CN102397550A - Medicinal composition composed of aspirin and estrogen and used for preventing and treating osteoporosis - Google Patents
Medicinal composition composed of aspirin and estrogen and used for preventing and treating osteoporosis Download PDFInfo
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Abstract
The invention discloses a medicinal composition composed of aspirin and an estrogen and used for preventing and treating osteoporosis, as well as its formula. The invention designs a medicinal composition composed of aspirin with antiplatelet and anti-inflammatory double effects and an estrogen which is 1/3 to 1/10 of its common clinical dose, and the composition is proved to have an obvious anti-osteoporosis effect. As the fact that 100mg of aspirin can substantially reduce the incidence of cardiovascular events in patients with coronary heart diseases through antiplatelet effect is proved clinically, the composition can play an obvious role in reducing the incidence of cerebral apoplexy, heart disease and vascular embolization of lower limbs and lungs due to application of an estrogen replacement therapy in osteoporosis patients. Compared with application of a single estrogen, the composition of the invention does not inhibit bone formation either, thus being an ideal anti-osteoporosis new medicine.
Description
Technical field the present invention relates to the pharmaceutical composition with aspirin and estrogen composition, and the compound preparation of this preparation of pharmaceutical compositions has prevention and therapeutical effect preferably to postmenopausal women after date osteoporosis.
The background technology postmenopausal osteoporosis belongs to the wherein a kind of of primary osteoporosis.Primary osteoporosis is that a kind of destruction with low bone amount and osseous tissue micro structure is characteristic, causes skeleton fragility to increase and be prone to take place the systemic disease of fracture, can be divided into postmenopausal osteoporosis and senile osteoporosis amphitypy.Postmenopausal osteoporosis is women's more than 60 years old a commonly encountered diseases, and frequently-occurring disease mainly is because due to the estrogen deficiency; Often betide the women in the several years after the menopause, wherein the bone turnover rate of most of patients increases, and old bone is lost rapidly in a large number; New bone formation is accelerated, and the new and old switching rate of bone is quickened, but because bone loss has surpassed bone formation; The bone amount is main to lose, and has formed osteoporosis, so the osteoporosis of this type is also referred to as high conversion type osteoporosis.
The women is in gestation and age of sucking; the normal women of requirement to calcium phosphorus doubles, as can not get rational addition, and just the bone amount reduces or osteoporosis easily; The quality of skeleton culminates usually during general women to 35 year old; From this time, the process of reconstruction of bone is still proceeded, but quality begins to reduce.The rapidest in the period of the climacteric head 3～5; The speed of losing slows down gradually later on, but continues to carry out, and epidemiological study shows; The sickness rate of 50～69 years old women's osteoporosis is higher than 50%; During this section just is postclimacteric 5～10 years, and women's estrogen level obviously reduces, and this and osteoporotic incidence rate are closely related; Elderly woman bone density more than 80 years old is lower, and the danger that fracture takes place is at any time arranged.Old-age group is the significant risk factor of fracture, and the probability of 85 years old group generation forearm, humerus, vertebral body and Hip Fracture is 8 times of 45 years old group women, is 5 times the male.The mechanism of elderly woman bone metabolism mainly is because marrow stromal cell receives to press down to the differentiation of osteoblast direction after menopause; The osteoblast division growth slowly reaches bone formation factor anabolism and is obstructed; Osteogenetic process by the osteoclast mediation is suppressed, the osteoblast activity decay causes the prolongation of bone formation phase, and the bone formation rate reduces; Osteoclast differentiation simultaneously, maturation and bone resorption activity be opposite position active state still but, and the bone resorption ability has surpassed bone formation, and bone turnover rate increases but bone loss also increases, so cause osteoporotic generation.In addition, the increase reactive oxygen species level along with the age increases the oxidation resistance attenuating; The level of glutathion reductase descends; The apoptosis of osteoblast and osteocyte is increased, quickened bone loss, so oxidative stress possibly be the major reason that senile osteoporosis takes place.
Menopause all can cause bone loss after natural menopause or the oophorectomize, and the latter is developing faster, and trabecular bone is lost more obvious, has explained that estrogen and osteoporosis have confidential relation, and menopause, estrogen secretion reduced because ovarian function fails.Estrogen has anti-bone resorption, is the critical hormone of keeping bone mineral content, its mechanism mainly with estrogen to osteogenetic direct effect and to resist parathyroid bone resorption relevant; Think that at present the anti-bone resorption of estrogen maybe be relevant with promotion osteoclast effect of apoptosis with its inhibition TNF-a Induced Apoptosis in Osteoblasts.Estrogen decrease is considered to the major reason that postmenopausal osteoporosis disease is taken place always, and estrogen can strengthen the expression of osteogenesis type cell and cyclic adenosine monophosphate that bone resorption is induced in minimizing forms, and can also combine with special DNA, promotes special mRNA to synthesize.Through the postmenopausal osteoporosis women being used the clinical observation that heavy dose of estradiol treatment is carried out, proved effectively bone density improving of heavy dose of estrogen, promote the remineralization of bone, help the treatment of osteoporosis.The mechanism of action that estrogen influences bone metabolism mainly is to realize through calcium-regulating hormone (parathyroid hormone, 1, the 25 pair of hydroxycholecalciferol, calcitonin).Adopt method such as radioligand analysis on the osteoclast of the elementary osteoblast of osteoblast, people of people and rat, bone in children membrance separation, to find estrogen receptor; The estrogen that prompting estrogen possibly directly act on the osteocyte directly acts on osteoblast and osteoclast, suppresses the osteoclast bone resorption through various cytokines (interleukin-6 etc.).Postmenopausal women's blood insulin, IGF-I and leptin level and bone density all do not have direct relation.
Controversies in hormone replacement in the elderly is to show the postmenopausal women to replenish an amount of estrogen, to alleviate a kind of therapy of the postmenopausal symptom that estrogen deficiency causes.Estrogen and progestogen share and are called Hormone Replacement Therapy, and adding the purpose of using progestogen is for preventing endometrial hyperplasia.Controversies in hormone replacement in the elderly and Hormone Replacement Therapy are the most definite anti-bone resorption therapies of present known curative effect.The propagation of estrogen and oestrogen-mimicking stimulating osteoblast and collagen are synthetic, are suppressed to osteocyte secretion bone resorption stimulating factor, thereby reduce the bone conversion, suppress bone resorption.And can promote activated vitamin D
3Generate; Reduce the sensitivity of osteoclast, reduce bone resorption parathyroid hormone; Promote the synthetic of calcitonin.Result of study shows that estrogen can prevent 80%～90% postmenopausal women's bone loss, keeps the bone amount, prevention of osteoporosis.Yet along with using increasing of case; The side effect of controversies in hormone replacement in the elderly exposes gradually; Taking estrogen for a long time separately can make breast carcinoma, carcinoma of endometrium incidence rate increase by 5 to 7 times; Make apoplexy and cardiopathic sickness rate improve 40% and 29%, and the probability that makes lower limb and pulmonary that blood vessel embolism take place has increased by 1 times.
Aspirin is the antipyretic analgesic of using always; Have antiplatelet and antiphlogistic double effect; It can significantly reduce patients with coronary heart disease cardiovascular event incidence rate through antiplatelet, and oneself obtains the confirmation of a large amount of extensive clinical trials; The research in recent years of this project team has confirmed that this medicine also has the effect of prevention of osteoporosis, and has designed low-dosage aspirin and low dose of diethylstilbestrol composition compound preparation (being called for short the A-D mixture) in view of the above, hopes through adding aspirin to reduce estrogenic consumption; When increasing osteoporosis, also can reduce cardiovascular accidents such as estrogenic thrombosis.
Summary of the invention the present invention proposes theory and the thinking with aspirin with antiplatelet and antiphlogistic double effect and estrogen Combined application control " osteoporosis " research; We find the square preparation that aspirin and estrogen are formed, and can reduce estrogenic clinical consumption, aspect the osteoporosis curative effect synergism are being arranged; When diethylstilbestrol and aspirin prescription; Aspirin tablet gets final product with the dosage 100mg of clinical prevention cardiovascular accident, and diethylstilbestrol can use 1/3rd to 1/10th dosage of clinical dosage to get final product, because aspirin 100mg dosage can significantly reduce patients with coronary heart disease cardiovascular event incidence rate through antiplatelet oneself obtains the confirmations of a large amount of extensive clinical trials clinical; It reduces the apoplexy that controversies in hormone replacement in the elderly causes; Cardiopathic sickness rate, the probability that blood vessel embolism takes place for lower limb and pulmonary must have tangible effect, and this compound recipe is compared with estrogen with single; Also having and do not suppress osteoplastic advantage, is ideal osteosporosis resistant medicament.
The present invention proposes to be meant diethylstilbestrol with estrogen, estrone, estradiol valerate; Nilestriol, tibolone, M3-PREMA woods etc.; These medicines and aspirin are formed compound preparation can use 1/2nd to 1/10th of its clinical common dose; Its best dosage is 1/3rd to 1/5th, the dosage that aspirin is formed this compound recipe be 50mg to 200mg, its optimum formula is 100mg.
The present invention proposes the pharmaceutical composition of the Prevention and Treatment of Osteoporosis of aspirin and estrogen composition; Mainly be meant the compositions that aspirin tablet and diethylstilbestrol are formed; The proportion of composing of aspirin and diethylstilbestrol is 1000: 1～2; Be that aspirin is calculated by weight to 100 milligram hours in this complex, diethylstilbestrol is calculated by weight to 0.1～0.2 milligram in this complex.This pharmaceutical composition can add the adjuvant of necessity of tablet manufacturing by the technology of pharmaceutics; Be pressed into tablet; Supply clinical practice, also can be prepared into pill, granule, capsule, injection and any clinical acceptable drug preparation, supply clinical answering by modern crafts.
The present invention proposes the compositions with aspirin and diethylstilbestrol composition, and when being prepared into tablet, every contains 100 milligrams of aspirin, 0.1～0.2 milligram of diethylstilbestrol.1～2 of every day during clinical practice.
The specific embodiment: embodiment one
Form compound preparation (being called for short the A-D mixture) for confirming low-dosage aspirin and low dose of diethylstilbestrol; Has function of resisting osteoporosis; This experiment is set up osteoporosis model with ovariectomized rats; Whether through research methoies such as blood biochemical, bone morphometry, bone densities, observing this compound preparation can have potentiation and reduce untoward reaction the removal ovary osteoporosis rat, the existing report as follows:
1 material and method
1.1 material
1.1.1 4 42 of monthly age SPF level female sd inbred rats (Guangdong Medical College's Experimental Animal Center provides), body weight (254 ± 20) g are selected in laboratory animal and grouping for use.Adaptability is fed 10d.Random choose goes out 6 as base set (BAS) before the experiment beginning, before experiment, draws materials.All the other 36 rats are divided into sham operated rats (SHAM) at random, ovariectomized group (OVX), diethylstilbestrol group (OVX+D), aspirin diethylstilbestrol compound recipe group (OVX+A-D), 9 every group.All animals are freely taken the photograph water and ingest (standard feed, calcic 1.33%, phosphorus 0.95%), 25～28 ℃ of room temperatures, feed in humidity 75～80% cleaning level environment.
1.1.2 medicine synestrin tablets, Hefei join pharmaceutical Co. Ltd for a long time, every 0.5mg; Aspirin diethylstilbestrol compound preparation (A-D mixture): every contains aspirin 100mg, diethylstilbestrol 0.1mg.(by Medicines Science and Technology Development Center, Guangdong Medical College's preparation); Quadracycline, U.S. Sigma Chemical Co; Calcein, U.S. Sigma Chemical Co.
1.1.3 instrument U.S. Buehler LTD saws at a slow speed; Germany Leica2155 sclerous tissues microtome; Germany Leica tungsten carbide steel knife; Japan Nikon automated image digital analyser; U.S. OsteoMetrics osseous tissue morphometry software; The p-DEXA Sabre scanner of U.S. Norland company.
1.2 method
1.2.1 animal is handled under animal general anesthesia condition, the reference literature method
[5]Each experimental group rat is done the operation of bilateral removal ovary, and sham operated rats is done same operation, but does not remove ovary.Postoperative beginning in three days random packet, 9 every group.Formal experiment: sham operated rats is with normal saline 5mlkg
-1D
-1Irritate stomach, the diethylstilbestrol group is with diethylstilbestrol 30 μ gkg
-1D
-1Irritate stomach, the A-D mixture is pressed aspirin 10mgkg
-1D
-1With diethylstilbestrol 10 μ gkg
-1 -1Irritate stomach, each organizes all continuous gastric infusion 90d of rat.Animal is weighed weekly once, according to body weight change adjustment dosage.All animals are 14,13 days and 4,3 days difference subcutaneous injection tetracycline 30mgkg before execution
-1With calcein 10mgkg
-1Carry out fluorescent labeling in the body.When experiment finished, the heart blood drawing was put to death behind the rat anesthesia, got blood and did biochemical indicator mensuration, and get left tibia and do the research of osseous tissue morphometry, got fl and did bone density scanning.。
1.2.3 blood biochemical detects blood parameters such as T-CHOL (TC), HDL-C (HDL-C), low-density lipoprotein cholesterol (LDL-C) and alkali phosphatase (ALP) all detect through test kit, test kit all builds up bio-engineering research institute available from Nanjing.Above-mentioned all operations all requires to carry out according to the test kit description.
1.2.2 the osseous tissue norphometry is got the left side tibia, exposes medullary cavity with saw at a slow speed, get its epimere with 10% formalin buffer fixedly 24h, carry out gradient alcohol dehydration subsequently, xylene is transparent to carry out the embedding of undecalcified bone with methyl methacrylate.Embedding medium sclerosis back is polished into suitable shape with the Gypsum Fibrosum polisher, is cut into 9 μ m sheets and 5 μ m thin slices with Leica 2155 type sclerous tissues microtomes subsequently.The direct mounting of 9 μ m sheets is measured dynamic parameter; The capable cma staining of 5 μ m thin slices, measure static parameter after the mounting, using formula
[6,7]Calculating has related parameter.
For avoiding primary sponge, tibia epimere measuring range is the cancellous bone region between growth plate far-end 1mm～4mm.The static measurement parameter comprises the osseous tissue gross area (T.Ar), bone trabecula area (Tb.Ar), bone trabecula girth (Tb.Pm), osteoclast number (N.Oc), the adherent length of osteoclast (Oc.S).The kinetic measurement parameter comprises single fluorescent perimeter (sL.Pm), two fluorescent perimeter (dL.Pm), double labelling gap (Ir.L.Wi).With reference to correlation formula, can calculate calculating parameter: bone trabecula area percent (%Tb.Ar) reduction, bone trabecula thickness (Tb.Th), bone trabecula number (Tb.N), bone trabecula separating degree (Tb.Sp), every millimeter osteoclast number (Oc.N), osteoclast girth percent (%Oc.Pm), labelling girth percent (%L.Pm), bone mineralising formation rate (MAR), bone formation rate (BFR/BV), bone formation rate (BFR/BS), bone formation rate (BFR/TV).
1.2.4 detecting, bone density adopt the U.S. p-DEXA Sabre of Norland company scanner that fl integral body is carried out bone density scanning; Sweep parameter comprises osseous tissue area (Bone Area), bone mineral content (BMC), and bone density BMD calculates according to following formula: BMD=BMC/Bone Area.
1.3 the statistical metering data is represented with mean ± standard deviation
; Adopt the capable ANOVA variance analysis of SPSS16.0 software and organize with the LSD-t check between relatively, P＜0.05 can think to have statistical significance.
2 results
2.1 diethylstilbestrol and A-D mixture are to the influence of removal ovary rat body weight and uterus weight variation
Diethylstilbestrol and A-D mixture are seen table 1 to the influence of removal ovary rat body weight and uterus weight variation:
Table 1: diethylstilbestrol and A-D mixture are to the influence
of removal ovary rat body weight and uterus weight variation
Annotate: b: compare with sham operated rats,
bP＜0.05,
BbP＜0.01; C: compare with ovariectomized group
cP＜0.05,
CcP＜0.01.
Can be known that by table 1 result compare with sham-operation (SHAM) group, removal ovary (OVX) group rat body weight increases by 11.5% (P＜0.01), uterus weight reduces by 78.8% (P＜0.01); Compare diethylstilbestrol group rat body weight decline 16.2% (P＜0.01) with the OVX group; A-D mixture group rat body weight decline 10.9% (P＜0.05); Compare with the OVX group, diethylstilbestrol group rat uterus weight increases by 272.2% (P＜0.01), and A-D mixture group rat uterus weight increases by 233.3% (P＜0.05).Two medication groups are compared, and rat body weight and uterus weight do not have significant difference (P＞0.05).
2.2 diethylstilbestrol and A-D mixture are to the influence of removal ovary rat fat and serum alkaline phosphatase
Diethylstilbestrol and A-D mixture are seen table 2 to the influence of removal ovary rat fat and serum alkaline phosphatase:
Table 2 diethylstilbestrol and A-D mixture are to the influence
of removal ovary rat fat and serum alkaline phosphatase
Annotate: b: compare with sham operated rats,
bP＜0.05,
BbP＜0.01; C: compare with ovariectomized group
cP＜0.05,
CcP＜0.01.d: compare with the diethylstilbestrol group:
dP＜0.05.
Can know by table 2 result, compare that rat blood serum T-CHOL (TC) has significantly increased by 47.5% (P＜0.01) behind the removal ovary, low-density lipoprotein cholesterol (LDL-C) and the no significant change of HDL-C (HDL-C) with sham operated rats; Compare with ovariectomized group, diethylstilbestrol group Serum TC reduces by 59.8% (P＜0.01), and LDL reduces by 23.6% (P＜0.05); Compare with sham operated rats, ovariectomized group rat blood serum alkali phosphatase (ALP) significantly increases (P＜0.05); Diethylstilbestrol group or A-D mixture group are compared with ovariectomized group, all no difference of science of statistics.Two medication groups are compared, the equal no difference of science of statistics of each item serological index.
2.3 diethylstilbestrol and A-D mixture are to the influence of removal ovary rat tibia epimere osseous tissue static parameter
Diethylstilbestrol and A-D mixture are seen table 3 to the influence of removal ovary rat tibia epimere osseous tissue static parameter:
Table 3: diethylstilbestrol and A-D mixture are to the influence
of removal ovary rat tibia epimere osseous tissue static parameter
Annotate: with table 2.
Visible from table 3 result, compare each static parameter of sham operated rats and absorption parameter there are no significant difference (P＞0.05) with base set; Compare with sham operated rats, ovariectomized group bone trabecula area percent (%Tb.Ar) reduces by 70.0% (P＜0.01), and bone trabecula thickness (Tb.Th) reduces by 21.7% (P＜0.01); Bone trabecula number (Tb.N) reduces by 62.8% (P＜0.01); Bone trabecula separating degree (Tb.Sp) increases by 378.6% (P＜0.01), compares with ovariectomized group, and diethylstilbestrol group %Tb.Ar increases by 124.2% (P＜0.01); Tb.N increases by 112.7% (P＜0.01), and Tb.Sp reduces by 69.5% (P＜0.01); Compare with ovariectomized group, A-D mixture group %Tb.Ar increases by 108.2% (P＜0.01), and Tb.Th does not have remarkable increase (P＞0.05), and Tb.N increases by 95.7% (P＜0.01), and Tb.Sp reduces by 64.5% (P＜0.01); Each static all no difference of science of statistics (P＞0.05) between two medication groups.
2.4 diethylstilbestrol and A-D mixture are to the influence of removal ovary rat tibia epimere osseous tissue bone resorption parameter
Diethylstilbestrol and A-D mixture are seen table 4 to the influence of removal ovary rat tibia epimere osseous tissue bone resorption parameter:
Table 4: diethylstilbestrol and A-D mixture are to the influence of removal ovary rat tibia epimere osseous tissue bone resorption parameter
Annotate: with table 2.
Visible from table 4 result, compare each absorption parameter there was no significant difference of sham operated rats rat (P＞0.05) with base set; Compare with sham operated rats, every millimeter osteoclast number of ovariectomized group rat (Oc.N) increases by 116.7% (P＜0.01), and osteoclast girth percent (%Oc.Pm) increases by 173.7% (P＜0.01); Compare with ovariectomized group, diethylstilbestrol group Oc.N reduces by 45.1% (P＜0.01), and %Oc.Pm reduces by 53.8% (P＜0.01); Compare with ovariectomized group, A-D mixture group Oc.N reduces by 39.6% (P＜0.01), and %Oc.Pm reduces by 46.2% (P＜0.01); Each static state and the equal no difference of science of statistics of absorption parameter (P＞0.05) between two medication groups.
2.5 diethylstilbestrol and A-D mixture are to the influence of removal ovary rat tibia epimere osseous tissue dynamic parameter
Diethylstilbestrol and A-D mixture are seen table 5 to the influence of removal ovary rat tibia epimere osseous tissue dynamic parameter:
Table 5: diethylstilbestrol and A-D mixture are to the influence
of removal ovary rat tibia epimere dynamic parameter
Annotate: with table 2.
Visible from table 5, compare each dynamic parameter there was no significant difference of sham operated rats with base set; Compare with sham operated rats, ovariectomized group rat labelling girth percent (%L.Pm) significantly increases by 33.5% (P＜0.05), and BFR/BV increases by 51.0% (P＜0.05), and BFR/BS, BFR/TV increase but no difference of science of statistics to some extent; Compare with ovariectomized group, diethylstilbestrol group %L.Pm significantly reduces by 29.2% (P＜0.01), and BFR/BS, BFR/BV and BFR/TV all lower to some extent but do not have significant difference (P＞0.05); Compare with ovariectomized group; A-D mixture group %L.Pm, BFR/BS, BFR/BV and BFR/TV all decrease but there was no significant difference; And compare with the diethylstilbestrol group, A-D mixture group fluorescent labeling girth percent (%L.Pm) significantly increases (P＜0.05), except that MAR is low slightly (P＞0.05); BFR/BS, BFR/BV and BFR/TV all increase to some extent, but difference does not have significance (P＞0.05).
2.6 diethylstilbestrol and A-D mixture are to the influence of removal ovary rat femur bone density
Diethylstilbestrol and A-D mixture are seen table 6 to the influence of removal ovary rat femur bone density:
Table 6: diethylstilbestrol and A-D mixture are to the influence of removal ovary rat femur bone density
Annotate: a: with the base set contrast,
aP＜0.05,
AaP＜0.01, all the other are with table 2.
Visible by table 6 result, to compare with base set, sham operated rats rat fl bone density (BMD) significantly increases (P＜0.01); Compare with sham operated rats, rat fl BMD significantly reduces (P＜0.01) behind the removal ovary, and prompting bone amount obviously reduces; Compare with ovariectomized group, diethylstilbestrol group rat and A-D mixture group rat all can significantly increase femoral bmd (P＜0.01), and the rat bone amount significantly increases behind the prompting chemoprophylaxis.Bone density value between two medication groups is approaching, no difference of science of statistics (P＞0.05).
3 discuss
3.1 removal ovary can cause rat and produce tangible osteoporosis performance
This experiment is observed through osseous tissue morphometry method, and ovariectomized rats is after 12 weeks, and it is sparse that bone trabecula becomes, broadening at interval, and %Tb.Ar reduces by 70.0% (P＜0.01); Present typical osteoporotic static performance, visible Oc.N of the observation of osteoclast and Oc.Pm% are significantly increased (P＜0.01), point out this model bone resorption activity to increase; To the skeletonization index observing; Bone formation parameter %L.Pm and BFR/BV obviously increase (P＜0.05), explain that the bone formation rate increases, and the osteoporosis bone resorption that this removal ovary causes increases; Bone formation also increases, and belongs to the osteoporosis of high conversion type.Detect through bone density, also confirm removal ovary after the rat femur bone density significantly reduce; In addition; Rat body weight obviously increased after removal ovary was also observed in research; Uterus weight obviously alleviates, serum total cholesterol and low density lipoprotein, LDL obviously increase; Explained that this osteoporosis follows characteristics such as metratrophia and blood fat increase, similar with human menopausal osteoporosis, consistent with this seminar report in the past
[5,8]
3.2 controversies in hormone replacement in the elderly can prevent the osteoporosis rat due to the removal ovary
This research is observed, and adopts estrogen 30 μ gkg
-1D
-1Irritate stomach and substitute prevention, after 12 weeks, compare with model group; Prevention group rat %Tb.Ar and Tb.N significantly increase (P＜0.01); Tb.Sp significantly reduces (P＜0.01), and bone loss obviously reduces, and osteoporosis performance model alleviates; The Oc.N and the %Oc.Pm of the rat of prevention group in addition, reflection bone resorption marker significantly reduce (P＜0.01); The %L.Pm of reflection bone formation index obviously reduces (P＜0.01), complementing estrogen has been described after, osteoclast activity reduces, the osteoblast osteogenic activity also reduces, and the osteoporosis of the high conversion type that removal ovary causes is suppressed.Research is also observed, and the femoral bmd of prevention group rat obviously increases, and rat body weight obviously alleviates, and uterus weight increases, and blood fat significantly reduces.Above results suggest diethylstilbestrol replacement therapy can effectively prevent osteoporosis behind the removal ovary, and this result and we report in the past is consistent.Controversies in hormone replacement in the elderly once was to prevent and treat the most widely used method of postmenopausal osteoporosis clinically, and controversies in hormone replacement in the elderly can obviously improve postmenopausal women's bone loss, alleviates menopausal symptom and osteoporosis
[9]But because the estrogen prolonged application can increase the sickness rate of breast carcinoma and uterus carcinoma, can also significantly increase the risk of thrombotic disease and cardiovascular event, therefore also limit the estrogen application.
3.3 aspirin and diethylstilbestrol drug combination can prevent the osteoporosis rat due to the removal ovary
This research is observed, and adopts the aspirin (10mgkg of low dosage
-1D
-1) and estrogen (the 30 μ gkg of low dosage
-1 -1) the A-D mixture formed irritates stomach and substitute prevention; After 12 weeks, compare with model group, A-D mixture prevention group rat %Tb.Ar increases by 108.2% (P＜0.01); Tb.N also significantly increases (P＜0.01); Tb.Sp significantly reduces (P＜0.01), and bone loss obviously reduces, and the osteoporosis performance obviously alleviates; In addition, the Oc.N and the %Oc.Pm of A-D mixture prevention group rat reflection bone resorption marker significantly reduce (P＜0.01); But Tb.Th, %L.Pm, MAR, BFR/BS, BFR/BV and the BFR/BV of reflection bone formation index all do not have significant difference; Explained that the A-D mixture is different with simple complementing estrogen group; The A-D mixture can make osteoclast activity reduce, and obviously suppresses bone resorption, but to the not obviously influence of osteoblast osteogenic activity; That is to say that active the increasing of the osteoblast that causes behind the removal ovary do not had inhibitory action.Research is also observed, and the femoral bmd of A-D mixture prevention group rat obviously increases, and rat body weight obviously alleviates, and uterus weight increases, and blood fat significantly reduces.Above results suggest A-D mixture replacement therapy can effectively prevent osteoporosis behind the removal ovary, and the osteoplastic characteristics that do not suppress are arranged.About the existing bibliographical information of aspirin prevention of osteoporosis; But aspirin and low dose estrogen Combined application be also not report at present, and this experiment has tentatively proved the curative effect of low dosage aspirin and low dose estrogen Combined application prevention of osteoporosis through the research of removal ovary rat bone tissue morphometry.
3.4 the advantage and the mechanism analysis of aspirin and diethylstilbestrol associating prescription
Osteoporotic mechanism is fully proved behind the controversies in hormone replacement in the elderly prevention removal ovary.And it is at present also indeterminate to the related mechanism of the preventive effect of removal ovary rat bone loss for aspirin.There is the scholar in vitro study, to confirm; The COX-2 of osteoblast and osteoclast precursor cellular expression is through inducing NF-κ B ligand receptor activator aglucon (receptor activator of nuclear factor-κ B ligand in the osseous tissue; RANKL) (osteoprotegerin, expression OPG) promote the differentiation of osteoclast for expression and inhibition osteoprotegerin; Aspirin has suppressed the COX-2 function and has regulated PGE2 and express, thus the effect of performance prevention of osteoporosis.Also have research to show, aspirin can effectively prevent bone marrow stroma stem cell (MSCs) apoptosis that exsomatizes, and can effectively reduce CFU-F quantity and make MSCs to the differentiation of skeletonization direction, and can suppress the osteoclast function.Have scholar's research to find, external utilization aspirin can raise the activity of MSCs telomerase, and telomerase activation increases and helps MSCs to pass through the Runx2 path to the differentiation of skeletonization direction, and the level of its telomerase activation is little than tumor cell far away again.Have the scholar also to point out, osteoporotic effect is the suppressor T cell activation behind the aspirin control removal ovary, thereby has suppressed the apoptosis bone resorption relevant with osteoclast of the MSCs of Fas/FasL path mediation.This experiment finds to unite the utilization aspirin and diethylstilbestrol can suppress osteoclast activity, obviously reduces serum cholesterol and low density lipoprotein, LDL content, and not obvious to osteoplastic influence.Osteoporotic mechanism is relevant with its inhibition osteoclast function after further confirming aspirin prevention removal ovary; In addition, also maybe with the metabolism of aspirin blood lipid regulation, prevention of arterial is atherosis and promote that the bone marrow blood circulation is relevant.
Clinical research is verified, and the prolonged application low-dosage aspirin can safe and effective Prevention of Cardiovascular incident, comprises acute myocardial infarction, ischemic shock and peripheral angiopathy.In recent years, the low-dosage aspirin effects such as having prevention of colorectal, breast carcinoma, pulmonary carcinoma, gastric cancer, the esophageal carcinoma, rheumatic arthritis that also comes to light.Therefore, low-dosage aspirin and diethylstilbestrol coupling for menopause after women's osteoporosis, 3 advantages are arranged: amount of estrogen, prevention of osteoporosis are reduced in (1); (2) effectively prevent cardiovascular and cerebrovascular disease; (3) have side effect incidence rates such as helping reduce the estrogen-primed breast carcinoma of prolonged application, strengthen drug safety.Dosage (the 10mgkg of the aspirin of this experiment A-D mixture
-1D
-1) with the prophylactic dosage (100mgd of human Prevention of Cardiovascular incident
-1) equivalence, the dosage of diethylstilbestrol (10 μ gkg
-1D
-1) be osteoporosis normal dose (30 μ gkg behind the prevention removal ovary
-1D
-1) 1/3rd, according to the conversion of rat and human body medication, rat 30 μ gkg
-1D
-1Consumption is equivalent to 0.25～0.3mgd of people
-1, be the low dosage of human estrogen replacement therapy, being used to treat the general consumption of osteoporosis is 1.2mgd
-1, the dosage of the diethylstilbestrol of this research be merely its 1/10th, therefore, the function of resisting osteoporosis of this compound recipe is indicating that its application prospect is fine.
Claims (6)
1. the pharmaceutical composition of one group of Prevention and Treatment of Osteoporosis is characterized in that two kinds of compatibility of drugss of aspirin and estrogen, adds the adjuvant of pharmaceutics aspect, can be made into to supply clinical practice tablet, capsule, granule, electuary, oral liquid, external preparation, injection.
2. the pharmaceutical composition of Prevention and Treatment of Osteoporosis as claimed in claim 1 is characterized in that estrogen is meant diethylstilbestrol, estrone, estradiol valerate, nilestriol, tibolone, M3-PREMA woods.
3. like the pharmaceutical composition of claim 2 described Prevention and Treatment of Osteoporosis, it is characterized in that these estrogen are 1/2nd to 1/10th and the aspirin combinations with its clinical practice dosage.
4. the pharmaceutical composition of Prevention and Treatment of Osteoporosis as claimed in claim 1 is characterized in that this pharmaceutical composition is made up of aspirin and diethylstilbestrol.
5. like the pharmaceutical composition of claim 1 and 4 described Prevention and Treatment of Osteoporosis; The proportion of composing that it is characterized in that aspirin and diethylstilbestrol is 1000～2000: 1; Be that aspirin is calculated by weight to 100～200 milligram hours in this complex, diethylstilbestrol is calculated by weight to 0.1～0.2 milligram in this complex.
6. like the pharmaceutical composition of claim 1 and 4 described Prevention and Treatment of Osteoporosis; The proportion of composing that it is characterized in that aspirin and diethylstilbestrol is 1000: 1～2; Be that aspirin is calculated by weight to 100 milligram hours in this complex, diethylstilbestrol is calculated by weight to 0.1～0.2 milligram in this complex.
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| CN 201110269822 CN102397550B (en) | 2011-08-30 | 2011-08-30 | Medicinal composition composed of aspirin and estrogen and used for preventing and treating osteoporosis |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106890363A (en) * | 2015-12-17 | 2017-06-27 | 西安组织工程与再生医学研究所 | A kind of preparation method for being engineered dental pulp |
| CN110876766A (en) * | 2019-12-07 | 2020-03-13 | 广东医科大学 | Application of peony seed oil in preparation of medicines and health-care foods for improving biomechanical properties of male bones |
| US11534420B2 (en) | 2019-05-14 | 2022-12-27 | Tyme, Inc. | Compositions and methods for treating cancer |
| US11607418B2 (en) | 2020-05-14 | 2023-03-21 | Tyme, Inc. | Methods of treating SARS-CoV-2 infections |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10300077B2 (en) | 2016-09-12 | 2019-05-28 | Steven Hoffman | Compositions and methods for treating dementia |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1279611A (en) * | 1997-11-21 | 2001-01-10 | 加利福尼亚大学董事会 | Mechod for treating postmenopausal women using ultra-low-doses of estrogen |
| CN1480142A (en) * | 2003-06-30 | 2004-03-10 | 广东医学院 | compound preparation composed of longspur epimedium and estrogen for treating osteoporosis of women after climacteric |
| CN1947719A (en) * | 2006-10-29 | 2007-04-18 | 广东医学院 | Application of aspirin for preventing and treating osteoporosis |
| US20090324714A1 (en) * | 2008-06-27 | 2009-12-31 | Wyeth | Dual adhesive technology |
-
2011
- 2011-08-30 CN CN 201110269822 patent/CN102397550B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1279611A (en) * | 1997-11-21 | 2001-01-10 | 加利福尼亚大学董事会 | Mechod for treating postmenopausal women using ultra-low-doses of estrogen |
| CN1480142A (en) * | 2003-06-30 | 2004-03-10 | 广东医学院 | compound preparation composed of longspur epimedium and estrogen for treating osteoporosis of women after climacteric |
| CN1947719A (en) * | 2006-10-29 | 2007-04-18 | 广东医学院 | Application of aspirin for preventing and treating osteoporosis |
| US20090324714A1 (en) * | 2008-06-27 | 2009-12-31 | Wyeth | Dual adhesive technology |
Non-Patent Citations (2)
| Title |
|---|
| DOUGLAS S. SCHERR，ET AL: "THE NONSTEROIDAL EFFECTS OF DIETHYLSTILBESTROL: THE RATIONALE FOR ANDROGEN DEPRIVATION THERAPY WITHOUT ESTROGEN DEPRIVATION IN THE TREATMENT OF PROSTATE CANCER", 《THE JOURNAL OF UROLOGY》 * |
| 蔡小华，等: "骨质疏松症药物研究进展", 《怀化医专学报》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106890363A (en) * | 2015-12-17 | 2017-06-27 | 西安组织工程与再生医学研究所 | A kind of preparation method for being engineered dental pulp |
| CN106890363B (en) * | 2015-12-17 | 2021-09-10 | 西安组织工程与再生医学研究所 | Preparation method of engineered dental pulp |
| US11534420B2 (en) | 2019-05-14 | 2022-12-27 | Tyme, Inc. | Compositions and methods for treating cancer |
| CN110876766A (en) * | 2019-12-07 | 2020-03-13 | 广东医科大学 | Application of peony seed oil in preparation of medicines and health-care foods for improving biomechanical properties of male bones |
| US11607418B2 (en) | 2020-05-14 | 2023-03-21 | Tyme, Inc. | Methods of treating SARS-CoV-2 infections |
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| Publication number | Publication date |
|---|---|
| CN102397550B (en) | 2013-05-08 |
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