-affecting and body treating compositions – Plant material or plant extract of undetermined constitution... – Containing or obtained from leguminosae
Reexamination Certificate
2000-12-22
2002-01-01
Prats, Francisco (Department: 1651)
Drug, bio-affecting and body treating compositions
Plant material or plant extract of undetermined constitution...
Containing or obtained from leguminosae
C424S768000, C424S436000
Reexamination Certificate
active
06335038
ABSTRACT:
The present invention relates to a composition for the prevention and/or treatment of osteoporosis and alterations due to menopause syndrome.
Accordingly the composition may take the form and exert the action of a dietary supplement or of an actual medicine, depending upon the support or preventive action, or the strictly therapeutic action, which the composition is intended to exert in relation to the particular individuals it is to be used in.
Particularly the present invention relates to a composition which comprises in combination:
(a) propionyl L-carnitine or a pharmacologically acceptable salt thereof, optionally in combination with at least another “carnitine” where for “carnitine” is intended L-carnitine or an alkanoyl L-carnitine selected from the group comprising acetyl-L-carnitine, valeryl L-carnitine, isovaleryl L-carnitine or their pharmacologically acceptable salts; and
(b) 4′,5,7-trihydroxyisoflavone (genistein) optionally in combination with at least another isoflavone selected from the group comprising 4′,7-dihidroxyisoflavone (daidzein), its 7-glucoside (daidzin) and its 4,7-diglucoside.
The new composition can be orally, parenterally, rectally or transdermally administered and results particularly useful both to humans and animals, as a dietary supplement or as an actual medicine.
As is well known, postmenopausal syndrome is characterised by numerous manifestations including vascular effects ranging from hot flushes to an increased risk of cardiovascular accidents, as well as mental and mood disorders, and the occurrence of osteoporosis.
The risk of tumours also increases in this period.
Osteoporosis is a prevalent disease in elderly subjects, but it is particularly postmenopausal women who are most affected.
Osteoporosis, cardiovascular accidents and tumour risk are, in fact, the most frequent events in postmenopausal women.
The therapeutic approaches for the prevention and treatment of the pathological abnormalities accompanying this period are multiple and involve the use of minerals such as calcium, vitamins such as vitamin D, or calcitonin, but the most wide-spread therapy consists in hormone replacement treatment (HRT).
Oestrogen treatment, in fact, is clearly indicated in postmenopausal disorders as replacement therapy for a well documented deficiency of such hormones.
The use of these hormones, however, is by no means risk-free. Well known are the thromboembolic risks related to the use of oestrogens and these constitute one of the factors limiting their use. The most serious factor, however, is above all the carcinogenic risk. Oestradiol and progesterone, as well as dihydrotestosterone receptors have, in fact, been described in primary tumours of the large bowel and breast. Activation of these receptors has been postulated as one of the pathogenetic causes of these tumours.
Hormone replacement therapy (HRT) is associated with a series of side effects consisting not only in the thromboembolic and carcinogenic risk, but also in weight gain, headache, nausea, depression, and breast swelling and tension.
Additional manifestations regarded as contraindications are the presence of endometriosis, uterine fibroids or previous breast and uterine tumours, which often prompt the physician to abandon this type of therapy and look for other safer solutions.
Isoflavones and phyto-oestrogens would appear to offer a valid alternative.
The indication that vegetable derivatives are capable of exerting an oestrogen-like action has emerged from the finding that animals fed on Medicago sativa or Trifolium repens present disorders of the reproductive capability. The cause of this effect has been traced to the presence in these plants of coumesterol, a substance structurally similar to oestradiol and classed among the phyto-oestrogens.
Substances which are naturally occurring in the vegetable world with structures and functions similar to 17&bgr;-oestradiol are regarded as phyto-oestrogens. This category includes numerous compounds such as lignans, isoflavones, coumestans and lactones of resorcylic acid. Phyto-oestrogens are present in many cereals and legumes. Legumes such as soy are particularly rich in isoflavones, while lignans are present in almost all cereals and, above all, in linseed oil.
Phyto-oestrogens may derive from precursors present in the diet after bacterial modification in the stomach or gut.
The main derivatives from bacterial modification of lignans are. enterodiol and enterolactone, whereas the main isoflavone derivatives after bacterial removal of the glycoside part are genistein, daidzein and equol.
Most of these phyto-oestrogens have been identified in human plasma and saliva, as well as in prostate fluid and mammary cyst aspirate.
All phyto-oestrogens possess oestrogen-like activity, though it is inferior to that of oestradiol.
Epidemiological research has demonstrated a lower incidence of breast, ovarian and large bowel tumours in populations consuming diets containing substantial amounts of isoflavones than in those consuming only small amounts of these substances.
There is a marked difference in this sense between Asiatic and Western populations.
The prognosis, e.g. of breast tumours, is also better in Asiatic populations such as the Japanese than in those of the U.S. or Great Britain.
In-vitro studies, moreover, have confirmed the antiproliferative activity of phyto-oestrogens, as assessed in breast tumour cell lines.
In the case of osteoporosis, too, it has been found that the incidence of this disease increases in relation to an oestrogen deficiency and is lower in Asiatic populations with a diet rich in isoflavonoids than in Western populations.
It has recently been postulated that phyto-oestrogens may behave differently, at oestrogen receptor level, according to the different tissues, as is the case with the synthetic oestrogens such as tamoxifen or 4-hydroxytamoxifen which act as antagonists at the level of the oestrogen receptors of breast tissue and as partial agonists at the level of the vessels and bone tissue.
As regards genistein (4′,5,7-trihydroxyisoflavone), we should also consider other mechanisms of action such as inhibition of membrane ATPase and inhibition of tyrosine kinase and topoisomerase II.
It has also been reported that genistein exerts a direct metabolic effect on bone metabolism and that it is capable of inhibiting bone reuptake in in-vitro cultures of femoral metaphyseal tissue. Genistein also protects the endothelial cells against atherogenic risk and prevents or inhibits tumour development. The tumour risk, however, generally appears to be reduced not only by intake of genistein but also by soy extracts.
Among the various isoflavones, genistein and daidzin appear to be the ones that show the closest interaction with oestrogen receptors.
These properties make phyto-oestrogens valid candidates as substitutes for oestradiol, presenting none of the latter's side effects and proving suitable for practically unlimited ingestion, as occurs in those populations whose diets include substantial consumption of vegetables and legumes.
The metabolic actions of the carnitines are very well known. L-carnitine, acetyl L-carnitine, propionyl L-carnitine and isovaleryl L-carnitine all present practically the same activity at the mitochondrial level and at the level of &bgr;-oxidation of fatty acids, though with some differences according to their kinetics and the tissues considered.
The carnitines also exert a substantial antioxidant action, thereby providing a protective effect against lipoperoxidation of the phospholipid membrane and against oxidative stress induced at myocardial and endothelial cell level.
The carnitines have also proved to be active on carbohydrate metabolism. In the course of ageing, tissue carnitine concentrations diminish and therefore so do the metabolic possibilities of the various tissues. Particularly adversely affected are tissues such as bone tissue which require a continuous reconstructive and metabolic functional capability on the part of the osteoblasts for maintenance of bone
Coe Susan D.
Prats Francisco
Sigma-Tau Healthscience S.p.A.
LandOfFree
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