IE920219A1 - Pharmaceutical combination for the prevention and treatment¹of postmenopausal osteoporosis - Google Patents
Pharmaceutical combination for the prevention and treatment¹of postmenopausal osteoporosisInfo
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- IE920219A1 IE920219A1 IE021992A IE920219A IE920219A1 IE 920219 A1 IE920219 A1 IE 920219A1 IE 021992 A IE021992 A IE 021992A IE 920219 A IE920219 A IE 920219A IE 920219 A1 IE920219 A1 IE 920219A1
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- estrogens
- ipriflavone
- treatment
- day
- pharmaceutical composition
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- 208000001685 postmenopausal osteoporosis Diseases 0.000 title claims abstract description 7
- 229960005431 ipriflavone Drugs 0.000 claims abstract description 51
- 229940011871 estrogen Drugs 0.000 claims abstract description 50
- 239000000262 estrogen Substances 0.000 claims abstract description 50
- SFBODOKJTYAUCM-UHFFFAOYSA-N Ipriflavone Chemical compound C=1C(OC(C)C)=CC=C(C2=O)C=1OC=C2C1=CC=CC=C1 SFBODOKJTYAUCM-UHFFFAOYSA-N 0.000 claims abstract description 47
- 238000011282 treatment Methods 0.000 claims abstract description 28
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- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 8
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- 102000055006 Calcitonin Human genes 0.000 description 3
- 108060001064 Calcitonin Proteins 0.000 description 3
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- 229960004015 calcitonin Drugs 0.000 description 3
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 3
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- DNXHEGUUPJUMQT-UHFFFAOYSA-N (+)-estrone Natural products OC1=CC=C2C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 DNXHEGUUPJUMQT-UHFFFAOYSA-N 0.000 description 1
- 208000006820 Arthralgia Diseases 0.000 description 1
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- 208000032928 Dyslipidaemia Diseases 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- DNXHEGUUPJUMQT-CBZIJGRNSA-N Estrone Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 DNXHEGUUPJUMQT-CBZIJGRNSA-N 0.000 description 1
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- CJWQYWQDLBZGPD-UHFFFAOYSA-N isoflavone Natural products C1=C(OC)C(OC)=CC(OC)=C1C1=COC2=C(C=CC(C)(C)O3)C3=C(OC)C=C2C1=O CJWQYWQDLBZGPD-UHFFFAOYSA-N 0.000 description 1
- 150000002515 isoflavone derivatives Chemical class 0.000 description 1
- 235000008696 isoflavones Nutrition 0.000 description 1
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- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
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- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A pharmaceutical composition for the treatment of postmenopausal syndrome, particularly for the prevention and therapy of postmenopausal osteoporosis and the treatment of climacteric disorders, containing ipriflavone in combination with estrogens, is described.
Description
PHARMACEUTICAL COMBINATION FOR THE PREVENTION AND TREATMENT OF POSTMENOPAUSAL OSTEOPOROSIS Osteoporosis is one of the major health problems in Western world, both for its high social cost and for the damages it brings about in patients, causing fractures in particular in forearm bones, in femur and in vertebrae.
As a matter of fact, osteoporosis is characterized by a quantitative decrease in the amount of the bone, which means that the quality of bone tissue is normal, but it is insufficient; hence the increase of bone fragility. Osteoporosis i s especially frequent in postmenopausal women, in relation with a decrease on ovaric function, and it is related to a deficit of estrogens .
Therefore, estrogens have represented, and they still represent, a good therapeutic protection in the prevention of postmenopausal osteoporosis, since they slow down the bone loss and decrease the fracture rate.
The use of estrogens in the treatment of 20 postmenopausal symptoms is especially preferred, since it is useful not only to contrast and balance the loss of bone mineral content, but also to control climacteric disorders (vasomotor, neuropsychic, genitourinary disorders).
There are several kinds of estrogens, both natural and synthetic.
For the substitutive therapy in menopause it is preferable to use natural estrogens, that exhibit less side-effects.
Among natural estrogens, conjugated estrogens are mainly used, whose minimal effective daily dose is known to be 0.625 mg, even though literature reports that a dose of 0.300 mg can be sufficient for the control of bone mass loss, if combined to an adequate calcium supply.
Lower doses are anyhow considered to be uneffective .
The use of estrogens in therapy, however, requires a careful evaluation of risks, since it can involve very serious side-effects.
There are absolute contra-indications to the use of estrogens, such as acute and chronic hepatopathies, cerebral vascular pathology and thromboembolic hypertension, mammary and endometrium disease, and several relative contraindications, such as cholecystopathies, endometriosis, fibrocystic mastopathy, uterine fibromyomatosis, diabetes, obesity, dyslipidemias, cardiocirculatory insufficiency, epilepsy.
In order to limitate the risks connected with estrogen chronic administration, and above all the ones of carcinogenetic kind at endometrium level, estrogens are usually combined with a progestinic preparation that would exert a protecting action at endometrium level. pathology, neoplastic Progestinic preparations, however, cause important side-effects on cardiovascular system, as well as changes of the serum lipid concentrations.
A drug that recently turned out to be effective in prevention and treatment of postmenopausal and senile osteoporosis is ipriflavone, a compound having a complex mechanism of action that, anyhow, seems to exert a direct inhibition on bone reabsorption.
Unlike other isoflavones, ipriflavone does not exert estrogen activity.
Yamazi I et al. (Life Science, vol. 38, pages 757764) proved that ipriflavone, in ovariectomized rats, is able to enhance the uterotropic activity of small doses of estrone, without, however, causing a direct estrogenic effect.
The absence of estrogenic effects was also reported in a group of 10 postmenopausal women, who were administered with oral unit doses of 600 or 1000 mg of ipriflavone; the LH (lutenizing hormone) and FSH (stimulating follicle) secretion were evaluated in a 24-hour period. LH secretion was also evaluated during a naloxone (NAL) infusion before and after 20 days from the ipriflavone treatment.
Naloxone is commonly used to evaluate the stimulation of endogenous opioid system exerted by estrogens in postmenopausal women.
It is well known that LH response to NAL is absent in postmenopausal women and can be restored by estrogen administration.
Ipriflavone did not affect LH and FSH basal levels, nor, unlike what happened in a control group of EC-treated women, LH response to NAL treatment, thus proving to be devoid of estrogenic activity at hypothalamus and hypophysis level.
Moreover, after 20 days of treatment with the drug, in his group of subjects no cytology variations at vaginal level were observed.
Yamazi et al. (Life Sci. vol. 38, pages 1535-1541) also determined the effects of ipriflavone increasing doses on calcitonin secretion in ovariectomized rats, in the presence and in the absence of estrogens, showing that ipriflavone, in the presence of the estrogen, stimulates calcitonin secretion.
Ipriflavone was administered orally, the estrogen subcutaneously.
According to these data, the authors assumed that ipriflavone, at least partially, had mechanism inhibiting bone mass loss mediated by an increase in calcitonin secretion in the presence of estrogens.
However, the effects and possible interferences of ipriflavone and estrogens combination were never investigated in animals, nor in man.
On the other hand, this therapeutic approach cannot ignore the fundamental role played by the substitutive hormonal therapy in the control of climacteric symptoms, with a direct dose-effect relationship (Jensen J, Christiansen C, Maturitas 1983, , 125).
It has now been found, and it is the object of the present invention, that ipriflavone can favourably be administered in combination with estrogens, either in the free or conjugated or esterified form, for a more effective and safer therapy of the complex postmenopausal symptoms.
The Applicant could evidence that ipriflavone, which is per se active on bone metabolism and able to stop mineral bone loss, when administered at normal therapeutic dosages in combination with estrogens not only does not interfere with the estrogen actions, but it dramatically reduces the required dosage of the latter, while keeping the effectiveness thereof in the control of climacteric symptoms.
This result is particularly surprising since it evidences an unforeseeable functional synergism between the two drugs, allowing to carry out a complete therapy of postmenopausal condition (osteoporosis prevention and treatment of climacteric disorders), with evident advantages .
As a matter of fact: a) ipriflavone, at normal therapeutic doses (600 mg/day) keeps unchanged its efficacy towards bone demineralization . b) estrogen proves to be active in the control of climacteric symptoms at very low doses (0.300 mg/day and even 0.150 mg/day), which is equal to about a half and about a quarter, respectively, of the usual daily dose (0.625 mg/day). c) the dramatic reduction of the estrogen daily dose reduces at the same extent the risk of serious side-effects; d) consequently, both the dosage and the frequence of administration of the progestinic therapy can be remarkably reduced.
The effect of the combined administration of ipriflavone and estrogens were shown in a one year study carried out in corresponding groups of patients, in physiological menopause for 12-24 months, confirmed by laboratory tests, which patients had not been subjected to previous treatments.
Each group was treated according to a different therapeutic scheme: - group 1: natural conjugated estrogens (CE) 0.3 mg/day + olacebo group 2: CE 0.3 mg/day + group 3 : CE 0.15 mg/day + group 4: CE 0.15 mg/day + A control group was only.
For ethical reasons towards the control group, and in order to ensure the maintainance of an adequate calcium exogenous intake, all the patients participating in the study were also administered with a daily dose of 1 g of calcium.
Ipriflavone and placebo were not distinguishable and were compared in double-blind conditions.
Months after the beginning of the treatment, a first clinical control was carried out, with the evaluation, inter alia, of typical menopausal symptoms.
Months after the beginning of the treatment, besides the clinical controls, also a mineralometric examination was carried out by means of dual-photon absorptiometry in fixed points.
The results obtained in the determination of bone mineral contents at the radius level in 76 women after a 6 month treatment are reported in Table 1.
Table 1. Bone mineral contents expressed in mg/cm (± S.E.) at the level of radius distal portion in menopausal women before and after 6 months of combined treatment with ipriflavone + conjugated estrogens.
P P+CE 0.15 P+CE 0.30 Ip+CE 0.15 Ip+CE 0 (n=13) (n=16) (n=17) (n«=17) basal 377.54 397.25 396.88 403.85 382.24 value 17.60 20.27 17.46 17.24 26.49 6 % % % % months 372.00 -1.44 394.31 -0.23 401.12 +1.47 414.85 +3.08 393.35 17.55 18.95 17.03 16.96 15.72 % +3.18°* P = placebo P+CE 0.15 - placebo + conjugated estrogens 0.15 mg/day P+CE 0.30 - placebo + conjugated estrogens 0.30 mg/day Ip+CE 0.15 - Ipriflavone 600 mg/day+ conjugated estrogens 0.15 mg/day Ip+CE 0.30 - Ipriflavone 600 mg/day+ conjugated estrogens 0.30 mg/day n - number of patients in each group % - percent difference vs. basal * - Wilcoxon test between treatments p < 0.001 vs. placebo ° - t Student test within treatments p < 0.002 vs. basal The results of Table 1 prove that the combination with sub-active doses of estrogens not only maintains unchanged the capability of ipriflavone to prevent bone mineral loss, but enhances said effect.
In fact, while already in the group of patients treated with Ip+CE 0.15 an effective control of the bone mass is attained after 6 months, the group treated with Ip+CE 0.30 surprisingly shows an unexpected statistically significant increase in bone mineral content.
This result is even more surprising in that no enhancements of the effects deriving from the combination with estrogens were reported hitherto for any drug acting on bone metabolism.
The results obtained in the evaluation of some typical climacteric symptoms are reported in Table 2.
Symptoms were evaluated according to the following scores : - hot flushes: 0 - none; 1 = less than 5 a day; 2 = 20 from 5 to 10 a day; 3 - more than 10 a day. - other symptoms: 0 - none; 1 - slight; 2 - medium; 3 severe .
In Table 2 the score average value and the related standard error are reported in correspondence of each time and for each treatment. Symptoms were analyzed according to significance test by Wilcoxon Signed-Rank, applied on differences at time t3 and t6.
Table 2. Evaluation of some vasomotor symptoms in menopausal women before and 3 and 6 months after the beginning of a combined treatment with ipriflavone + conjugated estrogens. Symptoms p P+CE 0.15 P+CE 0.30 Ip+CE 0.15 Ip+CE 0.30 n 12 15 14 11 13 to 1.42(+0.19) 1.80(+0.17) 1.93(+0.22) 1.73(+0.30) 2.08(+0.26, t3 1.17(+0.17) 0.87(+0.26) 0.79(+0.24) 0.18(+0.18) 0.69(+0.21) Hot N.S. p<0.01 p<0.01 p<0.01 p<0.01 flushes t6 0.63(+0.21) p<0.05 0.60(+0.21) p<0.01 0.64(+0.23) p<0.01 0.09(+0.09) p<0.01 0.69(+0.21) p<0.01 n 12 12 14 13 14 to 1.42(+0.23) 1.83(+0.21) 1.79(+0.21) 1.77(+0.20) 1.86(+0.25) Arthral- gia/ t3 1.00(+0.25) 1.00(+0.28) 1.14(+0.29) 0.77(+0.26) 1.07(+0.30) Myalgia N.S. p<0.05 p<0.01 p<0.01 p<0.05 t6 1.00(+0.28) N.S. 0.75(+0.28) p<0.05 1.00(+0.26) p<0.05 0.38(+0.18) p<0.01 1.00(+0.26) p<0.C5 n 10 11 12 7 13 to 1.00(+0.30) 1.36(+0.15) 1.33(+0.14) 1.14(+0.14) 1.46(+0.24) cardio- palmo t3 1.10(+0.23) N.S. 0.64(+0.20, p<0.01 0. 58(+0.19) p<0.01 0.57(+0.20) N.S. 0.69(+0.21, p<0.01 t6 P 0.80(+0.20) N.S. - placebo 0.64(+0.20) p<0.01 0.33(+0.22) p<0.01 0.29(+0.18, p<0.05 0.69(+0.17) p<0.05 P+CE 0.15 - : placebo + conjugated estrogens 0. 15 mg/day P+CE 0.30 - ' placebo + conjugated estrogens 0. 30 mg/day Ip+CE 0.15 - Ipriflavone 600 mg/day + conjugated estrogens 0.15 mg/day Ip+CE 0.30 - Ipriflavone 600 mg/day + conjugated estrogens 0.30 mg/day n - number of patients in each group The results of Table 2 evidence the effective control of climacteric symptoms which can be obtained with very low estrogen doses, for example from about 0.15 mg/day.
However, at such low doses, estrogens alone are inadequate in controlling the bone mineral loss, as the results of Table 1 clearly show. The combined treatment with ipriflavone, which is a drug acting on bone mineral metabolism, allows to use a very low estrogen dosage, thus obtaining: - a prevention and a control of bone mineral loss; - a prevention and a control of climacteric disorders; with a dramatic reduction in the side-effects deriving from the use of estrogens.
The combination of the two active ingredients can be carried out either extemporarily, by administering the two drugs separately, simultaneously or sequentially, or using unitary pharmaceutical compositions containing the two combined drugs.
In the first case, which allows to use a more adaptable and flexible treatment scheme, suitable packages will be prepared in form of kit-of-parts containing separate administration units for each drug, which units being sufficient to a given treatment time.
In the second case, novel pharmaceutical compositions will be used containing the two active ingredients in a single unit-dose.
Some illustrative compositions are reported hereinbelow. In said compositions, the estrogen unit dose is indicated in 0.15 mg or 0.30 mg for sake of simplicity and that of ipriflavone in 600 mg, any other estrogen or ipriflavone dosage (higher, intermediate or lower), as far as it is effective and non-toxic, being comprised within the scope of the invention.
EXAMPLE 1. Unitary composition of soft-gelatin capsules 5 containing as the active ingredient 300 mg of ipriflavone in combination with 0.15 mg conjugated estrogens. Ipriflavone 300.00 mg Natural conjugated estrogens 0.15 mg Soy lecithin 50.00 mg Medium-chain triglycerides 259.85 mg Hydrogenated vegetable oils 70.00 mg EXAMI LE 2. Unitary composition of soft-gelatin capsules containing as the active ingredient 300 mg of ipri f1avone in combination with 0.30 mg conjugated estrogens. Ipri f1avone 300.00 mg Natural conjugated estrogens 0.30 mg Soy lecithin 50.00 mg 20 Medium-chain triglycerides 259.70 mg Hydrogenated vegetable oils 70.00 mg EXAMPLE 3. Unitary composition of squeezable capsules containing as the active ingredient 600 mg of ipriflavone in combination with 0.30 mg of conjugated estrogens.
Ipri flavone 600.00 mg Natural conjugated estrogens 0.30 mg Soy lecithin 27.00 mg Medium-chain triglycerides 870.70 mg Mixture of palmitic and stearic 56.00 mg acids mono-, di- and tri-glycerides White chocolate 600.00 mg Sodium saccharine 1.00 mg Sorbitol 300.00 mg Orange flavour 25.00 mg The pharmaceutical compositions of the Examples 1 to 3 can be prepared according to the process disclosed in PCT Appl. n. WO 91/14429 , filed on March 19, 1991, in the Applicant's name.
The availability of both the two drugs in 10 separated units and one or more compositions containing the two active ingredients at set doses, allows the physician to choose the treatment type and scheme assumed to be the most suitable.
Various administration schemes could be used, for 15 instance 200-600 mg for ipriflavone and 0.15 to 0.30 mg for the estrogens, respectively.
Ipriflavone is provided in the form of 200 mg capsules, to be administered 3 times a day, at meals .
Recently, two novel pharmaceutical compositions containing ipriflavone have been prepared.
The first one consists of soft-gelatin capsules, each containing 300 mg of ipriflavone, to be administered twice a day; the other one consists of squeezable capsules containing 600 mg of ipriflavone, to be administered only once a day, during the evening meal.
The present invention also relates to pharmaceutical compositions containing the two active ingredients at set dosages, namely: Ipriflavone 300 mg + conjugated estrogens in unitary dose ranging from 0.15 mg to 0.30 mg; and Ipriflavone 600 mg + conjugated estrogens in an amount ranging from 0.15 to 0.30 mg.
Therefore, the possible daily therapeutical scheme 5 are as follows: A. Ipriflavone, 200 mg tablets: 3 tablets/day to be taken at meals + 0.15-0.30 mg of estrogens to be taken after the evening meal.
B. Ipriflavone, 300 mg capsules: 2 capsules/day, to be taken at the two main meals + 0.15-0.30 mg of estrogens to be taken after the evening meal.
C. Ipriflavone, 300 mg capsule: 1 capsule/day, to be taken at the noon meal + 1 capsule prepared according to the examples of the invention, containing 300 mg of ipriflavone in a set combination with 0.15-0.30 mg of estrogens, to be taken after the evening meal.
D. Ipriflavone, 300 mg capsules : 2 capsules/day in a set combination with 0.15 mg of estrogens, to be taken at the two main meals.
E. Ipriflavone, 600 mg squeezable capsule: 1 capsule/day in a set combination with 0.15-0.30 mg estrogens, to be taken at the evening meal.
The preferred treatment scheme, among the above 25 reported ones, will be selected according to the physician's judgement.
Since one of the more important objects of the invention is provided by a combination product of ipriflavone with very low doses of estrogens, which doses are per se ineffective in preventing bone mass loss but active in controlling climacteric symptoms, such a product can be prepared in a variety of ways, using the estrogens in all of the possible administration forms, including transdermic patches.
In order to make an effective therapy cycle easy, 5 suitable packages can be envisaged for each product of the invention, with specific information about the treatment sequence.
Claims (9)
1. A pharmaceutical composition for the treatment of postmenopausal syndrome, particularly for the 5 prevention and therapy of postmenopausal osteoporosis and the treatment of climacteric disorders, containing ipriflavone in combination with estrogens.
2. A pharmaceutical composition according to claim 1, characterized in that the estrogens are conjugated 10 estrogens or esterified estrogens.
3. A pharmaceutical composition according to claim 1, containing ipriflavone and estrogens as a combined preparation for simultaneous, separate or sequential use . 15
4. A pharmaceutical composition according to anyone of claims from 1 to 3, characterized in that ipriflavone is present in amounts from 200 mg to 600 mg and estrogens are present as unit-dose containing from 0.15 to 0.30 mg. 20
5. A pharmaceutical composition according to claims 1 or 2, in form of soft capsules, each containing as the active ingredient 300 mg of ipriflavone in combination with estrogens in amounts ranging from about 0.15 to about 0.30 mg. 25
6. A pharmaceutical composition according to claims 1 or 2, each containing as the active ingredient 600 mg of ipriflavone in combination with estrogens in amounts ranging from about 0.15 to about 0.30 mg.
7. A pharmaceutical composition according to anyone 30 of claims from 1 to 6, characterized in that the estrogen is estradiol.
8. The combined use of estrogens and ipriflavone for the preparation of a medicament for the prevention and treatment of postmenopausal osteoporosis and for the treatment of climacteric disorders.
9. A pharmaceutical composition according to any one of claims 1-7, substantially as described herein.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ITMI910253A IT1244697B (en) | 1991-02-01 | 1991-02-01 | PHARMACEUTICAL ASSOCIATION FOR THE PREVENTION AND TREATMENT OF POST-MENOPAUSAL OSTEOPOROSIS |
Publications (1)
Publication Number | Publication Date |
---|---|
IE920219A1 true IE920219A1 (en) | 1992-08-12 |
Family
ID=11358374
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IE021992A IE920219A1 (en) | 1991-02-01 | 1992-01-24 | Pharmaceutical combination for the prevention and treatment¹of postmenopausal osteoporosis |
Country Status (9)
Country | Link |
---|---|
EP (1) | EP0569415A1 (en) |
AU (1) | AU1188492A (en) |
CA (1) | CA2101547A1 (en) |
HU (1) | HUT64848A (en) |
IE (1) | IE920219A1 (en) |
IT (1) | IT1244697B (en) |
NZ (1) | NZ241418A (en) |
WO (1) | WO1992013538A1 (en) |
ZA (1) | ZA92661B (en) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994023716A1 (en) * | 1993-04-16 | 1994-10-27 | Tufts University School Of Medicine | Method for treatment of menopausal and premenstrual symptoms |
HU212932B (en) * | 1993-08-02 | 1996-12-30 | Chinoin Gyogyszer Es Vegyeszet | Parmaceutical composition containing ipriflavone, hydroxyapatit and tricalciumphosphate for treating lack of bones and process for producing the composition |
US5554601A (en) * | 1993-11-05 | 1996-09-10 | University Of Florida | Methods for neuroprotection |
US6319914B1 (en) | 1993-11-05 | 2001-11-20 | Apollo Biopharmaceuticals, Inc. | Cytoprotective effect of polycyclic phenolic compounds |
US5506211A (en) * | 1994-05-09 | 1996-04-09 | The Uab Research Foundation | Genistein for use in inhibiting osteroclasts |
US6326365B1 (en) | 1999-07-20 | 2001-12-04 | Apollo Biopharmaceutics, Inc. | Methods of prevention and treatment of ischemic damage |
US6339078B1 (en) | 1999-07-20 | 2002-01-15 | University Of Florida Research Foundation, Inc. | Methods of prevention and treatment of ischemic damage |
JP2004524354A (en) * | 2001-03-16 | 2004-08-12 | ワイス | Estrogen replacement therapy |
WO2008051586A2 (en) | 2006-10-24 | 2008-05-02 | Krempin David W | Anti-resorptive and bone building dietary supplements and methods of use |
-
1991
- 1991-02-01 IT ITMI910253A patent/IT1244697B/en active IP Right Grant
-
1992
- 1992-01-24 IE IE021992A patent/IE920219A1/en unknown
- 1992-01-27 NZ NZ241418A patent/NZ241418A/en unknown
- 1992-01-28 WO PCT/EP1992/000174 patent/WO1992013538A1/en not_active Application Discontinuation
- 1992-01-28 HU HU9302183A patent/HUT64848A/en unknown
- 1992-01-28 AU AU11884/92A patent/AU1188492A/en not_active Abandoned
- 1992-01-28 CA CA002101547A patent/CA2101547A1/en not_active Abandoned
- 1992-01-28 EP EP92903484A patent/EP0569415A1/en not_active Ceased
- 1992-01-30 ZA ZA92661A patent/ZA92661B/en unknown
Also Published As
Publication number | Publication date |
---|---|
ITMI910253A0 (en) | 1991-02-01 |
ZA92661B (en) | 1992-10-28 |
IT1244697B (en) | 1994-08-08 |
HUT64848A (en) | 1994-03-28 |
WO1992013538A1 (en) | 1992-08-20 |
AU1188492A (en) | 1992-09-07 |
ITMI910253A1 (en) | 1992-08-01 |
NZ241418A (en) | 1993-03-26 |
HU9302183D0 (en) | 1993-10-28 |
EP0569415A1 (en) | 1993-11-18 |
CA2101547A1 (en) | 1992-08-02 |
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