WO2022213230A1 - 一种药物组合及其在制备防治缺血性脑卒中药物中的应用 - Google Patents
一种药物组合及其在制备防治缺血性脑卒中药物中的应用 Download PDFInfo
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- 239000003814 drug Substances 0.000 title claims abstract description 20
- 208000032382 Ischaemic stroke Diseases 0.000 title claims abstract description 18
- 229940079593 drug Drugs 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 239000000890 drug combination Substances 0.000 title abstract description 17
- 230000002490 cerebral effect Effects 0.000 title abstract description 4
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 claims abstract description 15
- CXAGHAZMQSCAKJ-WAHHBDPQSA-N (4s,7s)-n-[(2r,3s)-2-ethoxy-5-oxooxolan-3-yl]-7-(isoquinoline-1-carbonylamino)-6,10-dioxo-2,3,4,7,8,9-hexahydro-1h-pyridazino[1,2-a]diazepine-4-carboxamide Chemical compound CCO[C@@H]1OC(=O)C[C@@H]1NC(=O)[C@H]1N(C(=O)[C@H](CCC2=O)NC(=O)C=3C4=CC=CC=C4C=CN=3)N2CCC1 CXAGHAZMQSCAKJ-WAHHBDPQSA-N 0.000 claims abstract description 13
- TZXKOCQBRNJULO-UHFFFAOYSA-N Ferriprox Chemical compound CC1=C(O)C(=O)C=CN1C TZXKOCQBRNJULO-UHFFFAOYSA-N 0.000 claims abstract description 13
- 208000006011 Stroke Diseases 0.000 claims abstract description 13
- 229960003266 deferiprone Drugs 0.000 claims abstract description 13
- 229960004308 acetylcysteine Drugs 0.000 claims abstract description 9
- 206010061216 Infarction Diseases 0.000 claims abstract description 7
- 230000007574 infarction Effects 0.000 claims abstract description 7
- 208000028389 Nerve injury Diseases 0.000 claims abstract description 4
- 230000008764 nerve damage Effects 0.000 claims abstract description 4
- 150000003839 salts Chemical class 0.000 claims description 10
- 230000002757 inflammatory effect Effects 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 3
- 239000004615 ingredient Substances 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims 1
- 210000002200 mouth mucosa Anatomy 0.000 claims 1
- 210000002850 nasal mucosa Anatomy 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 241000699666 Mus <mouse, genus> Species 0.000 abstract description 7
- 238000000034 method Methods 0.000 abstract description 3
- 206010008089 Cerebral artery occlusion Diseases 0.000 abstract 1
- 201000007309 middle cerebral artery infarction Diseases 0.000 abstract 1
- 238000010172 mouse model Methods 0.000 abstract 1
- 210000000269 carotid artery external Anatomy 0.000 description 7
- 230000000694 effects Effects 0.000 description 5
- 239000004677 Nylon Substances 0.000 description 4
- 210000004556 brain Anatomy 0.000 description 4
- 230000000926 neurological effect Effects 0.000 description 4
- 229920001778 nylon Polymers 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000005013 brain tissue Anatomy 0.000 description 3
- 210000004004 carotid artery internal Anatomy 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 238000011740 C57BL/6 mouse Methods 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 210000001367 artery Anatomy 0.000 description 2
- 206010008118 cerebral infarction Diseases 0.000 description 2
- 230000007658 neurological function Effects 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- CPKVUHPKYQGHMW-UHFFFAOYSA-N 1-ethenylpyrrolidin-2-one;molecular iodine Chemical compound II.C=CN1CCCC1=O CPKVUHPKYQGHMW-UHFFFAOYSA-N 0.000 description 1
- 208000035657 Abasia Diseases 0.000 description 1
- 206010008088 Cerebral artery embolism Diseases 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010028851 Necrosis Diseases 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 208000031481 Pathologic Constriction Diseases 0.000 description 1
- 229920000153 Povidone-iodine Polymers 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002146 bilateral effect Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 210000001168 carotid artery common Anatomy 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 229940000425 combination drug Drugs 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000002224 dissection Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 210000003194 forelimb Anatomy 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 229940042040 innovative drug Drugs 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 210000004237 neck muscle Anatomy 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 1
- 229960001621 povidone-iodine Drugs 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 230000036262 stenosis Effects 0.000 description 1
- 208000037804 stenosis Diseases 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 210000001186 vagus nerve Anatomy 0.000 description 1
- 210000002385 vertebral artery Anatomy 0.000 description 1
Classifications
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- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- the invention relates to a pharmaceutical composition for preventing and treating ischemic stroke, and belongs to the technical field of medicine.
- Ischemic stroke refers to the stenosis or occlusion of the arteries supplying blood to the brain, including the carotid and vertebral arteries, resulting in necrosis of brain tissue due to insufficient blood supply to the brain.
- ischemic stroke there is no specific drug for ischemic stroke, so it is necessary and urgent to develop new drugs to improve ischemic stroke and reduce the mortality of stroke.
- the object of the present invention is to provide a pharmaceutical composition for preventing and treating ischemic stroke.
- the present invention provides a pharmaceutical composition for preventing and treating ischemic stroke, which contains VX-740 or its salt, NAC or its salt, deferiprone or its salt.
- weight ratio of VX-740:NAC:deferiprone is 2-5:1-2:5-7.
- the weight ratio of VX-740:NAC:deferiprone is 3-4:1-2:5-6.
- described pharmaceutical composition takes VX-740 or its salt, NAC or its salt, deferiprone or its salt as active ingredient, adds pharmaceutically acceptable adjuvant or auxiliary ingredient, and prepares the preparation. .
- preparations are oral preparations, nasal mucosal preparations, oral mucosal preparations or injection preparations.
- Another aspect of the present invention provides the use of any of the above-mentioned drug combinations in preparing a drug for preventing and treating ischemic stroke.
- the use satisfies at least one of the following: the drug reduces stroke mortality; the drug reduces stroke infarct size; the drug reduces stroke nerve damage; the drug reduces the level of inflammatory factors.
- the application of the invention can provide a new drug source for the treatment of ischemic cerebral apoplexy, and has potentially significant economic and social benefits.
- the preparation prepared with VX-740, NAC and deferiprone as active ingredients has application prospects as a drug for the prevention and treatment of ischemic stroke.
- innovative drugs for stroke have broad prospects for industrialization.
- C57BL/6 mice were randomly divided into 3 groups, sham operation group, model group and drug intervention group, with 10 mice in each group.
- the drug group was given drug combination gavage intervention (VX-740: 12mg/kg; NAC: 8mg/kg; deferiprone: 24mg/kg) with a weight ratio of 3-4: 1-2: 5-6) every morning and evening. Each time, the intervention lasted for 14 days.
- mice 1h after the last administration, C57BL/6 mice were anesthetized by intraperitoneal injection of 3.5% sodium pentobarbital, and the mouse middle cerebral artery embolism model (ischemic stroke model) was established by suture method.
- the animals were fixed in a supine position. On the operating table, the neck hair was shaved, and the povidone-iodine was sterilized. Blunt dissection of the neck muscles revealed bilateral common carotid arteries and left external carotid arteries. Separate, ligate, and cut off the left external carotid artery branch, and ligate and cut the left external carotid artery with 5-0 nylon thread at the distal end of the carotid bifurcation.
- the left internal carotid artery was isolated, the vagus nerve was gently dissected, and the outer branch pterygopalatine artery was ligated.
- Serum IL-1 ⁇ level (ng/mL)
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- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种药物组合及其在制备防治缺血性脑卒中药物中的应用，涉及生物医药技术领域。本发明的药物组合在制备防治缺血性脑卒中药物中的应用，其中药物组合包括：VX-740、N-乙酰基半胱氨酸(NAC)、去铁酮，其中药物的质量比可为：VX-740(2-5)、NAC(1-2)、去铁酮(5-7)。在线栓法诱导的小鼠大脑中动脉栓塞模型中，本发明涉及的药物组合可改善脑卒中模型小鼠的梗塞面积、神经损伤。将本发明涉及的药物混合后制成药物组合，可减低脑卒中模型小鼠的死亡率，改善脑卒中。
Description
本发明涉及防治缺血性脑卒中的药物组合物，属于医药技术领域。
缺血性脑卒中是指由于大脑的供血动脉，包括颈动脉和椎动脉出现狭窄或闭塞，因为脑供血不足导致脑组织坏死。目前，针对缺血性脑卒中尚无特效药物，因此开发改善缺血性脑卒中的新型药物，减低脑卒中的死亡率十分必要与迫切。
发明内容
本发明的目的在于提供防治缺血性脑卒中的药物组合物。
本发明提供了防治缺血性脑卒中的药物组合物，其含有VX-740或其盐、NAC或其盐、去铁酮或其盐。
进一步地，VX-740：NAC：去铁酮重量配比为2～5：1～2：5～7。
优选地，VX-740：NAC：去铁酮重量配比为3～4：1～2：5～6。
进一步地，所述的药物组合物是以VX-740或其盐、NAC或其盐、去铁酮或其盐为活性成分，加入药学上可接受的辅料或者辅助性成分，制备而成的制剂。
进一步地，所述的制剂为口服制剂、鼻腔黏膜给药制剂、口腔黏膜给药制剂或注射制剂。
本发明的另一方面提供了上述任一药物组合在制备防治缺血性脑卒中药物中的用途。
进一步地，所述的用途满足以下至少一项：所述的药物降低卒中死亡率；所述的药物减轻卒中梗塞面积；所述的药物降低卒中神经损伤；所述的药物减低炎性因子水平。
本发明的应用能够为缺血性脑卒中的治疗提供新的药物来源，具有潜在的重大经济效应和社会效益。以VX-740、NAC、去铁酮为活性成分制备而成的制剂，具有作为缺血性脑卒中防治药物的应用前景，按照国家创新药物审批办法开发研制，有望成为高效低毒防治缺血性脑卒中的创新药物，产业化前景广阔。
实施例药物对脑梗模型的影响
随机将C57BL/6小鼠分成3组，分别是假手术组、模型组、药物干预组，每组10只。药物组进行药物组合灌胃干预(VX-740：12mg/kg；NAC：8mg/kg；去铁酮：24mg/kg)重量配比为3～4：1～2：5～6)，每天早晚各一次，干预十四天。
造模：末次给药1h后，腹腔注射3.5％戊巴比妥钠麻醉C57BL/6小鼠，线栓法构小鼠大脑中动脉栓塞模型(缺血型脑卒中模型)，首先仰卧式固定动物于手术台上，剃除颈部毛，碘伏消毒。钝性分离颈部肌肉，呈现出双侧颈总动脉和左侧颈外动脉。分离、结扎并离断左侧颈外动脉分支，并在颈动脉分叉远端用5-0尼龙线将左侧颈外动脉结扎并剪断，留取远端线头下拉，使其与颈内动脉接近一直线。分离左侧颈内动脉，轻轻剥离迷走神经，并结扎外分支翼腭动脉。用尼龙线在左侧颈外动脉起始处打一松结，在左侧颈外动脉上距颈动脉分叉约三毫米处剪一小口，从此小口将拴线***左侧颈外动脉管腔，并进入颈内动脉，将左侧颈外动脉起始处的尼龙线扎紧以防拴线移动及出血。移走颈内动脉上的微动脉夹，继续***拴线至黑色标记点，缝合皮肤，并于30min后抽出尼龙线，单笼饲养。检测：手术24h后。1)采用Zea-Longa评分标准对其神经功能进行评分。缺血性脑卒中愈严重，其神经功能损伤症状愈明显，神经功能评分愈高。1分：小鼠未损伤侧前肢不能完全伸展；2分：小鼠身体向未损伤侧转圈，并成追尾状；3分：小鼠行走时身体向未损伤侧倾倒；4分：小鼠出现意识障碍，不能自主行走。2)眼球取血，检测血液炎性因子。3)脑组织病理形态评价。对小鼠进行断头取脑，并在其囟门及囟门后2mm处冠状切开大脑，取部分脑组织，用4％多聚甲醛固定，梗塞体积通过2,3,5-氯化三苯四唑(TTC)染色来评估。试验结果如下表1～表3所示。
表1
| 分组 | 梗塞面积 |
| 假手术组 | 0％ |
| 模型组 | 36％ |
| 药物组合组 | 21％ |
表1示出了药物组合对脑梗面积的影响。从表1可知，本实施了的药物组合可以减少梗塞面积(A)。数值以均值±SED表示。n＝10,p#<0.05vs Model。
表2
| 分组 | 血清IL-1β水平(ng/mL) |
| 假手术组 | 0.15±0.04 |
| 模型组 | 1.65±0.19 |
| 药物组合组 | 1.12±0.13 # |
表2示出了药物组合对血清IL-1β水平的影响。从表2可知，药物组合可以减少缺血型脑卒中模型血清炎性因子水平。数值以均值±SED表示。n＝10,p#<0.05vs Model。
表3
| 分组 | 神经学评分(Zea-Longa评分) |
| 假手术组 | 0 |
| 模型组 | 3.1±0.3 |
| 药物组合组 | 1.8±0.6 # |
表3示出了药物组合对缺血型脑卒中模型神经学评分的影响。从表3可知，药物组合可以减少缺血型脑卒中模型神经损伤。数值以均值±SED表示。n＝10,p#<0.05vs Model。
从以上数据，我们发现组合药物VX-740、N-乙酰基半胱氨酸、去铁酮可显著缺血型脑卒中模型的梗塞面积、炎性因子和神经学评分，具有优良的抗缺血性脑卒中效果。
Claims (7)
- 一种药物组合，其特征是：含有如下所示的化合物或其盐：VX-740、N-乙酰基半胱氨酸(NAC)、去铁酮。
- 如权利要求1所述的药物组合，其特征是：VX-740：NAC：去铁酮重量配比为2～5：1～2：5～7。
- 如权利要求2所述的药物组合，其特征是：VX-740：NAC：去铁酮重量配比为3～4：1～2：5～6。
- 如权利要求1～3中任一项所述的药物组合，其特征是：它是以VX-740或其盐、NAC或其盐、去铁酮或其盐为活性成分，加入药学上可接受的辅料或者辅助性成分，制备而成的制剂。
- 如权利要求4所述的药物组合，其特征是：所述的制剂为口服制剂、鼻腔黏膜给药制剂、口腔黏膜给药制剂或注射制剂。
- 权利要求1～5任意一项所述药物组合在制备防治缺血性脑卒中药物中的用途。
- 如权利要求6所述的用途，其特征是：满足以下至少一项：所述的药物降低卒中死亡率；所述的药物减轻卒中梗塞面积；所述的药物降低卒中神经损伤；所述的药物减低炎性因子水平。
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017059427A1 (en) * | 2015-10-02 | 2017-04-06 | Children's National Medical Center | Methods for monitoring and determining the prognosis of strokes, peripheral vascular disease, shock, and sickle cell disease and its complications |
| CN110392568A (zh) * | 2017-01-19 | 2019-10-29 | 耳科制药公司 | N-乙酰半胱氨酸的制剂及其用途 |
| CN113244241A (zh) * | 2021-04-04 | 2021-08-13 | 四川大学华西医院 | 一种防治出血性脑卒中的药物组合物及其应用 |
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2021
- 2021-04-05 WO PCT/CN2021/085504 patent/WO2022213230A1/zh active Application Filing
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| WO2017059427A1 (en) * | 2015-10-02 | 2017-04-06 | Children's National Medical Center | Methods for monitoring and determining the prognosis of strokes, peripheral vascular disease, shock, and sickle cell disease and its complications |
| CN110392568A (zh) * | 2017-01-19 | 2019-10-29 | 耳科制药公司 | N-乙酰半胱氨酸的制剂及其用途 |
| CN113244241A (zh) * | 2021-04-04 | 2021-08-13 | 四川大学华西医院 | 一种防治出血性脑卒中的药物组合物及其应用 |
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| ROSS, J. BROUGH, D. GIBSON, R.M. LODDICK, S.A. ROTHWELL, N.J.: "A selective, non-peptide caspase-1 inhibitor, VRT-018858, markedly reduces brain damage induced by transient ischemia in the rat", NEUROPHARMACOLOGY, vol. 53, no. 5, 6 October 2007 (2007-10-06), AMSTERDAM, NL, pages 638 - 642, XP022288518, ISSN: 0028-3908, DOI: 10.1016/j.neuropharm.2007.07.015 * |
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