CN113244241A - Pharmaceutical composition for preventing and treating hemorrhagic stroke and application thereof - Google Patents
Pharmaceutical composition for preventing and treating hemorrhagic stroke and application thereof Download PDFInfo
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- CN113244241A CN113244241A CN202110364291.2A CN202110364291A CN113244241A CN 113244241 A CN113244241 A CN 113244241A CN 202110364291 A CN202110364291 A CN 202110364291A CN 113244241 A CN113244241 A CN 113244241A
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- Prior art keywords
- hemorrhagic stroke
- pharmaceutical composition
- medicine
- deferiprone
- nac
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- 208000016988 Hemorrhagic Stroke Diseases 0.000 title claims abstract description 41
- 208000020658 intracerebral hemorrhage Diseases 0.000 title claims abstract description 41
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 22
- 239000003814 drug Substances 0.000 claims abstract description 29
- 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 18
- 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 16
- TZXKOCQBRNJULO-UHFFFAOYSA-N Ferriprox Chemical compound CC1=C(O)C(=O)C=CN1C TZXKOCQBRNJULO-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229960003266 deferiprone Drugs 0.000 claims abstract description 16
- 229960004308 acetylcysteine Drugs 0.000 claims abstract description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 230000002757 inflammatory effect Effects 0.000 claims description 5
- 210000005036 nerve Anatomy 0.000 claims description 5
- 230000000740 bleeding effect Effects 0.000 claims description 4
- 230000006378 damage Effects 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 3
- 239000004615 ingredient Substances 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 8
- 241000699666 Mus <mouse, genus> Species 0.000 abstract description 6
- 241000699670 Mus sp. Species 0.000 abstract description 6
- 102000029816 Collagenase Human genes 0.000 abstract description 3
- 108060005980 Collagenase Proteins 0.000 abstract description 3
- 208000028389 Nerve injury Diseases 0.000 abstract description 3
- 229960002424 collagenase Drugs 0.000 abstract description 3
- 230000008764 nerve damage Effects 0.000 abstract description 3
- 230000002008 hemorrhagic effect Effects 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 abstract 1
- 102000001554 Hemoglobins Human genes 0.000 description 5
- 108010054147 Hemoglobins Proteins 0.000 description 5
- 210000005013 brain tissue Anatomy 0.000 description 5
- 210000004556 brain Anatomy 0.000 description 4
- 208000032843 Hemorrhage Diseases 0.000 description 3
- 102000003777 Interleukin-1 beta Human genes 0.000 description 3
- 108090000193 Interleukin-1 beta Proteins 0.000 description 3
- 239000000890 drug combination Substances 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 230000000926 neurological effect Effects 0.000 description 3
- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 2
- 210000003625 skull Anatomy 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- 102100035904 Caspase-1 Human genes 0.000 description 1
- 108090000426 Caspase-1 Proteins 0.000 description 1
- 206010008111 Cerebral haemorrhage Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 208000008574 Intracranial Hemorrhages Diseases 0.000 description 1
- 201000008450 Intracranial aneurysm Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 208000001106 Takayasu Arteritis Diseases 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000002639 bone cement Substances 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 210000003194 forelimb Anatomy 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 230000003188 neurobehavioral effect Effects 0.000 description 1
- 230000007658 neurological function Effects 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 229960002275 pentobarbital sodium Drugs 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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
- A61K31/33—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
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Urology & Nephrology (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Heart & Thoracic Surgery (AREA)
Abstract
The invention discloses a pharmaceutical composition for preventing and treating hemorrhagic stroke and application thereof, and relates to the technical field of biological medicines. The invention discloses application of a pharmaceutical composition in preparing a medicine for treating hemorrhagic stroke, wherein the pharmaceutical composition comprises the following components: VX-740, N-acetyl cysteine (NAC) and deferiprone, wherein the mass ratio of the medicines can be: VX-740(1-2), NAC (3-5), deferiprone (5-7). The VII collagenase is adopted to construct a hemorrhagic stroke model, and the effect of the pharmaceutical composition on hemorrhagic stroke is evaluated, so that the pharmaceutical composition provided by the invention can improve the hemorrhagic quantity and nerve injury of a hemorrhagic stroke model mouse. The medicine composition prepared by mixing the medicines can reduce the death rate of mice of hemorrhagic stroke models and improve the hemorrhagic stroke.
Description
Technical Field
The invention relates to a pharmaceutical composition for preventing and treating hemorrhagic stroke, and belongs to the technical field of medicines.
Background
Hemorrhagic stroke refers to a disease caused by rupture of cerebral vessels due to various causes, and its common causes include long-term poor control of hypertension, Takayasu arteritis, rupture of cerebral aneurysm, etc. At present, no specific medicine is available for hemorrhagic stroke, so that the development of a novel medicine for improving the hemorrhagic stroke is necessary and urgent to reduce the death rate of the stroke.
Disclosure of Invention
The invention aims to provide a pharmaceutical composition for preventing and treating hemorrhagic stroke.
The invention provides a pharmaceutical composition for preventing and treating hemorrhagic stroke, which contains VX-740 or salt thereof, NAC or salt thereof, and deferiprone or salt thereof.
Further, VX-740: NAC: the weight ratio of deferiprone is 1-4: 2-6: 4-8.
Preferably, VX-740: NAC: the weight ratio of deferiprone is 1-2: 3-5: 5-6.
Furthermore, the pharmaceutical composition is a preparation prepared by taking VX-740 or a salt thereof, NAC or a salt thereof, deferiprone or a salt thereof as active ingredients and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.
On the other hand, the invention provides the application of any one of the pharmaceutical compositions in preparing medicines for preventing and treating hemorrhagic stroke.
Further, the use satisfies at least one of the following: the medicine can reduce the death rate of hemorrhagic stroke; the medicine can reduce the hemorrhagic stroke bleeding amount; the medicine can reduce the damage of hemorrhagic stroke nerves; the medicine can reduce the level of inflammatory factors of hemorrhagic stroke.
The study of the invention finds that the combined use of Caspase-1 inhibitors VX-740, NAC and deferiprone can obviously reduce the collagenase-induced bleeding amount, nerve injury and mortality of a mouse model with hemorrhagic stroke. More importantly, the invention provides the optimal proportion of the combination of the three medicines, and the invention can better improve hemorrhagic stroke under the proportion. VX-740: NAC: the weight ratio of deferiprone is 1-4: 2-6: 4-8; preferably, VX-740: NAC: the weight ratio of deferiprone is 1-2: 3-5: 5-6.
The application of the invention can provide a new medicine source for the treatment of hemorrhagic stroke, and has potential significant economic effect and social benefit. The preparation prepared by taking VX-740, NAC and deferiprone as active ingredients has an application prospect of being used as a medicine for preventing and treating hemorrhagic stroke, is developed according to the approval method of national innovative medicines, is expected to become an innovative medicine for preventing and treating hemorrhagic stroke with high efficiency and low toxicity, and has a wide industrialization prospect.
Detailed Description
EXAMPLES Effect of drugs on the cerebral infarction model
The SD rats were randomly divided into 3 groups, i.e., sham operation group, model group, and drug intervention group, 10 per group. The weight ratio of the medicine groups to the medicine groups for medicine combination intragastric intervention (VX-740: 12 mg/kg; NAC: 24 mg/kg; deferiprone: 36mg/kg) is 3-4: 1-2: 5-6), one time in the morning and at night every day, and intervening for fourteen days.
Molding: after the last administration for 1h, 3.5% sodium pentobarbital was intraperitoneally injected to anesthetize C57BL/6 mice, and fixed on a stereotaxic apparatus in a prone position, the skin of the mice was partially sterilized with iodine, the skull of the mice was exposed to drill holes, 0.3. mu.l of type VII collagenase (0.35U) was slowly injected with a microsyringe, the needle head was slowly pulled out after the needle was retained for 5min, the skull drill holes were covered with bone cement, and the skin was sutured. Mice in sham groups were injected in the same manner but without injection. Neuro-behavioral scoring: nerve function was measured 24 hours after the brain hemorrhage model was created. 1) Its neurological function was scored using the Zea-Longa scoring criteria. The more severe the hemorrhagic stroke is, the more obvious the symptom of nerve function damage is, and the higher the score of the nerve function is. 1 minute: the uninjured side forelimb of the mouse cannot be fully extended; and 2, dividing: the body of the mouse turns to the undamaged side and becomes a tail chasing shape; and 3, dividing: when the mouse walks, the body of the mouse topples over to the undamaged side; and 4, dividing: mice develop disturbance of consciousness and cannot walk autonomously. 2) Measurement of cerebral hemorrhage amount: pentobarbital sodium is subjected to abdominal anesthesia after 24h of modeling, after PBS heart perfusion, the brain is taken immediately, the mouse bleeding side brain is cut off by scissors, the surface blood is removed by normal saline washing, then homogenate is carried out, the supernatant is taken and used for detecting the hemoglobin content in the brain by using a hemoglobin detection kit, and the level of the inflammatory factor of the brain tissue is detected by using an IL-1 beta kit. 3) The mortality of each group of mice was measured within 24 hours. The test results are shown in tables 1 to 4.
TABLE 1
Table 1 shows the effect of the pharmaceutical composition on mortality in a hemorrhagic stroke model. As can be seen from Table 1, the pharmaceutical composition can reduce hemorrhagic stroke mortality. Values are expressed as mean ± SED. n 10, p # <0.05vs Model.
TABLE 2
| Grouping | Brain hemoglobin content (μ g/mL) |
| Artificial operation group | 420±45 |
| Model set | 876±67 |
| Pharmaceutical combination set | 620±76# |
Table 2 shows the effect of the drug combination on the hemoglobin content of the model in hemorrhagic stroke. As can be seen from Table 2, the pharmaceutical composition can reduce the hemoglobin content in the brain tissue of the hemorrhagic stroke model. Values are expressed as mean ± SED. n 10, p # <0.05vs Model.
TABLE 3
| Grouping | Neurological score (Zea-Longa score) |
| Artificial operation group | 0 |
| Model set | 2.4±0.3 |
| Pharmaceutical combination set | 1.1±0.3# |
Table 3 shows the effect of drug combinations on neurological scores in a hemorrhagic stroke model. From table 3, it can be seen that the pharmaceutical composition can reduce the nerve damage of the hemorrhagic stroke model. Values are expressed as mean ± SED. n 10, p # <0.05vs Model.
TABLE 4
| Grouping | Brain tissue IL-1 beta level (ng/mL) |
| Artificial operation group | 0.12±0.06 |
| Model set | 1.89±0.21 |
| Pharmaceutical combination set | 1.22±0.14# |
Table 4 shows the effect of the drug combinations on IL-1 β levels in brain tissue. From table 4, it can be seen that the pharmaceutical composition can reduce the level of inflammatory factors in brain tissue of a hemorrhagic stroke model. Values are expressed as mean ± SED. n 10, p # <0.05vs Model.
From the data, the combined medicine VX-740, N-acetyl cysteine and deferiprone are found to be capable of remarkably treating hemorrhagic stroke model hemorrhagic output, inflammatory factors, mortality and neurological damage, and have excellent effect of preventing and treating hemorrhagic stroke.
Claims (6)
1. The pharmaceutical composition for preventing and treating hemorrhagic stroke is characterized in that: a compound containing:
VX-740, N-acetyl cysteine (NAC), deferiprone.
2. The pharmaceutical composition of claim 1, wherein: VX-740: NAC: the weight ratio of deferiprone is 1-4: 2-6: 4 to 8.
3. The pharmaceutical composition of claim 2, wherein: VX-740: NAC: the weight ratio of deferiprone is 1-2: 3-5: 5 to 6.
4. A pharmaceutical composition according to any one of claims 1 to 3, characterized in that: the preparation is prepared by taking VX-740 or salt thereof, NAC or salt thereof and deferiprone or salt thereof as active ingredients and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.
5. Use of the pharmaceutical composition of any one of claims 1-4 in the preparation of a medicament for preventing and treating hemorrhagic stroke.
6. Use according to claim 5, characterized in that: at least one of the following is satisfied:
the medicine can reduce the death rate of hemorrhagic stroke;
the medicine can reduce the hemorrhagic stroke bleeding amount;
the medicine can reduce the damage of hemorrhagic stroke nerves;
the medicine can reduce the level of inflammatory factors of hemorrhagic stroke.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110364291.2A CN113244241B (en) | 2021-04-04 | 2021-04-04 | Pharmaceutical composition for preventing and treating hemorrhagic stroke and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110364291.2A CN113244241B (en) | 2021-04-04 | 2021-04-04 | Pharmaceutical composition for preventing and treating hemorrhagic stroke and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113244241A true CN113244241A (en) | 2021-08-13 |
| CN113244241B CN113244241B (en) | 2022-12-09 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110364291.2A Active CN113244241B (en) | 2021-04-04 | 2021-04-04 | Pharmaceutical composition for preventing and treating hemorrhagic stroke and application thereof |
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| Country | Link |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022213230A1 (en) * | 2021-04-05 | 2022-10-13 | 四川大学华西医院 | Drug combination and use thereof in preparation of drug for preventing and treating cerebral ischemic stroke |
| CN116392486A (en) * | 2023-05-29 | 2023-07-07 | 四川大学华西医院 | Pharmaceutical composition for preventing and treating ischemic cerebral apoplexy and application thereof |
| CN116407557A (en) * | 2023-05-29 | 2023-07-11 | 四川大学华西医院 | Pharmaceutical composition for preventing and treating cerebral arterial thrombosis and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107569502A (en) * | 2017-09-11 | 2018-01-12 | 中国药科大学 | A kind of medicine for preventing and treating cerebral apoplexy |
-
2021
- 2021-04-04 CN CN202110364291.2A patent/CN113244241B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107569502A (en) * | 2017-09-11 | 2018-01-12 | 中国药科大学 | A kind of medicine for preventing and treating cerebral apoplexy |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022213230A1 (en) * | 2021-04-05 | 2022-10-13 | 四川大学华西医院 | Drug combination and use thereof in preparation of drug for preventing and treating cerebral ischemic stroke |
| CN116392486A (en) * | 2023-05-29 | 2023-07-07 | 四川大学华西医院 | Pharmaceutical composition for preventing and treating ischemic cerebral apoplexy and application thereof |
| CN116407557A (en) * | 2023-05-29 | 2023-07-11 | 四川大学华西医院 | Pharmaceutical composition for preventing and treating cerebral arterial thrombosis and application thereof |
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| Publication number | Publication date |
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| CN113244241B (en) | 2022-12-09 |
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