AU755900B2 - Utilization of extracts from iris plants, cimicifuga racemosa and tectorigenin as an estrogen-like organ-selective medicament without uterotropic effects - Google Patents
Utilization of extracts from iris plants, cimicifuga racemosa and tectorigenin as an estrogen-like organ-selective medicament without uterotropic effects Download PDFInfo
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Abstract
The invention relates to the utilization of extracts from iris plants, cimicifuga racemosa and tectorigenin as an estrogen-like organ-selective medicament for selectively treating and/or for the prophylaxis of cardiovascular diseases, especially arteriolosclerosis, osteoporosis and climacteric symptoms, for example, for preventing or alleviating hot flashes. Virtually no uterotropic effects are observed when using said abstracts.
Description
-1- Description Use of extracts from Iridaceae and Cimicifuga racemosa and of tectorigenin as an estrogen-type, organoselective medicament having no uterotrophic effect The present invention relates to the used of extracts from Iridaceae, and those from Cimicifuga racemosa as an estrogen-type, organoselective medicament, and tectorigenin and/or tectorigenin glycosides as a medicament.
17-p-estradiol, which is formed in the ovaries (whenever estradiol is mentioned hereinafter, this always refers to physiological 17-p-estradiol) [hereinafter also referred to as E 2 generally has a proliferation-promoting effect in the organism. Apart from controlling the female cycle, it i.a. has a homeostatic influence on the metabolism of the bone and prevents formation of 15 atherotic plaques at the endothelium of the vessels.
During menopause, lowering of the estradiol level takes place due to cessation of the ovarial function. This results in a weakening of proliferative processes, and in the hypothalamus results in an intensified activity of the 20 GnRH impulse generator. (The gonadotropin-releasing hormone impulse generator is a timer in the hypothalamus, as it were, and times the pulsatile LH secretion, with steroids influencing amplitude and frequency.) In climacteric women, the resulting, stimulated LH secretion brings about the so-called "hot flushes" which are felt to be disturbing.
In the absence of sufficiently high estradiol levels in the blood, osteoclast activity and thus destruction of the bone mass is prominent, accompanied by an increased risk of skeleton breakage. At the same time, there is in the long term a risk of plaque formation in the vascular system and thus an increased risk of infarctions.
-2- Extracts from Cimicifuga racemosa and from Belamcanda sinensis are both known from popular medicine to be capable of alleviating peri-menopausal and post-menopausal disorders. Hitherto this has been explained through the fact that the extracts of both plant drugs exhibit an estrogen-type effect with all the positive effects thereof on a multiplicity of organs of the human body, particularly the brain, ovaries, bones, vascular system. Estrogen-type effects on uterus, vagina, breast tissue and liver would in turn be disadvantageous.
What is undesirable, however, is that up to the present, a medicament from these plant drugs which might be used for organoselective prophylaxis or therapy in cases of estrogen deficiency, has not been available in the prior art.
Starting out from this state of the art, it is therefore an object of the present invention to furnish plant medicaments with an estrogen-type effect, the effect of which is organoselective with no effect or only slight effect on the 15 uterus.
This object is independently achieved in one aspect through the invention residing in the use of extracts from Iridaceae for producing an estrogen-type, organoselective medicament having no uterotrophic effect or one S 20 that is at least negligible, under the proviso that Belamcanda sinensis extract is not used if the medicament is used for alleviating peri-menopausal and postmenopausal disorders.
This object may also be achieved through a further aspect of the invention residing in the use of extracts from Cimicifuga racemosa for producing an estrogen-type, organoselective medicament having no uterotrophic effect or one that is at least negligible, under the proviso that the medicament is not used for alleviating peri-menopausal and post-menopausal disorders and dysmenorrhea.
In a preferred embodiment the extracts are produced from Belamcanda I R4inensis. The above object is moreover achieved by -2Aa still further aspect of the invention that resides in the use tectorigenin and/or its glycosides for producing an estrogen-type, organoselective medicament having no uterotrophic effect or one that is at least negligible.
Another independent solution is represented by a plant extract containing tectorigenin and/or tectorigenin glycoside or enriched with tectorigenin and/or tectorigenin glycoside.
Both in in-vitro and in-vivo experiments it was surprisingly found that extracts produced both from Iridaceae, particularly Belamcanda sinensis, and from Cimicifuga racemosa with organic solvents or with supercritical C02, organoselectively act on the central nervous system, the bone system and the vascular system, with an effect on the uterus the so-called uterotrophic effect not existing. The extracts used in accordance with the invention are thus 15 suited for producing a ready formulated medicament for the selective treatment and/or prophylaxis of osteoporosis.
They are moreover suited for production of a ready-formulated medicament for the selective treatment and/or prophylaxis of cardiovascular 20 diseases, particularly of atherosclerosis.
o *0oeo They are moreover suited for producing a ready-formulated medicament for the selective treatment and/or prophylaxis of perimenopausal and post-menopausal psychovegetative disorders such as, e.g., hot flushes.
It was moreover found that the component tectorigenin, which was isolated from Belamcanda sinensis, essentially exerts the same effects as the whole extract.
HO
Tectorigenin This component is also found, besides Belamcanda sinensis, in other Iridaceae such as, Iris germanica, I. tectorum, I. illyrica, I. dichotoma.
Taxonomically speaking, Belamcanda sinensis is classified as follows: Order Liliales Family Iridaceae Genus Belamcanda Species Belamcanda sinensis (Leman) DC. Pardanthus chinensis Ker-Gawler, also: Ixia chinensis L.
(=Gemmingia chinensis O. Kuntze) Preferably rhizomes, stalks, leaves and/or petals of the plants are used for producing the extracts.
A fundamental phytochemical description of Belamcanda sinensis and its components was given in the dissertation by Ms. A. Nenninger: (LMU Munchen, 1997) entitled: "Phytochemische und pharmakologische Untersuchungen von Belamcanda sinensis, einer Arzneipflanze der TCM und anderer Irisarten".
[File:ANM\BI5720B1.doc] Description, 24.07.00 S PCT/EP99/01860, CIMICIFUGA-Anwendung BIONORICA Arzneimittel GmbH -4- With the medicaments of the invention, medicaments from Cimicifuga racemosa and Belamcanda sinensis and other Iridaceae and tectorigeninbased medicaments are for the first time available, which act as full estrogen receptor agonists in bones, in the cardiovascular system and in the brain.
Further advantages and features of the present invention become clear from the description of experimental data and by referring to the drawings, showing: Fig. 1: a comparison of the organic and aqueous phases of Cimicifuga racemosa. Displacement graph of a representative estrogen receptor ligand binding assay. The concentration of the start solution is 17.66 mg/ml, followed by dilutions 1:2, 1:4 etc. up to 1:64; Fig. 2: serum LH prior to, and 2 hours after, intravenous injection of Belamcanda sinensis extract, E2 and vehicle. The Belamcanda sinensis extract has a similar capacity of lowering the elevated Serum LH levels as E2; Fig. 3. effects of Cimicifuga racemosa and E2 on uterus weights (Fig. 3a) and LH levels in the blood (Fig. 3b) in ovariectomised rats after seven-day subcutaneous treatment; (mean values SEM, n 8, p 0.05 vs.
cremophor as vehicle); Fig. 3a) uterus weights; Fig. 3b) LH concentrations in the blood; Fig 4a) effects of Cimicifuga racemosa and E2 in ovariectomised rats after seven-day subcutaneous treatment; (mean values SEM, n 8, p 0.05 vs. cremophor as vehicle) on the expression of the mRNA for E2-receptor a in the preoptic region of the hypothalamus; S[File:ANM\BI5720B1.doc] Description, 24.07.00 PCT/EP99/01860, CIMICIFUGA-Anwendung BIONORICA Arzneimittel GmbH Fig 4 b) the expression of the mRNA for IGF1 and C3 in the uterus of ovariectomised rats after 7 days of subcutaneous administration; and Fig 4 c) the expression of the mRNA for collagen 1 (Colll) and osteocalcin in the bone of ovariectomised rats after 7 days of subcutaneous administration.
Experimental evidence for the estrogenic effect of Cimicifuga racemosa and Belamcanda sinensis Selective estrogenic effect was demonstrated in stages in the course of a series of test systems of various degrees of complexity.
1. in-vitro experimentation 1.1 in-vitro experiments for Cimicifuga racemosa Recognition of the estrogen-type structure of components by an antibody directed against 17-13-estradiol was shown in vitro.
The Cimicifuga racemosa extract was evaporated over residue. By phase distribution between dichloromethane and water, substances having different polarities were enriched. Binding affinities of the components of both phases were determined in vitro on estrogen receptors from pig's uterus. The cytosolic estrogen receptors from the pig uteri were isolated in accordance with standard procedures and used for the ligand displacement experiments.
Herein it was found that the estrogen-type structures e.g. from Cimicifuga racemosa are not hydrophilic in nature but lipophilic inasmuch as they may be extracted from the extract by means of an organic solvent. The substances present in the organically extracted phase bind about ten times more strongly to the antibody than the substances remaining in the aqueous phase.
The difference between the two phases is even greater in the estradiol receptor binding assay. The similarity of the binding substance with estradiol I [File:ANM\BI5720B1.doc] Description, 24.07.00 PCT/EP99/01860, CIMICIFUGA-Anwendung BIONORICA Arzneimittel GmbH -6must be high enough to enable a selective competitive interaction with the estradiol receptor to take place in a cell-free preparation. Inside this test system, the aqueous phase does not possess any activity, whereas the organic phase binds very strongly to the receptor.
The results are shown in Fig. 1.
1.2 in-vitro Belamcanda sinensis It is known from other studies that extracts from Belamcanda sinensis also possess components which are recognised by an antibody against 17- B-estradiol and bind to the 17-f1-estradiol receptor (cf. Nenninger loc.cit.).
Surprisingly, however, the inventors of the present application have found that these extracts have different estrogenic effects on different organ systems, particularly that they do not have a uterotrophic effect.
2. in-vivo experiments: Evidence for the estrogenic effect on ovariectomised rat Binding to the receptor E2 is very selective; it is, however, not possible to say whether the subsequent processes within the cell are promoted or inhibited, i.e. whether the substance is an agonist or an antagonist. This property can only be determined in suitable cellular systems or in the overall animal.
The ovariectomised rat is a recognised model for the post-menopausal woman in whom the endogenous estradiol production has subsided. As a result of the external supply of 17-B-estradiol or of substances which have an estrogen-type effect, there occurs a restauration of estrogen-sensitive anatomical-morphological parameters, such as increase of the uterus weights and the occurrence of hornified cells, i.e. plaque epithelium cells at the vaginal epithelium, or hormonal changes such as lowering of the LH levels in the blood of the treated animals.
All experiments described hereinbelow were carried out with ovariectomised Sprague-Dawley rats (=ovx rats) having a weight between 240 and 280 g.
[File:ANM\BI5720B1.doc] Description, 24.07.00 PCT/EP99/01860, CIMICIFUGA-Anwendung BIONORICA Arzneimittel GmbH -7- 2.1 Single administration of Belamcanda sinensis The onset of the effect of the estradiol-type effect of Belamcanda sinensis extract occurs very quickly. Even after a single i.v. administration of vehicle, estradiol and Belamcanda sinensis extract to ovx rats, pulsatility ceases both under E2 and under Belamcanda sinensis. In the medicament value development, there result significant inhibitions of the serum LH levels, both in comparison with the previous values and in comparison with the cremophor-treated control animals. Cremophor is an emulsifier on the basis of polyethoxylated castor oil derivatives.
The results are represented in Fig. 2.
In the uterus of the animals six hours after injection of the Belamcanda sinensis extract, the expression of the uterine VEGF, IGF1 and C3 genes is not changed in comparison with the controls, whereas the estradiol injection brings about a clear increase of the gene expression of these three estrogen-regulated proteins. The constitutively expressed CCO gene was not significantly influenced by any one of these treatments.
These findings indicate that components of Belamcanda sinensis bring about an inhibition of the GnRH pulse generator in hypothalamic estrogenreceptive structures and thus have estrogen-agonistic effects. Hereby the hypophysary LH secretion is inhibited significantly both by components in Belamcanda sinensis and by estradiol. In contrast with estradiol, the components in Belamcanda sinensis do not have a uterotrophic effect.
Estradiol significantly regulates the gene expression of VEGF, IGF1 and C3 upwardly, an effect which is not observed under Belamcanda sinensis.
Execution of the acute experiment on the effect of an i.v. injection of Belamcanda sinensis extract 24 rats 8 animals/group) had a jugular vein catheter implanted under ether anesthesia on the day preceding the experiment. On the day of the experiment, 6 blood samples were taken at 10-min intervals. Immediately following taking of the 6th sample, 62.5 mg of the Belamcanda sinensis extract or 10 pg 17-13-estradiol (E2) or the solvent (5 cremophor in isotonic NaCI 1 ml), respectively, were injected intravenously, and blood [File:ANM\B15720B1.doc] Description, 24.07.00 PCT/EP99/01860, CIMICIFUGA-Anwendung BIONORICA Arzneimittel GmbH samples were taken for another 2 hours in 10-minute intervals. 6 hours after the intravenous administration, the animals were decapitated, blood was obtained and the uteri removed, weighed and deep-frozen in liquid nitrogen.
2.2 One-time administration of tectorigenin Following a single administration of tectorigenin, the time development of influence on the LH levels in the blood and the estradiol-type immunoreactivity were determined. The concentration of tectorigenin in the blood of the animals, determined with the aid of E2-RIA, after 20 min corresponds to about 100 pg equivalent estradiol.
Tectorigenin triggers a rapid LH reduction. The kinetics of the LH reduction achieved under tectorigenin up to the time 60 min following i.v.
administration precisely correspond to the one of estradiol, but then do not result in further reduction but slowly increases again.
Execution: OVX rats had catheters placed in the vena jugularis externa under ether anesthesia 24 hours before the beginning of the experiment, in accordance with the method of Harms and Ojeda (Harms PG; Ojeda SR: A rapid and simple procedure for chronic cannulation of the rat jugular vein. J.
Appl. Physiol. (1974) 36: 391-392). The tube end was positioned in a skin pocket in the neck. In order not to have to touch the animals for obtaining the blood samples, the catheter was prolonged with the aid of a silicone tube.
Catheter and tube were rinsed with Ringer solution containing 50 IU heparin/ml.
Blood samples of 100 pl each were drawn from the animals at intervals, and the withdrawn volume replaced with Ringer/heparin solution.
After the 6th sample, 1.0 ml of the respective test solution was applied intravenously. As test solutions there were used: 2% cremophor (=vehicle solution), tectorigenin 7mg/ml vehicle, 17-f1-estradiol 10 g/ml vehicle. Blood was taken at ten-minute intervals through additional 140 min.
The blood samples thus obtained were filled into a 0.5 ml Eppendorf reaction vessel containing 10 pl heparin-Losung (5000 IU/ml, Liquemin), S [File:ANM\BI5720B1.doc] Description, 24.07.00 PCT/EP99/01860, CIMICIFUGA-Anwendung S BIONORICA Arzneimittel GmbH centrifuged for 10 min at 10 000 g, and the plasma stored at -20 0 C until performance of the radioimmunoassays.
The RIAs for LH and Prolaktin are based on antisera, reference and iodisation preparations from NIH (Bethesda, Maryland, USA). The concentrations of estradiol and of the cross-reactive isoflavones were measured with the aid of an RIA from DPC, Bad Nauheim.
2.3 Effect of Belamcanda sinensis extract after administration through 7 days The effects of repeated administration of estradiol, Belamcanda sinensis extract and vehicle on overall weight, uterus weight, hormone level and gene activation of uterus and bone were examined on ovariectomised rats after daily s.c. application through seven days.
The average body weights of the cremophor- and Belamcanda sinensis-treated animals do not differ, whereas the E 2 -treated animals were significantly lighter. Neither do the uterus weights of the animals treated with cremophor and Belamcanda sinensis differ significantly, whereas the E2treatment more than tripled the uterus weights.
The serum LH levels in the Belamcanda sinensis-treated animals were reduced slightly, but significantly in comparison with the cremophor controls; reduction through estradiol was more marked.
In the uterine mRNA extract, estradiol significantly raised the gene expression of VEGF to 149% of the control value after a one-week treatment. Unter Belamcanda sinensis extract, expression was raised slightly but not significantly. Expression of the non estrogen-regulated constitutive genes for the cytochrome C oxidase CCO) was not influenced.
In extracts of the femur head, the collagen-1A1, osteocalcin, IGF1 and TGFIf-mRNA expression was determined. Estradiol as well as Belamcanda sinensis significantly inhibited the expression of all 4 genes without having an influence on the constitutive CCO gene.
The different effects of estradiol and Belamcanda become very clear Safter the seven-day treatment. Belamcanda sinensis extract has an estradiol- [File:ANM\BI5720B1.doc] Description, 24.07.00 PCT/EP99/01860, CIMICIFUGA-Anwendung S BIONORICA Arzneimittel GmbH agonistic influence on the hypophysary LH secretion by inhibiting the GnRH impulse generator, and on the gene expression of four estrogen-regulated genes in the bone. In contrast, there is no estrogenic effect on the uterus: neither the uterus weight nor the estrogen-regulated VEGF gene are influenced by the Belamcanda sinensis extract. In contrast, estradiol brings about ballooning of the uterus and an activation of the VEGF gene.
Execution of the subacute test on the effect of daily s.c. injection through 7 days: 8 animals each per test group (24 altogether) were daily injected subcutaneously between 8:00 and 9:00 a.m. with 62.5 mg Belamcanda sinensis extract and 10 pg estradiol or the solvent (cremophor 1 ml), respectively. 6 h after the last application, the animals were decapitated and from every animal the aorta, the uterus and the left femur head were removed, cleaned, and frozen in liquid nitrogen.
In the blood samples, LH and the estradiol immunoreactivity were determined.
2.4 Repeated administration of Cimicifuga racemosa 14 days following ovarectomy at the earliest, the animals have the respective test substance injected subcutaneously in a dose of 62.5 mg Cimicifuga racemosa/rat or 8 pg estradiol/rat once daily in the morning over a period of 7 days. Both substances were dissolved in 5%0cremophor, the control animals only received the vehicle.
Following decapitation of the animals, brains, uterus and femur were prepared for mRNA-recovery. The LH concentration in the blood of the animals was determined by means of RIA. The expression of the estrogenregulated genes in the above identified organs was determined by means of semi-quantitative RT-PCR.
The uteri of the estradiol-treated animals have more than three times the weight of those of the animals treated with Cimicifuga racemosa and vehicle which basically do not differ in their mean values. This means that the components of Cimicifuga racemosa have no influence on the uterus of the animals. This is also true for the vagina, where no hornification of the [File:ANM\BI5720B1 .doc] Description, 24.07.00 PCT/EP99/01860, CIMICIFUGA-Anwendung ,BIONORICA Arzneimittel GmbH -11 epithelium tissue occurs in the animals treated with Cimicifuga racemosa and vehicle, quite contrary to the estradiol-treated animals.
The LH levels of the vehicle-treated animals remain high, however are lowered significantly both by estradiol and Cimicifuga racemosa.
The results are shown in Figs. 3a) and 3b).
Uterus weights (wet) Cremophor Cimicifuga E2 [control] racemosa Number animals 8 8 8 Mean values [mg] 185.6 192.3 702.1 SD 18.81 22.53 194.97 SEM 6.65 7.97 68.92 LH concentrations in the blood Cremophor Cimicifuga [control] racemosa Number animals 8 8 8 Mean values [ng/ml] 16.9 12.5 7.83 SD 3.99 3.4 5.57 SEM 1.41 1.2 1.97 As another marker for the estrogene effect, the activation of mRNA of estrogen-induceable proteines was measured. What was measured here was tissue from uterus, from bone tissue (femur) and from the preoptic region of the hypothalamus.
In the hypothalamus, both Cimicifuga racemosa and E2 stimulate the expression of the mRNA for the estrogen receptor a (Fig 4a). In the bone tissue, too, Cimicifuga racemosa behaves like an estrogen and reduces, in analogy with estradiol, the expression of the mRNA for the bone-specific collagen 1 and for osteocalcin genes (Fig 4b).
[File:ANM\B15720B1.doc] Description, 24.07.00 PCT/EP99/01860, CIMICIFUGA-Anwendung BIONORICA Arzneimittel GmbH -12- In contrast, no effect of Cimicifuga racemosa on estrogen-regulated genes in the uterus is observed. Only estradiol increases the mRNA for IGF1 and complement factor C3 (Fig 4c).
These findings prove that the components from Cimicifuga racemosa selectively act on single organs: the extract acts estrogenically in the hypothalamus (expression of the E2 receptor a, liberation of LH) and on the bone, proven by the expression of the genes for collagen 1 and osteocalcin.
Other than estradiol, however, Cimicifuga racemosa does not have an effect on the uterus, as the absence of an effect on the uterus weights and the expression of the genes for IGF1 and C3 shows.
By the experiments carried out in vitro and in vivo, it could be demonstrated that Cimicifuga racemosa and Belamcanda sinensis extracts exert an estrogenic effect. Surprisingly it was found that the extracts from the named drugs act organoselectively on central nervous system, bone and vessels, but not on the uterus, and are thus excellently suited for the prophylaxis and therapy of estrogen deficiency without having a negative influence on the endometrium.
Identical effects are achieved by the tectorigenin contained in Belamcanda.
Thus for the first time medicaments having an estrogen-type effect, however without a uterotrophic effect, are available.
The like medicaments may be used for the treatment and/or prophylaxis of cardiovascular diseases, particularly atherosclerosis, osteoporosis, and of peri- and post-menopausal psychovegetative disorders such as, hot flushes.
Among types of application, oral, intravenous and subcutaneous application are prominent.
[File:ANM\BI5720B1.doc] Description, 24.07.00 PCT/EP99/01860, CIMICIFUGA-Anwendung BIONORICA Arzneimittel GmbH
Claims (9)
1-? Amended Claims 1. Use of extracts from Iridaceae for producing an estrogen-type, organoselective medicament having no uterotrophic effect or one that is at least negligible, under the proviso that Belamcanda chinensis extract is not used if the medicament is used for alleviating peri- menopausal and post-menopausal disorders. 10
2. Use in accordance with claim 1, characterised in that the extracts are produced from Belamcanda chinensis. *O
3. Use of extracts from Cimicifuga racemosa for producing an estrogen- type, organoselective medicament having no uterotrophic effect or one that is at least negligible, under the proviso that the medicament is not used for alleviating peri-menopausal and post-menopausal disorders and dysmenorrhea.
4. Use of extracts containing tectorigenin and/or tectorigenin glycoside, with the exception of extracts from Iridaceae, or extracts enriched with tectorigenin and/or tectorigenin glycoside for producing an estrogen- type, organoselective medicament having no uterotrophic effect or one that is at least negligible.
5. Use in accordance with any one of claims 1 to 3, characterised in that the extract serves for producing a ready-formulated medicament for the selective treatment and/or prophylaxis of cardiovascular diseases, particularly atherosclerosis.
6. Use in accordance with any one of claims 1 to 3, characterised in that the extract serves for producing a ready-formulated medicament for the selective treatment and/or prophylaxis of osteoporosis.
7. Use in accordance with any one of claims 1 to 4, characterised in that the extract serves for producing a ready-formulated medicament for the LU [File:ANM\BI5720B1.doc] Description, 24.07.00 S PCT/EP99/01860, CIMICIFUGA-Anwendung r O BIONORICA Arzneimittel GmbH selective treatment and/or prophylaxis of climacteric disorders, particularly for preventing or alleviating hot flushes.
8. Use of tectorigenin and/or its glycosides for producing an estrogen- type, organoselective medicament having no uterotrophic effect or one that is at least negligible.
9. Use in accordance with claim 8, characterised in that it is a medicament for the selective treatment and/or prophylaxis of cardiovascular diseases, particularly atherosclerosis; osteoporosis; and climacteric disorders, particularly for preventing or alleviating hot flushes. aY a ANM\BI5720B1.doc] Description, 24.07.00 EP9901860, CIMICIFUGA-Anwendung ONORICA Arzneimittel GmbH
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19812204 | 1998-03-19 | ||
DE19812204A DE19812204A1 (en) | 1998-03-19 | 1998-03-19 | Use of extracts from Cimicifuga racemosa and Belamcanda sinensis as an estrogen-like organ-selective drug without uterotropic effects |
PCT/EP1999/001860 WO1999047149A1 (en) | 1998-03-19 | 1999-03-19 | Utilization of extracts from iris plants, cimicifuga racemosa and tectorigenin as an estrogen-like organ-selective medicament without uterotropic effects |
Publications (3)
Publication Number | Publication Date |
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AU3146699A AU3146699A (en) | 1999-10-11 |
AU755900B2 true AU755900B2 (en) | 2003-01-02 |
AU755900C AU755900C (en) | 2005-04-21 |
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AU31466/99A Ceased AU755900C (en) | 1998-03-19 | 1999-03-19 | Utilization of extracts from iris plants, cimicifuga racemosa and tectorigenin as an estrogen-like organ-selective medicament without uterotropic effects |
Country Status (21)
Country | Link |
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EP (1) | EP1064009B2 (en) |
JP (2) | JP2002506827A (en) |
KR (1) | KR100623333B1 (en) |
CN (2) | CN100581541C (en) |
AT (1) | ATE225182T1 (en) |
AU (1) | AU755900C (en) |
BR (1) | BR9908256A (en) |
CA (1) | CA2321444C (en) |
CZ (1) | CZ292684B6 (en) |
DE (2) | DE19812204A1 (en) |
DK (1) | DK1064009T4 (en) |
ES (1) | ES2184427T5 (en) |
HK (1) | HK1035660A1 (en) |
HU (1) | HU227694B1 (en) |
MX (1) | MXPA00007986A (en) |
PL (1) | PL194096B1 (en) |
PT (1) | PT1064009E (en) |
RU (2) | RU2228188C2 (en) |
SE (1) | SE1064009T4 (en) |
TR (1) | TR200002686T2 (en) |
WO (1) | WO1999047149A1 (en) |
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DE10054641A1 (en) | 2000-11-03 | 2002-05-16 | Schaper & Bruemmer Gmbh | Use of a preparation of Cimicifuga racemosa |
DE10123503A1 (en) * | 2001-05-15 | 2002-11-21 | Bionorica Ag | Use of Belamcanda chinensis extract, or its active ingredient, for treating sex hormone-dependent urogenital disorders and prostatic hyperplasia |
DE10127897B4 (en) * | 2001-06-08 | 2006-04-20 | Bionorica Ag | Coated tablet with dry plant extracts |
DE10146159A1 (en) * | 2001-09-19 | 2003-04-10 | Bionorica Ag | Use of extracts from Cimicifuga species as an organ-selective drug for the treatment of sex hormone-dependent diseases of the urogenital tract |
EP1325681A1 (en) * | 2001-12-11 | 2003-07-09 | Société des Produits Nestlé S.A. | Composition for promotion of bone growth and maintenance of bone health |
DE10206390A1 (en) * | 2002-02-15 | 2003-08-28 | Bionorica Ag | Use of phytoestrogen-containing extracts that selectively modulate the estrogen receptor beta |
JP4605984B2 (en) * | 2002-12-20 | 2011-01-05 | アサヒビール株式会社 | Stress relieving agent |
EP1630160B1 (en) * | 2003-05-15 | 2009-04-08 | Chengdu Dikang Pharmaceutical Institute | The isoflavone derivatives of tectoridin, the preparation thereof and the anti-virus medicines containing the same as the effective constituents |
EP1591143A1 (en) * | 2004-04-26 | 2005-11-02 | Schaper & Brümmer Gmbh & Co. Kg | Composition comprising a combination of Calcium, Cimicifugae racemosae rhizoma and vitamin D and its use as a pharmaceutical in conditions or disorders associated with or resulting from calcium deficiency or as a nutritional supplement |
EP1588739A1 (en) * | 2004-04-23 | 2005-10-26 | Schaper & Brümmer Gmbh & Co. Kg | Composition comprising a combination of calcium, Cimicifugae racemosae rhizoma and vitamin D and its use as a pharmaceutical in conditions or disorders associated with or resulting from calcium deficiency or as a nutritional supplement |
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CN100381435C (en) * | 2005-03-24 | 2008-04-16 | 深圳海王药业有限公司 | Extractive of general flavone from blackberry lily, preparation method and application in preparing medication |
EP1745796A1 (en) | 2005-07-19 | 2007-01-24 | Bionorica Research GmbH | Compound preparation for treating prostate carcinoma |
CN101057854B (en) * | 2006-05-31 | 2010-05-12 | 南京大学 | Application of cycloartane type triterpenoids compound of cimicifuga rhizome for anti-osteoporosis and menopausal syndrome |
DE102007044916A1 (en) | 2007-09-19 | 2009-04-23 | Bionorica Ag | Cosmetic or dermatological composition for topical use |
KR100928013B1 (en) * | 2008-01-25 | 2009-11-24 | 이화여자대학교 산학협력단 | Method for improvement in growth of Echinochola crusgalli using Belamcanda chinensis extract and method for remediation of heavy-metal contaminated soil using the method |
CN101797265A (en) * | 2010-04-09 | 2010-08-11 | 中国人民解放军第二军医大学 | Application of belamcanda chinensis total isoflavone or isoflavone compounds in preparing medicaments and food for preventing and treating women's disease |
WO2013007807A1 (en) | 2011-07-12 | 2013-01-17 | Bionorica Se | Selected cimicifuga fractions for the treatment of osteoporosis |
EP2545932A1 (en) | 2011-07-12 | 2013-01-16 | Bionorica Se | Selected cimicifuga fractions for treating osteoporosis |
EP2620155A1 (en) | 2012-01-30 | 2013-07-31 | Bionorica SE | Medicine containing Cimicifuga for use in the treatment of sarcopenia and myocardial weakness |
CN102525907B (en) * | 2012-02-22 | 2013-06-05 | 四川省中医药科学院 | Tectorigenin sodium sulfonate injection |
CN102631363A (en) * | 2012-04-11 | 2012-08-15 | 李超生 | Application of tectoridin in preparing medicine for preventing osteoporosis |
WO2013192114A1 (en) * | 2012-06-22 | 2013-12-27 | Golden Biotechnology Corporation | Methods and compositions for treating arteriosclerotic vascular diseases |
US11541093B2 (en) | 2012-07-03 | 2023-01-03 | Max Zeller Soehne Ag | Pharmacological use of Cimicifuga extract |
JP2014091706A (en) * | 2012-11-02 | 2014-05-19 | Kao Corp | Glp-1 secretion promoter |
KR101964841B1 (en) * | 2017-03-07 | 2019-08-07 | 주식회사 엘지생활건강 | Composition for relieving menopausal symptom |
KR101965849B1 (en) * | 2017-03-07 | 2019-04-04 | 주식회사 엘지생활건강 | Composition for relieving menopausal symptom comprising Tectorigenin 7-O-xylosylglucoside |
TWI761372B (en) * | 2017-09-22 | 2022-04-21 | 日商東洋新藥股份有限公司 | combination |
EP3906040A1 (en) | 2018-12-31 | 2021-11-10 | Max Zeller Söhne AG | Combination of cimicifuga and petasites extracts for anticancer therapy and prophylaxis |
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JPS6330417A (en) * | 1986-07-23 | 1988-02-09 | Tsumura Juntendo Inc | Anti-allergic agent |
PL186769B1 (en) * | 1995-09-07 | 2004-02-27 | Oreal | Extract from iridaceae and compositions containing same |
AU706262B2 (en) * | 1995-10-23 | 1999-06-10 | Osteoscreen, Inc. | Compositions and methods for treating bone deficit conditions |
JPH09301884A (en) * | 1996-05-15 | 1997-11-25 | Ichimaru Pharcos Co Ltd | Testosterone 5 alpha-reductase inhibitor containing blackberry lily extract and alpha-hydroxyl acid and its application |
JPH107580A (en) * | 1996-06-15 | 1998-01-13 | Michio Yoshida | Collagenase inhibitor |
JP3665848B2 (en) * | 1996-09-18 | 2005-06-29 | 木村 幸代 | Fermented beverage of Himeogi dwarf bulb extract and method for producing the same |
DE19652183C1 (en) * | 1996-12-14 | 1998-02-12 | Schaper & Bruemmer Gmbh | Treating oestrogen-dependent tumour with Cimicifuga racemosa extract |
-
1998
- 1998-03-19 DE DE19812204A patent/DE19812204A1/en not_active Withdrawn
-
1999
- 1999-03-19 JP JP2000536389A patent/JP2002506827A/en not_active Withdrawn
- 1999-03-19 MX MXPA00007986A patent/MXPA00007986A/en active IP Right Grant
- 1999-03-19 RU RU2000126476/15A patent/RU2228188C2/en not_active IP Right Cessation
- 1999-03-19 PT PT99913282T patent/PT1064009E/en unknown
- 1999-03-19 KR KR1020007008724A patent/KR100623333B1/en not_active IP Right Cessation
- 1999-03-19 PL PL99342486A patent/PL194096B1/en not_active IP Right Cessation
- 1999-03-19 CA CA2321444A patent/CA2321444C/en not_active Expired - Fee Related
- 1999-03-19 RU RU2003137324/15A patent/RU2263505C2/en not_active IP Right Cessation
- 1999-03-19 EP EP99913282A patent/EP1064009B2/en not_active Expired - Lifetime
- 1999-03-19 CN CN03145494A patent/CN100581541C/en not_active Expired - Fee Related
- 1999-03-19 HU HU0200921A patent/HU227694B1/en not_active IP Right Cessation
- 1999-03-19 ES ES99913282T patent/ES2184427T5/en not_active Expired - Lifetime
- 1999-03-19 AU AU31466/99A patent/AU755900C/en not_active Ceased
- 1999-03-19 DE DE59902932T patent/DE59902932D1/en not_active Expired - Lifetime
- 1999-03-19 SE SE99913282T patent/SE1064009T4/en unknown
- 1999-03-19 TR TR2000/02686T patent/TR200002686T2/en unknown
- 1999-03-19 CN CNB998041238A patent/CN100444867C/en not_active Expired - Fee Related
- 1999-03-19 CZ CZ20002810A patent/CZ292684B6/en not_active IP Right Cessation
- 1999-03-19 WO PCT/EP1999/001860 patent/WO1999047149A1/en not_active Application Discontinuation
- 1999-03-19 DK DK99913282T patent/DK1064009T4/en active
- 1999-03-19 BR BR9908256-0A patent/BR9908256A/en not_active IP Right Cessation
- 1999-03-19 AT AT99913282T patent/ATE225182T1/en active
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2001
- 2001-07-03 HK HK01104552A patent/HK1035660A1/en not_active IP Right Cessation
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