WO2024108560A1 - 阿托莫西汀在制备增加骨血管h亚型内皮细胞药物中的应用 - Google Patents
阿托莫西汀在制备增加骨血管h亚型内皮细胞药物中的应用 Download PDFInfo
- Publication number
- WO2024108560A1 WO2024108560A1 PCT/CN2022/134397 CN2022134397W WO2024108560A1 WO 2024108560 A1 WO2024108560 A1 WO 2024108560A1 CN 2022134397 W CN2022134397 W CN 2022134397W WO 2024108560 A1 WO2024108560 A1 WO 2024108560A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- atomoxetine
- pharmaceutical composition
- endothelial cells
- subtype
- deferoxamine mesylate
- Prior art date
Links
- 210000000988 bone and bone Anatomy 0.000 title claims abstract description 38
- VHGCDTVCOLNTBX-QGZVFWFLSA-N atomoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=CC=C1C VHGCDTVCOLNTBX-QGZVFWFLSA-N 0.000 title claims abstract description 33
- 229960002430 atomoxetine Drugs 0.000 title claims abstract description 33
- 239000003814 drug Substances 0.000 title claims abstract description 31
- 210000003556 vascular endothelial cell Anatomy 0.000 title abstract description 13
- 229960001425 deferoxamine mesylate Drugs 0.000 claims abstract description 35
- IDDIJAWJANBQLJ-UHFFFAOYSA-N desferrioxamine B mesylate Chemical compound [H+].CS([O-])(=O)=O.CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN IDDIJAWJANBQLJ-UHFFFAOYSA-N 0.000 claims abstract description 35
- 208000001132 Osteoporosis Diseases 0.000 claims abstract description 26
- 206010039984 Senile osteoporosis Diseases 0.000 claims abstract description 8
- 229940079593 drug Drugs 0.000 claims description 26
- 239000008194 pharmaceutical composition Substances 0.000 claims description 24
- 210000002889 endothelial cell Anatomy 0.000 claims description 22
- 230000037182 bone density Effects 0.000 claims description 13
- 239000007928 intraperitoneal injection Substances 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 7
- 238000003304 gavage Methods 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 230000002792 vascular Effects 0.000 claims description 6
- 238000003305 oral gavage Methods 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 230000011164 ossification Effects 0.000 abstract description 6
- 229910052500 inorganic mineral Inorganic materials 0.000 abstract 2
- 239000011707 mineral Substances 0.000 abstract 2
- 238000002648 combination therapy Methods 0.000 abstract 1
- 241000699670 Mus sp. Species 0.000 description 7
- 210000000056 organ Anatomy 0.000 description 6
- 102100038566 Endomucin Human genes 0.000 description 5
- 101001030622 Homo sapiens Endomucin Proteins 0.000 description 5
- 102100024616 Platelet endothelial cell adhesion molecule Human genes 0.000 description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 3
- 206010065973 Iron Overload Diseases 0.000 description 3
- 208000007502 anemia Diseases 0.000 description 3
- 210000001930 leg bone Anatomy 0.000 description 3
- 229960002748 norepinephrine Drugs 0.000 description 3
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 3
- 206010072735 Aluminium overload Diseases 0.000 description 2
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 description 2
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 description 2
- 208000020084 Bone disease Diseases 0.000 description 2
- 206010065687 Bone loss Diseases 0.000 description 2
- 230000005913 Notch signaling pathway Effects 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 210000003989 endothelium vascular Anatomy 0.000 description 2
- 238000000799 fluorescence microscopy Methods 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 210000002997 osteoclast Anatomy 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 208000014644 Brain disease Diseases 0.000 description 1
- 208000032274 Encephalopathy Diseases 0.000 description 1
- 206010017076 Fracture Diseases 0.000 description 1
- 208000031856 Haemosiderosis Diseases 0.000 description 1
- 208000018565 Hemochromatosis Diseases 0.000 description 1
- 208000035186 Hemolytic Autoimmune Anemia Diseases 0.000 description 1
- 208000034767 Hypoproteinaemia Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 1
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 1
- 201000010273 Porphyria Cutanea Tarda Diseases 0.000 description 1
- 206010036186 Porphyria non-acute Diseases 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000002903 Thalassemia Diseases 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 102000035181 adaptor proteins Human genes 0.000 description 1
- 108091005764 adaptor proteins Proteins 0.000 description 1
- 239000002269 analeptic agent Substances 0.000 description 1
- 201000000448 autoimmune hemolytic anemia Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000008468 bone growth Effects 0.000 description 1
- 230000004097 bone metabolism Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000004624 confocal microscopy Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 206010013781 dry mouth Diseases 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000004349 growth plate Anatomy 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 238000003125 immunofluorescent labeling Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000010603 microCT Methods 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 239000002767 noradrenalin uptake inhibitor Substances 0.000 description 1
- 229940127221 norepinephrine reuptake inhibitor Drugs 0.000 description 1
- 210000000963 osteoblast Anatomy 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 208000031162 sideroblastic anemia Diseases 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
Images
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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
Definitions
- the invention relates to bones and blood vessels, and uses drugs in combination to control the specificity of vascular endothelial cells in bones, and in particular to the application of atomoxetine in the preparation of drugs for increasing bone vascular H subtype endothelial cells.
- Osteoporosis is a bone disease characterized by bone loss and bone microarchitecture degeneration, which can lead to increased bone brittleness and a higher risk of fractures.
- the two generally accepted risk factors for osteoporosis are low estrogen levels and advanced age.
- Most of the existing drugs for the treatment of osteoporosis are based on the pharmacological principle of preventing osteoclasts from further breaking down bones and reducing bone density, but they are not very helpful for the elderly who have already lost a lot of bone mass.
- Endothelial cells are monolayer cells distributed in the inner wall of blood vessels, with rich heterogeneity and organ specificity. Through dense capillary branches, endothelial cells establish connections with almost all cells in various organs. In different organs, endothelial cells have significant morphological specificity. At the same time, endothelial cells in different organs have different transcription factor clusters, corresponding to different organs and needs to express and secrete different vascular secretory factors to support the physiological functions of organs. Endothelial cells in bones are found to have rich heterogeneity. One subtype of endothelial cells, H subtype bone endothelial cells, can promote osteogenesis.
- Bone vascular H subtype endothelial cells are mainly distributed in the shape of arches near the bone growth plate and endostea. They are a subtype of endothelial cells with highly active growth metabolism. They couple themselves with bone metabolism through the Notch signaling pathway to promote osteogenesis. With the increase of age, the expression of CD31 and EMCN in H subtype endothelial cells decreases, and they are transformed into L subtype endothelial cells, which no longer retain the properties of active metabolic growth and promoting osteogenesis.
- subtype H endothelial cells were correlated with hypoxia-inducible factor, Notch signaling pathway, blood flow, platelet-derived growth factor secreted by osteoclast precursors, and the adaptor protein Schnurri311 secreted by osteoblasts.
- Deferoxamine mesylate for injection is a mature chemical drug with the following indications: 1. For treatment of chronic iron overload, such as hemosiderosis caused by blood transfusion, such as severe thalassemia, sideroblastic anemia, autoimmune hemolytic anemia and other chronic anemias. Idiopathic (primary) hemochromatosis patients are hampered by venesection due to concomitant diseases (such as severe anemia, heart disease, hypoproteinemia). Iron overload caused by porphyria cutanea tarda cannot be performed by venesection. Treatment of acute iron poisoning. Treatment of chronic aluminum overload in patients with advanced renal failure (continuous dialysis), accompanied by the following conditions: aluminum-related bone disease and/or dialysis encephalopathy and/or aluminum-related anemia. 2. For diagnosis of iron or aluminum overload. Studies have shown that the drug deferoxamine mesylate can promote the reverse conversion of L subtype vascular endothelial cells to H subtype, increasing the bone density of elderly C57BL/6J male mice.
- Atomoxetine is a drug used to treat attention deficit hyperactivity disorder. It is a non-central nervous system stimulant. The main side effects are: dry mouth, fatigue, etc.
- This drug is a norepinephrine reuptake inhibitor. It is mainly used to treat the symptoms of patients with attention deficit hyperactivity disorder.
- Norepinephrine is an important substance in the brain that regulates attention, pulsatility and activity level. This drug mainly works by blocking or slowing the reuptake of norepinephrine, thereby increasing the concentration of norepinephrine.
- the object of the present invention is to provide the use of atomoxetine in the preparation of a drug for increasing bone vascular H subtype endothelial cells.
- the first aspect of the present invention provides the use of atomoxetine in the preparation of any one of the drugs (1) to (3):
- the second aspect of the present invention provides the use of a combination of atomoxetine and deferoxamine mesylate in the preparation of any one of the drugs described in (1) to (3):
- the osteoporosis is senile osteoporosis.
- a third aspect of the present invention provides a pharmaceutical composition for increasing bone vascular H subtype endothelial cells, the pharmaceutical composition comprising atomoxetine and deferoxamine mesylate.
- a fourth aspect of the present invention provides a pharmaceutical composition for increasing bone density, the pharmaceutical composition comprising atomoxetine and deferoxamine mesylate.
- a fifth aspect of the present invention provides a pharmaceutical composition for treating osteoporosis, the pharmaceutical composition comprising atomoxetine and deferoxamine mesylate.
- osteoporosis is senile osteoporosis.
- the above-mentioned pharmaceutical composition also contains a pharmaceutically acceptable carrier.
- the administration method of the above-mentioned pharmaceutical composition is: intraperitoneal injection of deferoxamine mesylate and oral administration of atomoxetine;
- the pharmaceutical composition is administered by intraperitoneal injection of deferoxamine mesylate every other day for a certain period of time, and then intraperitoneal injection of deferoxamine mesylate every other day while gavage of atomoxetine.
- the dosage of each intraperitoneal injection of deferoxamine mesylate is 300 mg/kg, and the dosage of each intragastric administration of atomoxetine is 10 mg/kg.
- a sixth aspect of the present invention provides a method for treating osteoporosis, comprising: administering an effective dose of atomoxetine and deferoxamine mesylate to a patient.
- osteoporosis is senile osteoporosis.
- the present invention finds that the combined use of atomoxetine and deferoxamine mesylate can further promote the generation of H subtype bone vascular endothelial cells.
- the generation of H subtype bone vascular endothelial cells increases the bone density coupled thereto, thereby promoting bone formation.
- the combined drug of the present invention can promote the generation of H subtype bone vascular endothelial cells and thus promote bone formation, thereby achieving the treatment of senile osteoporosis.
- Figure 1 shows the fluorescence imaging of the vascular endothelium in the long bones of mice and the microCT imaging of the bones.
- Control control group
- DFM group injected with deferoxamine mesylate alone
- DFM+ATX group injected with deferoxamine mesylate and gavage with atomoxetine.
- Figure 1A Fluorescence imaging of the vascular endothelium, characterizing the heterogeneity of endothelial cells.
- Figure 1B MicroCT imaging of the bones.
- Control a control group
- DMF deferoxamine mesylate alone
- DMF+ATX a group injected with deferoxamine mesylate intraperitoneally and administered with atomoxetine by gavage
- Control group injected with normal saline.
- Deferoxamine mesylate injection group (DFM): Deferoxamine mesylate was injected intraperitoneally every other day for four weeks, with a dose of 300 mg/kg
- Intraperitoneal injection of deferoxamine mesylate and oral gavage of atomoxetine (DFM+ATX): First, intraperitoneal injection of deferoxamine mesylate was given every other day for two weeks, with a dosage of 300 mg/kg. Starting from the third week, intraperitoneal injection of deferoxamine mesylate and oral gavage of atomoxetine were performed every other day, with a dosage of 300 mg/kg for deferoxamine mesylate and 10 mg/kg for atomoxetine, and the combination was used for four weeks.
- the leg bones of mice were sampled to observe the heterogeneity of vascular endothelial cells in the long bones.
- the specific operations were as follows: the leg bones of mice were fixed, decalcified, dehydrated, embedded, and sliced, and two endothelial cell-specific markers (CD31 and EMCN) were used for immunofluorescence staining. Laser confocal microscopy was used to observe CD31 + vessels (green), EMCN + vessels (red), and CD31 + EMCN + vessels (H subtype vessels) in the long bones. The yellow vessels represent CD31 + EMCN + co-localized H subtype vessels.
- the leg bones of mice were sampled to measure the long bone density.
- the specific operation was as follows: the bone specimens were fixed with 4% PFA and scanned by MicroCT under the same conditions. Bone parameters were counted.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Physical Education & Sports Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Epidemiology (AREA)
- Rheumatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明公开了阿托莫西汀在制备增加骨血管H亚型内皮细胞药物中的应用，本发明公开阿托莫西汀和甲磺酸去铁胺的组合物在制备增加骨血管H亚型内皮细胞的药物、增加骨密度的药物或治疗骨质疏松的药物中的应用：本发明发现阿托莫西汀与甲磺酸去铁胺联合用药能够进一步促进H亚型骨血管内皮细胞的生成，H亚型骨血管内皮细胞的生成使得与其偶联的骨密度增加，促进骨生成。采用本发明联合用药，可实现对老年性骨质疏松的治疗。
Description
本发明涉及骨和血管，利用药物联合应用控制骨骼内血管内皮细胞的特异性，具体涉及阿托莫西汀在制备增加骨血管H亚型内皮细胞药物中的应用。
骨质疏松症是以骨量丢失和骨微结构退变为特点的骨骼疾病，可导致骨骼脆性增加，发生骨折的风险也随之变高。目前，普遍接受的两种骨质疏松的危险因素是雌激素水平降低和高龄。已有的治疗骨质疏松的药物中，绝大多数都是以阻止破骨细胞进一步破骨降低骨密度为药理学原理的，但对于骨质已经大量流失的老年人来说，帮助不大。
血管内皮细胞是分布在血管内壁的单层细胞，具有丰富的异质性与器官特异性。通过密集的毛细血管分支，血管内皮在各个器官内与几乎所有的细胞建立联系。在不同的器官当中，血管内皮有着显著的形态特异性，同时，不同器官的血管内皮细胞有着不同的转录因子簇，对应不同的器官和需求表达分泌不同的血管分泌因子以支持器官的生理功能。骨内的血管内皮被发现存在丰富的异质性，其中一类亚型血管内皮，H亚型骨血管内皮，能够促进骨质生成，骨血管H亚型内皮主要成拱柱状分布在骨生长板及骨内膜附近，是一类生长代谢高度活跃的内皮细胞亚型，它通过Notch信号通路将自身和骨代谢偶联在一起，促进骨质生成。随着年龄的增长，H亚型内皮细胞中CD31与EMCN的表达降低，转变为L亚型内皮，不再保留活跃代谢生长和促进骨生成的性质。H亚型内皮细胞的体内水平与缺氧诱导因子、Notch信号通路、血流、由破骨细胞前体分泌的血小板衍生生长因子以及由成骨细胞分泌的衔接蛋白Schnurri311相关。
注射用甲磺酸去铁胺是一种成熟的化学药，适应症为1.用于治疗方面治疗慢性铁负荷过重，例如输血引起的含铁血黄素沉着病，如重症地中海贫血、铁粒幼细胞性贫血、自身免疫性溶血性贫血及其他慢性贫血。特发性(原发性)血色病者因伴随疾病(例如严重贫血，心脏疾病，低蛋白血症)妨碍了静脉切开放血术。迟发性皮肤卟啉病引起的铁负荷过载，不能进行静脉切开。治疗急性铁中毒。治疗晚期肾功能衰竭(持续透析)患者的慢性铝负荷过载，伴有下列情况：铝相关的骨病和/或透析性脑病和/或-铝相关性贫血。2.用于诊断方面用于诊断铁或铝负荷过载。有研究表明，通过药物甲磺酸去铁胺能促进L亚型血管内皮逆向转变成 H亚型，增加老年C57BL/6J雄鼠的骨密度。
阿托莫西汀为一种用于治疗注意力不足过动症的药物，属于非中枢神经刺激药物。主要副作用有：口干、疲倦等。该药为去甲肾上腺素再摄取抑制剂。主要用来治疗注意力不足过动症患者的症状。去甲肾上腺素是脑中调节注意力、搏动性和活动水平的重要物质，该药主要透过阻断或减缓去甲肾上腺素的再摄取使得去甲肾上腺素浓度增加而发挥作用。
发明内容
为了解决现有技术中的不足，本发明的目的是提供阿托莫西汀在制备增加骨血管H亚型内皮细胞药物中的应用。
本发明的具体技术方案如下：
本发明第一方面提供阿托莫西汀在制备(1)-(3)任一项所述药物中的应用：
(1)增加骨血管H亚型内皮细胞的药物；
(2)增加骨密度的药物；
(3)治疗骨质疏松的药物。
本发明第二方面提供阿托莫西汀和甲磺酸去铁胺的组合物在制备(1)-(3)任一项所述药物中的应用：
(1)增加骨血管H亚型内皮细胞的药物；
(2)增加骨密度的药物；
(3)治疗骨质疏松的药物。
进一步地，上述应用中，所述骨质疏松为老年性骨质疏松。
本发明第三方面提供一种增加骨血管H亚型内皮细胞的药物组合物，所述药物组合物包含阿托莫西汀和甲磺酸去铁胺。
本发明第四方面提供一种增加骨密度的药物组合物，所述药物组合物包含阿托莫西汀和甲磺酸去铁胺。
本发明第五方面提供一种治疗骨质疏松的药物组合物，所述药物组合物包含阿托莫西汀和甲磺酸去铁胺。
进一步地，所述骨质疏松为老年性骨质疏松。
进一步地，上述药物组合物还包含药学上可接受的载体。
进一步地，上述药物组合物的给药方式为：腹腔注射甲磺酸去铁胺，灌胃阿托莫西汀；
优选地，所述药物组合物的给药方式为：先隔天腹腔注射甲磺酸去铁胺一定时间，之后隔天腹腔注射甲磺酸去铁胺的同时灌胃阿托莫西汀。
进一步地，上述药物组合物的施用对象为小鼠时，每次腹腔注射甲磺酸去铁胺的用药剂量为300mg/kg，每次灌胃阿托莫西汀的用药剂量为10mg/kg。
本发明第六方面提供一种治疗骨质疏松的方法，其方法为：给予患者有效剂量的阿托莫西汀和甲磺酸去铁胺。
进一步地，所述骨质疏松为老年性骨质疏松。
本发明的有益效果为：
本发明发现阿托莫西汀与甲磺酸去铁胺联合用药能够进一步促进H亚型骨血管内皮细胞的生成，H亚型骨血管内皮细胞的生成使得与其偶联的骨密度增加，促进骨生成。
针对老年人骨质已经大量流失的问题，采用本发明联合用药，通过促进H亚型骨血管内皮细胞的生成从而促进骨质生成，可实现对老年性骨质疏松的治疗。
图1为小鼠长骨内血管内皮的荧光成像图与骨骼microCT成像图。Control：对照组，DFM：单独注射甲磺酸去铁胺组，DFM+ATX：腹腔注射甲磺酸去铁胺与灌胃阿托莫西汀联合用药组。图1A，血管内皮荧光成像图，表征内皮细胞异质性变化。图1B，骨骼microCT成像图。图1C，骨参数变化，n＝3。
为了更清楚地理解本发明，现参照下列实施例及附图进一步描述本发明。实施例仅用于解释而不以任何方式限制本发明。实施例中，各原始试剂材料均可商购获得，未注明具体条件的实验方法为所属领域熟知的常规方法和常规条件，或按照仪器制造商所建议的条件。
实施例1
本实施例设置对照组(Control)，单独注射甲磺酸去铁胺组(DFM)，腹腔注射甲磺酸去铁胺与灌胃阿托莫西汀联合用药组(DFM+ATX)。每组60周龄老年C57小鼠3-4只。各组的处理如下：
对照组(Control)：注射生理盐水。
单独注射甲磺酸去铁胺组(DFM)：隔天腹腔注射甲磺酸去铁胺四周，用药剂量为300 mg/kg
腹腔注射甲磺酸去铁胺与灌胃阿托莫西汀联合用药组(DFM+ATX)：先隔天腹腔注射甲磺酸去铁胺两周，用药剂量为300mg/kg。从第三周开始，隔天腹腔注射甲磺酸去铁胺的同时灌胃阿托莫西汀，甲磺酸去铁胺的用药剂量为300mg/kg，阿托莫西汀的用药剂量为10mg/kg，联合用药四周。
各组给药结束后，取样小鼠腿骨观察长骨内骨血管内皮细胞异质性，具体操作为：取小鼠腿骨经固定、脱钙、脱水、包埋、切片等处理，采用两种内皮细胞特异性标记(CD31、EMCN)进行免疫荧光染色，激光共聚焦显微镜观察长骨中CD31
+血管(绿色)、EMCN
+血管(红色)、CD31
+EMCN
+血管(H亚型血管)，黄色的血管代表CD31
+EMCN
+共定位的H亚型血管。
各组给药结束后，取样小鼠腿骨测量长骨骨密度，具体操作为：取材的骨标本经4％PFA固定，在相同条件下行MicroCT扫描。统计骨参数。
结果如图1。相比对照组，单独腹腔注射甲磺酸去铁胺用药组，长骨内H亚型骨血管内皮细胞上升，同时骨密度上升，而联合灌胃阿托莫西汀组进一步提升了H亚型骨血管内皮细胞数量，骨密度也进一步上升。本发明通过腹腔注射甲磺酸去铁胺与灌胃阿托莫西汀联合用药，改变骨血管内皮细胞异质性，同时影响骨密度。
显然，上述实施例仅仅是为清楚地说明所作的举例，而并非对实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引伸出的显而易见的变化或变动仍处于本发明创造的保护范围之中。
Claims (12)
- 阿托莫西汀在制备(1)-(3)任一项所述药物中的应用：(1)增加骨血管H亚型内皮细胞的药物；(2)增加骨密度的药物；(3)治疗骨质疏松的药物。
- 阿托莫西汀和甲磺酸去铁胺的组合物在制备(1)-(3)任一项所述药物中的应用：(1)增加骨血管H亚型内皮细胞的药物；(2)增加骨密度的药物；(3)治疗骨质疏松的药物。
- 根据权利要求1或2所述的应用，其特征在于，所述骨质疏松为老年性骨质疏松。
- 一种增加骨血管H亚型内皮细胞的药物组合物，其特征在于，所述药物组合物包含阿托莫西汀和甲磺酸去铁胺。
- 一种增加骨密度的药物组合物，其特征在于，所述药物组合物包含阿托莫西汀和甲磺酸去铁胺。
- 一种治疗骨质疏松的药物组合物，其特征在于，所述药物组合物包含阿托莫西汀和甲磺酸去铁胺。
- 根据权利要求6所述的药物组合物，其特征在于，所述骨质疏松为老年性骨质疏松。
- 根据权利要求4-7任一项所述的药物组合物，其特征在于，所述药物组合物还包含药学上可接受的载体。
- 根据权利要求4-7任一项所述的药物组合物，其特征在于，所述药物组合物的给药方式为：腹腔注射甲磺酸去铁胺，灌胃阿托莫西汀；优选地，所述药物组合物的给药方式为：先隔天腹腔注射甲磺酸去铁胺一定时间，之后隔天腹腔注射甲磺酸去铁胺的同时灌胃阿托莫西汀。
- 根据权利要求9所述的药物组合物，其特征在于，所述药物组合物的施用对象为小鼠时，每次腹腔注射甲磺酸去铁胺的用药剂量为300mg/kg，每次灌胃阿托莫西汀的用药剂量为10mg/kg。
- 一种治疗骨质疏松的方法，其特征在于，给予患者有效剂量的阿托莫西汀和甲磺酸去铁胺。
- 根据权利要求12所述的方法，其特征在于，所述骨质疏松为老年性骨质疏松。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/CN2022/134397 WO2024108560A1 (zh) | 2022-11-25 | 2022-11-25 | 阿托莫西汀在制备增加骨血管h亚型内皮细胞药物中的应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/CN2022/134397 WO2024108560A1 (zh) | 2022-11-25 | 2022-11-25 | 阿托莫西汀在制备增加骨血管h亚型内皮细胞药物中的应用 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2024108560A1 true WO2024108560A1 (zh) | 2024-05-30 |
Family
ID=91195023
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CN2022/134397 WO2024108560A1 (zh) | 2022-11-25 | 2022-11-25 | 阿托莫西汀在制备增加骨血管h亚型内皮细胞药物中的应用 |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2024108560A1 (zh) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102526005A (zh) * | 2011-12-23 | 2012-07-04 | 苏州大学 | 甲磺酸去铁胺在制备治疗绝经后骨质疏松疾病药物中的用途 |
| CN109771424A (zh) * | 2019-03-11 | 2019-05-21 | 马慧 | 一种防治老年ⅱ型糖尿病性骨质疏松症的药物组合物及其应用 |
| CN112438949A (zh) * | 2019-09-05 | 2021-03-05 | 北京兴源联合医药科技有限公司 | 一种含钙补充剂的盐酸托莫西汀口服液及其制备方法 |
| WO2022173333A2 (en) * | 2021-02-10 | 2022-08-18 | Gero Pte. Ltd. | Compounds, compositions and methods for treating age-related diseases and conditions |
-
2022
- 2022-11-25 WO PCT/CN2022/134397 patent/WO2024108560A1/zh unknown
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102526005A (zh) * | 2011-12-23 | 2012-07-04 | 苏州大学 | 甲磺酸去铁胺在制备治疗绝经后骨质疏松疾病药物中的用途 |
| CN109771424A (zh) * | 2019-03-11 | 2019-05-21 | 马慧 | 一种防治老年ⅱ型糖尿病性骨质疏松症的药物组合物及其应用 |
| CN112438949A (zh) * | 2019-09-05 | 2021-03-05 | 北京兴源联合医药科技有限公司 | 一种含钙补充剂的盐酸托莫西汀口服液及其制备方法 |
| WO2022173333A2 (en) * | 2021-02-10 | 2022-08-18 | Gero Pte. Ltd. | Compounds, compositions and methods for treating age-related diseases and conditions |
Non-Patent Citations (2)
| Title |
|---|
| BATTAGLINO R, VOKES M.; SCHULZE‐SPÄTE U.; SHARMA A.; GRAVES D.; KOHLER T.; MÜLLER R.; YOGANATHAN S.; STASHENKO P.: "Fluoxetine treatment increases trabecular bone formation in mice", JOURNAL OF CELLULAR BIOCHEMISTRY, JOHN WILEY & SONS, INC. JOHN WILEY & SONS, INC., HOBOKEN, USA, vol. 100, no. 6, 15 April 2007 (2007-04-15), Hoboken, USA, pages 1387 - 1394, XP093173170, ISSN: 0730-2312, DOI: 10.1002/jcb.21131 * |
| JIANG WENJUAN; HU KE; ZHANG TONGTONG; WANG GUOQIANG; ZHOU DEYI: "Effects of Duloxetine on Depression Symptoms and Expression of Bone Turnover Markers in Young and Middle-aged Women with Depression", JOURNAL OF CLINICAL PSYCHOSOMATIC DISEASES, vol. 26, no. 5, 30 September 2020 (2020-09-30), pages 17 - 20, 45, XP009554830, ISSN: 1672-187X * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Tyrer et al. | Outbreak of anticonvulsant intoxication in an Australian city | |
| JP5227492B2 (ja) | 癌におけるｅｄｇレセプター結合剤の使用 | |
| EP1001760B1 (en) | Composition for controlling mood disorders in healthy individuals | |
| Ross | Evolution of treatment strategies for calciphylaxis | |
| RU2484815C2 (ru) | Продолжительное 24-часовое введение в кишечник леводопа/карбидопа | |
| US20190254995A1 (en) | Pharmaceutical composition for inhibiting growth of cancer stem cells, containing aldehyde inhibitor and biguanide-based compound | |
| EA025421B1 (ru) | Лечение липодистрофии | |
| Sanders et al. | Is it feasible to use magnesium sulphate as a hypotensive agent in oral and maxillofacial surgery? | |
| US6693133B1 (en) | Methods of cardioprotection using dichloroacetate in combination with an inotrope | |
| WO2024108560A1 (zh) | 阿托莫西汀在制备增加骨血管h亚型内皮细胞药物中的应用 | |
| Imbelloni et al. | Low dose of isobaric bupivacaine provides lower incidence of spinal hypotension for hip surgery in elderly patients | |
| CN118078789A (zh) | 阿托莫西汀在制备增加骨血管h亚型内皮细胞药物中的应用 | |
| CN1151793C (zh) | 多发性骨髓瘤的骨病变治疗用医药组合物 | |
| TW200400025A (en) | Method of treating attention deficit hyperactivity disorder | |
| JP2020040892A (ja) | 肺高血圧治療薬 | |
| EP1708692B1 (en) | Dichloroacetate in combination with an inotrope for cardioprotection | |
| Ephros et al. | A Review of Sedation Agents. | |
| RU2694544C1 (ru) | Способ профилактики развития инфекционных осложнений и сепсиса у нейрохирургических больных с аневризматической болезнью сосудов головного мозга в остром периоде разрыва аневризмы. Варианты | |
| US20180015056A1 (en) | Pharmaceutical composition for inhibiting growth of cancer stem cells, containing aldehyde inhibitor and biguanide-based compound | |
| Xavier et al. | Evaluation of intranasal administration of dexmedetomidine during therapeutic extraction | |
| Nour Eldeen et al. | Magnesium Sulphate, Lidocaine or Nitroglycerin for Controlled Hypotension and Quality of the Surgical Field in Patients Undergoing Tympanoplasty | |
| JPS60155115A (ja) | 血圧上昇剤 | |
| JP5707137B2 (ja) | レバミピドの骨粗鬆症治療用途 | |
| TW202304437A (zh) | 食慾激素２受體促效劑對於手術後復原的用途 | |
| Tarrés et al. | Severe hypotension following spinal anesthesia in a patient treated with risperidone |