CN102526005A - Application of deferoxamine mesylate in preparing medicaments for treating postmenopausal osteoporosis - Google Patents
Application of deferoxamine mesylate in preparing medicaments for treating postmenopausal osteoporosis Download PDFInfo
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- CN102526005A CN102526005A CN2011104371172A CN201110437117A CN102526005A CN 102526005 A CN102526005 A CN 102526005A CN 2011104371172 A CN2011104371172 A CN 2011104371172A CN 201110437117 A CN201110437117 A CN 201110437117A CN 102526005 A CN102526005 A CN 102526005A
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Abstract
The invention relates to application of deferoxamine mesylate, in particular to application of the deferoxamine mesylate in preparing medicaments for treating postmenopausal osteoporosis. The deferoxamine mesylate has low toxicity and safety and can greatly reduce the loss of postmenopausal bone mineral contents.
Description
Technical field
the present invention relates to the purposes of deferoxamine mesylate, particularly the purposes of deferoxamine mesylate in preparation treatment postmenopausal osteoporosis disease medicament.
Background technology
The chemical name of deferoxamine mesylate (DFO) is N-[5-[3-[(5-ammonia amyl group)-oxyammonia formyl]-propionyl ammonia] amyl group]-3-[[(5-(N-hydroxyacetamide) amyl group]-carbamyl]-third rare-hydroxyl methanesulfonic acid, molecular formula is C
25
H
48
N
6
O
8
.CH
3
SO
3
H, molecular weight are 656.8.Deferoxamine mesylate is a kind of chelating agen, main and ferric ion and aluminium ion formation chelate, and its chelate forms constant and is respectively 10
31
With 10
25
, because its chelating properties, no matter in the blood plasma or the free iron in the cell, all can combine with it, form the sideramines chelate.Be mainly used in clinically chronic iron load overload, acute iron poisoning, end-stage renal failure patient the Chronic Aluminum traffic overload treatment and be used for ferrum or the diagnosis of aluminum traffic overload.In recent years animal experiment study show deferoxamine to liver transplantation ischemia-reperfusion, IARF exhaust, acute ischemia anoxia encephalopathy etc. all has protective effect.
in recent years discover that iron metabolism and bone metabolism are in close relations.2005, reports such as Guggenbuhl: in 38 routine holandric inheritance property hemachromatosis patients diagnosed, patient's ratio that the bone amount reduces was 78.9%, and osteoporotic ratio also reaches 34.2%.2006, Liu etc. removed rat ovary and make osteoporosis model, observed the variation of ferrum in the rat body then, and the result shows: the content of free iron significantly increases than sham operated rats in the castrated rats body; Confirm that for further the formation of this osteoporosis model is relevant with ferrum; Liu etc. began to give oral iron chelating agent again in second day after the rat castration; Its influence that osteoporosis model is formed of back observation of nine weeks; The result shows: BMD is still low than sham operated rats after the oral iron chelating agent, but compares with not oral iron chelating agent, and BMD significantly increases.2009; Researchs such as Jian are pointed out: estradiol level and ferritin level just in time change in the opposite direction in the menopause transition period female body; The interior ferritin level of body raise 2010 in the time of decrease in estrogen; The injection iron dextran is after 2 weeks in " Blood " magazine report rat abdominal cavity for Tsay etc., and rat part organ iron content significantly increases, and finds that simultaneously bone micro-structure, bone trabecula and thickness of cortex of bone take place obviously to change; Bone resorption increases, and the ferrum overload increases rat activity in vivo oxygen (ROS); After giving the processing of ferrum overload rat anti oxidant N-acetyl-L-cysteine, the bone trabecular abnormal development of rat is effectively suppressed.In sum, ferrum is the risk factor that is independent of another postmenopausal osteoporosis beyond the estrogen.Also do not report about the research of deferoxamine mesylate treatment postmenopausal osteoporosis at present.
Summary of the invention
The problem that
the present invention solves is to provide the purposes of a kind of deferoxamine mesylate in preparation treatment postmenopausal osteoporosis disease medicament.
in order to solve these problems of the prior art, technical scheme of the present invention is: the purposes of deferoxamine mesylate in preparation treatment postmenopausal osteoporosis disease medicament.
are according to the zoopery result of deferoxamine mesylate treatment postmenopausal osteoporosis; And deferoxamine mesylate clinical application method; The present invention is when treatment postmenopausal women osteoporosis disease; Preferably, described deferoxamine mesylate dosage is 15-60mg/Kg every day.
preferably, described deferoxamine mesylate dosage is 20-50mg/Kg every day.
preferably, described deferoxamine mesylate is added in the normal saline slowly subcutaneous or venoclysis.
preferably, the each infusion 8-24h of described deferoxamine mesylate, 3 times weekly.
preferably, described deferoxamine mesylate dosage is an oral dose.
not only are used for ferrum or diseases related diagnosis and the treatment of aluminum as clinical application, also are widely used in scientific research as a tool drugs.We intervene the postmenopausal osteoporosis animal model with deferoxamine mesylate and find that it has function of resisting osteoporosis.This discovery will produce great influence to the research and the treatment of postmenopausal osteoporosis disease, and value for clinical application is arranged, for deferoxamine mesylate has been opened up new clinical pathway.
deferoxamine mesylate human administration can be processed the absorbed capsule that comprises this chemical compound; Gelatine capsule for example; Or process syrup, solvent or suspension, the appropriate liquid pharmaceutical carrier comprises ethanol, glycerol, saline and water, can addings such as spice, pigment wherein be formed syrup; Also can be designed to extended release preparation, for example contain the tablet of enteric coating.The human oral administration, if tablet, so any pharmaceutical carrier that is suitable for disposing this kind solid composite is gone into magnesium stearate, starch, lactose, glucose, rice flour, flour and Chalk etc. and all can be used.
The fluid units metering form that contains this chemical compound and sterile carrier is then processed in
with regard to parenterai administration, different with concentration according to carrier, this chemical compound can suspend or be dissolved in wherein.The general method for preparing of the solution of parenterai administration is; Chemical compound is dissolved in the carrier; Aseptic filtration is dashed then and is injected suitable bottle or the sealing of ampere bottle, and preferably the adjuvant with antiseptic and buffer agent and so on also is dissolved in the carrier; For improving stability, compositions makes it freezing and freeze vaccum dewatering after being injected into bottle.
The suspension or the solution manufacturing method of
parenteral administration are basic identical, preferably surfactant or wetting agent are added in the compositions, help the homodisperse of deferoxamine mesylate.
preferred parenteral formulation comprises use sterilized water or the brinish liquid preparation of generic physiological.
advantage of the present invention is: 1. deferoxamine mesylate has been proved to be little, the safety of toxicity as clinical application; 2. deferoxamine mesylate can reduce losing of bone amount after the menopause significantly.
Description of drawings
Below in conjunction with accompanying drawing and embodiment the present invention is further described:
Fig. 1 has shown the detected value of the rat Grafting Cancellous Bone Bolt density of each group of experiment.
Fig. 2 has shown rat spongy bone volume fraction (BV/TV) detected value of each group of experiment.
Fig. 3 has shown the rat bone girder quantity detected value of each group of experiment.
Fig. 4 has shown the rat bone girder interval detected value of each group of experiment.
Fig. 5 respectively organizes the two dimensional image of the distal part of femur of rat for Micro-CT scanning experiment; Wherein A is the SHAM group, and B is the OVX group, and C is the DFO+OVX group.
Fig. 6 scans the distal part of femur of experimental rat and carries out 3D image reconstruction for Micro-CT and shows; Wherein A ' is the SHAM group, and B ' is the OVX group, and C ' is the DFO+OVX group.
Fig. 7 is the influence of the DFO of variable concentrations to TNF-a Induced Apoptosis in Osteoblasts.Left side lower area: living cells (the Annexin V-/PI-); Lower right area: viable apoptotic cell (the Annexin V +/PI-); Right regions: the cell of dying in heaven (the Annexin V +/PI+).
Fig. 8 is the influence of the DFO of variable concentrations to the osteoblast mineralising.
The specific embodiment
below will describe in detail the present invention through concrete embodiment for the ease of understanding.What need particularly point out is that these descriptions only are exemplary descriptions, do not constitute limitation of the scope of the invention.According to the argumentation of this description, many variations of the present invention, change all are conspicuous concerning one of ordinary skill in the art.
embodiment: according to the zoopery result of deferoxamine mesylate treatment postmenopausal osteoporosis; And deferoxamine mesylate clinical application method; The present invention is when treatment postmenopausal osteoporosis disease; Can adopt the slow venoclysis of deferoxamine mesylate, each 50mg/kg, 3 times weekly.
Support that the result of study of this experiment is following:
experiment grouping situation is following: sham-operation SHAM group, removal ovary OVX group and deferoxamine mesylate (DFO+OVX) group.6 of every group of SD rats.
The SHAM group is: incision skin, muscle are only visited and ovary, do not remove ovary, remove the interference of this technical operation of operation to experimental result;
The OVX group is: excise the rat bilateral ovaries after cutting skin, muscle;
DFO+OVX group is: give deferoxamine mesylate DFO 100mg/Kg (being dissolved in normal saline) lumbar injection after removing the rat bilateral ovaries, on every Wendesdays time, continued for 12 weeks altogether, and other two groups give the contrast of normal saline lumbar injection.
result finds: compare with the SHAM group, removal ovary OVX group rat blood serum ferrum significantly increases (P< than sham-operation SHAM group; 0.01); After using DFO to intervene, DFO+OVX group serum levels of iron significantly reduces (P< than removal ovary OVX group rat blood serum ferrum; 0.01) (seeing table 1).The experimental result prompting: DFO can significantly reduce castrated rats serum levels of iron level.
Table 1 is respectively organized the rat blood serum concentration of iron
| GroupSham-operation (SHAM) group removal ovary (OVX) group deferoxamine mesylate (DFO+OVX) group |
| Serum levels of iron (umol/ml)35.6±1.9 59.7±3.5▲ 42.3±2.0▲★ |
Annotate: OVX group, DFO+OVX group are compared ▲ P< with the SHAM group; 0.01 the DFO+OVX group is compared ★ P< with the OVX group; 0.01.
are passable through above-mentioned experiment, and DFO can increase castrated rats Grafting Cancellous Bone Bolt density, spongy bone volume, bone trabecula quantity and thickness, reduce bone trabecula at interval, thereby improve bone micro-structure.
are tested grouping situation and are intervened the same.After 12 weeks, all rats are got the capable Micro-CT inspection of femoral inferior segment BIAO and BEN.The detection index is: rat Grafting Cancellous Bone Bolt density (BMD), spongy bone volume, bone trabecula quantity, bone trabecula are at interval.Rat Grafting Cancellous Bone Bolt density, spongy bone volume, bone trabecula quantity and osteoporosis are proportionate, and bone trabecula is negative correlation with osteoporosis at interval.Bone trabecula is big more at interval, and sclerotin is loose more.
The result is shown in Fig. 1-4, and Fig. 1 shows that OVX organizes and deferoxamine mesylate intervention (DFO+OVX) group is compared P with the SHAM group
a
<0.01 the DFO+OVX group is compared P with the OVX group
b
<0.01, explain that DFO can significantly increase Grafting Cancellous Bone Bolt density BMD.Fig. 2 shows: the DFO+OVX group after DFO intervenes is compared the spongy bone volume fraction with the OVX group significantly increases P
b
<0.01; Fig. 3 shows: the DFO+OVX group is compared bone trabecula quantity with the OVX group significantly increases P
b
<0.01; Fig. 4 shows: the DFO+OVX group after DFO intervenes is compared bone trabecula with the OVX group and is significantly reduced P at interval
b
<0.01.
are shown in Figure 5; Utilization Micro-CT scans the two dimensional image of the distal part of femur of above-mentioned three groups of experimental rats; And carry out image reconstruction and quantitative analysis, can describe bone density and bone micro-structure more accurately, thereby judge degree of osteoporosis.Wherein, A is the SHAM group, and B is the OVX group, and C is the DFO+OVX group.Two dimensional image shows: compares with the OVX group, and the bone trabecula quantity showed increased of the DFO+OVX group after DFO intervenes, bone trabecula significantly reduces at interval.
Fig. 6 scans the distal part of femur of experimental rat and carries out 3D image reconstruction for Micro-CT and shows; Wherein, A ' is the SHAM group, and B ' is the OVX group, and C ' is the DFO+OVX group.3D image reconstruction shows: the DFO+OVX group after DFO intervenes is significantly improved than the bone micro-structure of OVX group.
We find to use DFO intervention removal ovary rat after 12 weeks
; Though can not return to matched group (sham-operation) group level; But compare with removal ovary (OVX) group, Grafting Cancellous Bone Bolt density (BMD), spongy bone volume fraction (BV/TV), bone trabecula quantity (Tb.N) obviously increase (P< 0.01), bone trabecula obviously reduces (P< at interval; 0.01).Based on above experimental evidence, we reach a conclusion: the DFO osteoporosis is effective.And the interior ferrum of body was accumulated increase after clinical existing research showed women's menopause.
DFO is to the influence of human osteoblast cell's apoptosis and the formation of calcium tuberosity
calcium tuberosity is osteoblast forms mineralising when In vitro culture a extracellular matrix, is the final stage of osteoblast differentiation.Therefore the calcium tuberosity is not only and is identified one of osteoblastic important indicator, also is the final embodiment of osteoblast mineralising skeletonization.Add in human osteoblast cell's culture medium with the DFO of variable concentrations (0,5,10,20umol/L), flow cytometer detects TNF-a Induced Apoptosis in Osteoblasts; The capable calcium tuberosity dyeing of Von kossa staining.The result finds: after (1) DFO intervened osteoblast 48h, apoptosis rate and matched group comparison obviously reduced in 5umol/L, 10umol/L concentration group, and relatively there were significant differences (P ﹤ 0.05) between group; It is as shown in Figure 7 significantly to increase (P ﹤ 0.05) at 20umol/L concentration group apoptosis rate and matched group.(2) the DFO group makes the osteoblast mineralization ability strengthen when 5umol/L, 10umol/L concentration, and calcification area, mineralising calcium tuberosity all increase, and then are suppressed to the osteocyte mineralization function during 20umol/L concentration, and be as shown in Figure 8.
above-mentioned instance only is explanation technical conceive of the present invention and characteristics, and its purpose is to let the people who is familiar with this technology can understand content of the present invention and enforcement according to this, can not limit protection scope of the present invention with this.All equivalent transformations that spirit is done according to the present invention or modification all should be encompassed within protection scope of the present invention.
Claims (6)
1.
deferoxamine mesylate is treated the purposes in the postmenopausal osteoporosis disease medicament in preparation.
2.
purposes according to claim 1 is characterized in that, described deferoxamine mesylate dosage is 15-60mg/Kg every day.
3.
purposes according to claim 1 and 2 is characterized in that, described deferoxamine mesylate is added in slowly subcutaneous or venoclysis in the normal saline.
4.
purposes according to claim 1 is characterized in that, described deferoxamine mesylate dosage is 20-50mg/Kg every day.
5.
purposes according to claim 3 is characterized in that, the each infusion 8-24h of described deferoxamine mesylate, 3 times weekly.
6.
purposes according to claim 2 is characterized in that described deferoxamine mesylate dosage is an oral dose.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107184570A (en) * | 2017-06-02 | 2017-09-22 | 中国科学院遗传与发育生物学研究所 | Deferoxamine is preparing the application in being used to treat the medicine of NASH |
| CN111544374A (en) * | 2020-05-13 | 2020-08-18 | 中国人民解放军总医院第四医学中心 | Application of deferoxamine mesylate for injection in treating age-increasing bone loss and bone marrow stem cell senescence |
| CN112807293A (en) * | 2021-03-01 | 2021-05-18 | 滨州医学院 | Application of deferoxamine mesylate in preparing medicine for treating otitis media |
Citations (1)
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| CN101945668A (en) * | 2008-02-19 | 2011-01-12 | 诺瓦提斯公司 | Combination of an iron chelator and an immunosuppressant and use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101945668A (en) * | 2008-02-19 | 2011-01-12 | 诺瓦提斯公司 | Combination of an iron chelator and an immunosuppressant and use thereof |
Non-Patent Citations (1)
| Title |
|---|
| 俞晨等: "去铁胺对去势后骨质疏松大鼠治疗作用的实验研究", 《中华医学会第六次全国骨质疏松和骨矿盐疾病学术会议暨中华医学会骨质疏松和骨矿盐疾病分会成立十周年论文汇编》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107184570A (en) * | 2017-06-02 | 2017-09-22 | 中国科学院遗传与发育生物学研究所 | Deferoxamine is preparing the application in being used to treat the medicine of NASH |
| CN107184570B (en) * | 2017-06-02 | 2019-08-02 | 中国科学院遗传与发育生物学研究所 | Deferoxamine is preparing the application in the drug for treating nonalcoholic fatty liver |
| CN111544374A (en) * | 2020-05-13 | 2020-08-18 | 中国人民解放军总医院第四医学中心 | Application of deferoxamine mesylate for injection in treating age-increasing bone loss and bone marrow stem cell senescence |
| CN112807293A (en) * | 2021-03-01 | 2021-05-18 | 滨州医学院 | Application of deferoxamine mesylate in preparing medicine for treating otitis media |
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| CN102526005B (en) | 2013-07-10 |
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