CN116407557A - Pharmaceutical composition for preventing and treating cerebral arterial thrombosis and application thereof - Google Patents
Pharmaceutical composition for preventing and treating cerebral arterial thrombosis and application thereof Download PDFInfo
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- CN116407557A CN116407557A CN202310614447.7A CN202310614447A CN116407557A CN 116407557 A CN116407557 A CN 116407557A CN 202310614447 A CN202310614447 A CN 202310614447A CN 116407557 A CN116407557 A CN 116407557A
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- deferiprone
- disulfiram
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 39
- 206010008092 Cerebral artery thrombosis Diseases 0.000 title claims abstract description 23
- AUZONCFQVSMFAP-UHFFFAOYSA-N disulfiram Chemical compound CCN(CC)C(=S)SSC(=S)N(CC)CC AUZONCFQVSMFAP-UHFFFAOYSA-N 0.000 claims abstract description 60
- XEYBHCRIKKKOSS-UHFFFAOYSA-N disodium;azanylidyneoxidanium;iron(2+);pentacyanide Chemical compound [Na+].[Na+].[Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].[O+]#N XEYBHCRIKKKOSS-UHFFFAOYSA-N 0.000 claims abstract description 35
- 229940083618 sodium nitroprusside Drugs 0.000 claims abstract description 35
- TZXKOCQBRNJULO-UHFFFAOYSA-N Ferriprox Chemical compound CC1=C(O)C(=O)C=CN1C TZXKOCQBRNJULO-UHFFFAOYSA-N 0.000 claims abstract description 33
- 229960003266 deferiprone Drugs 0.000 claims abstract description 33
- 239000003814 drug Substances 0.000 claims abstract description 33
- 208000016988 Hemorrhagic Stroke Diseases 0.000 claims abstract description 32
- 208000020658 intracerebral hemorrhage Diseases 0.000 claims abstract description 32
- 229960002563 disulfiram Drugs 0.000 claims abstract description 30
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 claims abstract description 30
- 229960003883 furosemide Drugs 0.000 claims abstract description 30
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 4
- 239000000463 material Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 3
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- 230000000694 effects Effects 0.000 abstract description 20
- 230000002490 cerebral effect Effects 0.000 abstract description 19
- 229940079593 drug Drugs 0.000 abstract description 19
- 206010008190 Cerebrovascular accident Diseases 0.000 abstract description 16
- 208000006011 Stroke Diseases 0.000 abstract description 16
- 230000002008 hemorrhagic effect Effects 0.000 abstract description 14
- 230000000740 bleeding effect Effects 0.000 abstract description 13
- 238000000034 method Methods 0.000 abstract description 12
- 208000028389 Nerve injury Diseases 0.000 abstract description 8
- 230000002757 inflammatory effect Effects 0.000 abstract description 8
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- 230000002265 prevention Effects 0.000 abstract description 3
- 238000010172 mouse model Methods 0.000 abstract description 2
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- 102000003777 Interleukin-1 beta Human genes 0.000 description 4
- 108090000193 Interleukin-1 beta Proteins 0.000 description 4
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- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 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 4
- 238000005259 measurement Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
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- 210000003625 skull Anatomy 0.000 description 4
- 229960003495 thiamine Drugs 0.000 description 4
- 239000011721 thiamine Substances 0.000 description 4
- FIPWRIJSWJWJAI-UHFFFAOYSA-N Butyl carbitol 6-propylpiperonyl ether Chemical compound C1=C(CCC)C(COCCOCCOCCCC)=CC2=C1OCO2 FIPWRIJSWJWJAI-UHFFFAOYSA-N 0.000 description 3
- 206010008111 Cerebral haemorrhage Diseases 0.000 description 3
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- 238000011740 C57BL/6 mouse Methods 0.000 description 2
- 102000029816 Collagenase Human genes 0.000 description 2
- 108060005980 Collagenase Proteins 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- 102100037388 Gasdermin-D Human genes 0.000 description 2
- 101001026262 Homo sapiens Gasdermin-D Proteins 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
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- 229960002424 collagenase Drugs 0.000 description 2
- 229940000425 combination drug Drugs 0.000 description 2
- 239000000306 component Substances 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229940030828 disulfiram 200 mg Drugs 0.000 description 2
- 230000001882 diuretic effect Effects 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 230000010412 perfusion Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- -1 sulfoxide amine Chemical group 0.000 description 2
- 150000003462 sulfoxides Chemical class 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
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- 210000001364 upper extremity Anatomy 0.000 description 2
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- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
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- 208000004880 Polyuria Diseases 0.000 description 1
- 208000032023 Signs and Symptoms Diseases 0.000 description 1
- 206010070863 Toxicity to various agents Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000005978 brain dysfunction Effects 0.000 description 1
- 210000001627 cerebral artery Anatomy 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 229940062234 furosemide 50 mg Drugs 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
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- 238000010253 intravenous injection Methods 0.000 description 1
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- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 230000009437 off-target effect Effects 0.000 description 1
- 239000005426 pharmaceutical component Substances 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
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- 238000006467 substitution reaction Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 210000003462 vein Anatomy 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
- A61K31/185—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
- A61K31/13—Amines
- A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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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
- A61K31/33—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
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/26—Iron; Compounds thereof
-
- 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
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- 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
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Vascular Medicine (AREA)
- Cardiology (AREA)
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Abstract
The invention discloses a pharmaceutical composition for preventing and treating hemorrhagic cerebral apoplexy and application thereof, relates to the technical field of medicines, and solves the technical problems that no special method is available for the hemorrhagic cerebral apoplexy in the prior art and the clinical prevention and treatment effects are limited. The invention relates to a pharmaceutical composition for preventing and treating cerebral arterial thrombosis, which consists of the following compounds or salts thereof: sulfoxylamine, deferiprone, furosemide, disulfiram, and sodium nitroprusside; the weight ratio of the sulfoxylamine, the deferiprone, the furosemide, the disulfiram and the sodium nitroprusside is 100-400:100-400:50-200:1-4. The pharmaceutical composition for preventing and treating hemorrhagic stroke can obviously reduce the mortality, the bleeding amount, the nerve injury and the inflammatory factor level of a mouse model of the hemorrhagic stroke, can provide a new medicine source for treating the hemorrhagic stroke, and has potential great economic and social benefits.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a pharmaceutical composition for preventing and treating cerebral arterial thrombosis and application thereof.
Background
Cerebral apoplexy is commonly known as cerebrovascular accident, is an acute cerebrovascular disease, and comprises two subtypes of ischemic and hemorrhagic.
Hemorrhagic stroke is a disease in which cerebral blood circulation is impaired due to cerebral vascular hemorrhage. Cerebral vascular hemorrhage in patients with hemorrhagic stroke is mainly induced by stenosis, occlusion or rupture of cerebral arteries, and clinically presents as symptoms and signs of disposable or permanent brain dysfunction. The hemorrhagic cerebral apoplexy seriously endangers the physical health of human beings worldwide due to the characteristics of high morbidity, disability rate and mortality rate. At present, no specific treatment method is available for the diseases with serious harm clinically, and development of novel treatment means is urgently needed.
Disclosure of Invention
The invention discloses a pharmaceutical composition for preventing and treating hemorrhagic cerebral apoplexy and application thereof, and solves the technical problems that no specific method exists for the hemorrhagic cerebral apoplexy and clinical prevention and treatment effects are limited in the prior art.
In order to solve the problems, the invention adopts the following technical scheme:
the first aspect of the invention provides a pharmaceutical composition for preventing and treating cerebral arterial thrombosis.
The invention relates to a pharmaceutical composition for preventing and treating cerebral arterial thrombosis, which consists of the following compounds or salts thereof:
sulfoxylamine, deferiprone, furosemide, disulfiram, and sodium nitroprusside;
the weight ratio of the sulfoxylamine, the deferiprone, the furosemide, the disulfiram and the sodium nitroprusside is 100-400:100-400:50-200:1-4.
Preferably, the weight ratio of the sulfoxylamine, the deferiprone, the furosemide, the disulfiram and the sodium nitroprusside is 100-200:100-200:50-100:1-2.
Preferably, the pharmaceutical composition for preventing and treating cerebral arterial thrombosis also comprises pharmaceutically acceptable auxiliary materials or auxiliary components.
Preferably, the pharmaceutical composition for preventing and treating cerebral arterial thrombosis is a preparation prepared by taking sulfoxylamine, deferiprone, furosemide, disulfiram and sodium nitroprusside or salts thereof as active ingredients and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.
The second aspect of the invention provides application of a pharmaceutical composition for preventing and treating cerebral arterial thrombosis.
The application of the pharmaceutical composition for preventing and treating the hemorrhagic stroke in preparing the medicine for preventing and treating the hemorrhagic stroke is provided in any technical scheme.
The technical scheme adopted by the invention can achieve the following beneficial effects:
the invention relates to a pharmaceutical composition for preventing and treating cerebral arterial thrombosis, which consists of the following compounds or salts thereof: the method comprises the steps of taking a sodium nitroprusside as a perforating protein GSDMD inhibitor, inhibiting DAMPs (damage associated molecular patterns, damage related molecular modes) such as IL-1 beta and the like, wherein the sodium nitroprusside can be used for remarkably reducing copper death of tissues in a hemorrhagic stroke model, the deferiprone can be used for remarkably reducing iron death of the tissues in the hemorrhagic stroke model, the furosemide has remarkable diuretic effect on the hemorrhagic stroke model, the sodium nitroprusside can be used for remarkably reducing blood pressure in the hemorrhagic stroke model, and the sodium nitroprusside can be used for remarkably reducing the death rate, the bleeding amount, the nerve damage and the inflammatory factor level of a mouse model in the hemorrhagic stroke model.
On the other hand, the invention provides the optimal ratio of the components of the medicine composition, and the medicine composition can better improve the hemorrhagic cerebral apoplexy under the ratio. Specifically, the weight ratio of the sulfoxylamine, the deferiprone, the furosemide, the disulfiram and the sodium nitroprusside is 100-400:100-400:50-200:1-4, and particularly preferred proportions are as follows: the weight ratio of the sulfoxylamine, the deferiprone, the furosemide, the disulfiram and the sodium nitroprusside is 100-200:100-200:50-100:1-2.
The application of the pharmaceutical composition can provide a new medicine source for treating hemorrhagic cerebral apoplexy, and has potential significant economic and social benefits. The preparation prepared by taking the sulfoxylamine, the deferiprone, the furosemide, the disulfiram and the sodium nitroprusside as active ingredients has application prospect as a medicament for preventing and treating the cerebral arterial thrombosis, is developed and researched according to a national innovation medicament approval method, is expected to become an innovation medicament for preventing and treating the cerebral arterial thrombosis with high efficiency and low toxicity, and has wide industrialization prospect.
The invention solves the technical problems that no specific method exists for treating hemorrhagic cerebral apoplexy and the clinical prevention and treatment effects are limited in the prior art.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention will be described in detail below. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments, based on the examples herein, which are within the scope of the invention as defined by the claims, will be within the scope of the invention as defined by the claims.
Example 1
This example illustrates the effect of the pharmaceutical composition of the present invention on a hemorrhagic stroke model.
Grouping and administration: the C57BL/6 mice were randomly divided into 9 groups of 10 each, a sham operation group, a model group, a drug intervention group 1, a drug intervention group 2, a drug intervention group 3, a drug intervention group 4, a drug intervention group 5, a drug intervention group 6, and a drug intervention group 7. Drug intervention group 1-drug intervention group 7 performs drug combination gastric lavage intervention (sulfoxylamine, deferiprone, furosemide and disulfiram) and tail intravenous injection intervention (sodium nitroprusside) once a day, and administration is started one day before molding.
Molding and collecting samples: the mice were anesthetized by intraperitoneal injection of 3.5% pentobarbital sodium and fixed on a stereotactic apparatus in prone position, which was fixed on the stereotactic apparatus, iodine was sterilized locally and the skull bore was exposed, then 0.3 μl of type VII collagenase (0.35U) was injected using a microsyringe, the needle was slowly withdrawn after 5 split charging, and the bone cement covered the skull bore and the skin was sutured. The sham group was injected with collagenase-free vehicle in the same way.
Nerve function measurement was performed 24 hours after the construction of the hemorrhagic stroke model. Its neurological function was scored using the Zea-Longa scoring criteria. The more severe the hemorrhagic stroke, the more pronounced the symptoms of impaired neurological function, and the higher the neurological score.
4, the following steps: mice have disturbance of consciousness and cannot walk autonomously.
3, the method comprises the following steps: the body of the mouse was inclined to the undamaged side when walking.
2, the method comprises the following steps: the body of the mouse turns towards the undamaged side and is shaped like a tail.
1, the method comprises the following steps: the intact lateral forelimbs of the mice were not fully extended.
Measurement of cerebral hemorrhage: after model 24 h, pentobarbital sodium is anesthetized, after PBS heart perfusion, brain tissues are immediately taken, the brain on the bleeding side of the mice is cut off, blood on the surface of the brain tissues is removed by washing with normal saline, then the brain tissues are homogenized, the supernatant is taken, the content of hemoglobin is detected by using a hemoglobin detection kit, the inflammatory factor level of the brain tissues is detected by using an IL-1 beta kit, and the death rate of each group of mice is detected within 24 hours.
The pharmaceutical intervention group 1-7 comprises the following pharmaceutical components in parts by weight:
drug intervention group 1: 200 mg/kg of sulfoxylamine-butyl-thiamine, 125 mg/kg of deferiprone, 100 mg/kg of furosemide, 50 mg/kg of disulfiram, 1 mg/kg of sodium nitroprusside;
drug intervention group 2: 100 mg/kg of sulfoxylamine-butyl-thiamine, 400 mg/kg of deferiprone, 300 mg/kg of furosemide, 200 mg/kg of disulfiram, 4 mg/kg of sodium nitroprusside;
drug intervention group 3: sulfoxylamine butoxide 400 mg/kg, deferiprone 100 mg/kg, furosemide 400 mg/kg, disulfiram 100 mg/kg, sodium nitroprusside 4 mg/kg;
drug intervention group 4: sulfoxylamine butoxide 400 mg/kg, deferiprone 400 mg/kg, furosemide 100 mg/kg, disulfiram 200 mg/kg, sodium nitroprusside 2 mg/kg;
drug intervention group 5: 50 mg/kg of sulfoxylamine-butyl-thiamine, 400 mg/kg of deferiprone, 300 mg/kg of furosemide, 200 mg/kg of disulfiram, 4 mg/kg of sodium nitroprusside;
drug intervention group 6: sulfoxylamine butoxide 400 mg/kg, deferiprone 50 mg/kg, furosemide 400 mg/kg, disulfiram 100 mg/kg, sodium nitroprusside 4 mg/kg;
drug intervention group 7: sulfoxylamine-butyl-thiamine 400 mg/kg, deferiprone 400 mg/kg, furosemide 50 mg/kg, disulfiram 200 mg/kg, sodium nitroprusside 2 mg/kg.
TABLE 1 influence of pharmaceutical combinations on mortality in hemorrhagic stroke patterns
| Grouping | Mortality (%) |
| False operation group | 0 |
| Model group | 40 |
| Pharmaceutical intervention group 1 | 0 |
| Pharmaceutical intervention group 2 | 10 |
| Pharmaceutical intervention group 3 | 10 |
| Pharmaceutical intervention group 4 | 10 |
| Pharmaceutical intervention group 5 | 20 |
| Pharmaceutical intervention group 6 | 20 |
| Pharmaceutical intervention group 7 | 20 |
Table 1 shows the effect of the pharmaceutical composition on hemorrhagic stroke pattern mortality. From the data in table 1, it can be seen that: the pharmaceutical composition used in the pharmaceutical intervention groups 1-7 can obviously reduce the death rate of the hemorrhagic cerebral apoplexy, and particularly the pharmaceutical composition used in the pharmaceutical intervention group 1 has the optimal effect. Values are expressed as mean ± SED. n= 10,p<0.05 vs Model.
TABLE 2 influence of pharmaceutical combinations on hemorrhagic stroke pattern hemorrhage
| Grouping | Brain tissue hemoglobin content (μg/mL) |
| False operation group | 232 ± 32 |
| Model group | 980 ± 81 |
| Pharmaceutical intervention group 1 | 311 ± 31 |
| Pharmaceutical intervention group 2 | 370 ± 33 |
| Pharmaceutical intervention group 3 | 378 ± 36 |
| Pharmaceutical intervention group 4 | 367 ± 39 |
| Pharmaceutical intervention group 5 | 454 ± 38 |
| Pharmaceutical intervention group 6 | 483 ± 48 |
| Pharmaceutical intervention group 7 | 421 ± 40 |
Table 2 shows the effect of the pharmaceutical composition on the amount of bleeding in the hemorrhagic stroke pattern. From the data in table 2, it can be seen that: the pharmaceutical composition used in the pharmaceutical intervention groups 1-7 can obviously reduce the bleeding amount of the bleeding cerebral apoplexy model, and particularly the pharmaceutical composition used in the pharmaceutical intervention group 1 has the optimal effect. Specifically, the bleeding volume in the model group increased 748 μg/mL and decreased 89% after treatment with the pharmaceutical intervention group 1 composition. Values are expressed as mean ± SED. n= 10,p<0.05 vs Model.
TABLE 3 influence of pharmaceutical combinations on cerebral arterial thrombosis type nerve damage
| Grouping | Neurological score (Zea-Longa score) |
| False operation group | 0 |
| Model group | 2.9 ± 0.4 |
| Pharmaceutical intervention group 1 | 0.8 ± 0.2 |
| Pharmaceutical intervention group 2 | 1.2 ± 0.2 |
| Pharmaceutical intervention group 3 | 1.3 ± 0.3 |
| Pharmaceutical intervention group 4 | 1.2 ± 0.1 |
| Pharmaceutical intervention group 5 | 1.5 ± 0.3 |
| Pharmaceutical intervention group 6 | 1.6 ± 0.4 |
| Pharmaceutical intervention group 7 | 1.6 ± 0.3 |
Table 3 shows the effect of the pharmaceutical composition on hemorrhagic stroke-type nerve damage. From the data in table 3, it can be seen that: the pharmaceutical composition used in the pharmaceutical intervention groups 1-7 can reduce nerve damage of cerebral arterial thrombosis, and especially the pharmaceutical composition used in the pharmaceutical intervention group 1 has the optimal effect. Values are expressed as mean ± SED. n= 10,p<0.05 vs Model.
TABLE 4 influence of pharmaceutical combinations on serum inflammatory factors of hemorrhagic cerebral apoplexy type
| Grouping | Serum IL-1 beta level (ng/mL) |
| False operation group | 0.21 ± 0.06 |
| Model group | 2.87 ± 0.25 |
| Pharmaceutical intervention group 1 | 0.31 ± 0.07 |
| Pharmaceutical intervention group 2 | 0.57 ± 0.06 |
| Pharmaceutical intervention group 3 | 0.62 ± 0.05 |
| Pharmaceutical intervention group 4 | 0.68 ± 0.07 |
| Pharmaceutical intervention group 5 | 1.17 ± 0.12 |
| Pharmaceutical intervention group 6 | 1.23 ± 0.10 |
| Pharmaceutical intervention group 7 | 1.15 ± 0.11 |
Table 4 shows the effect of the pharmaceutical composition on serum inflammatory factors of the hemorrhagic stroke pattern. From the data in table 4, it can be seen that: the pharmaceutical composition used in the pharmaceutical intervention groups 1-7 can reduce the inflammatory factor level of cerebral tissue in hemorrhagic cerebral apoplexy, and especially the pharmaceutical composition used in the pharmaceutical intervention group 1 has the optimal effect. Values are expressed as mean ± SED. n= 10,p<0.05 vs Model.
From the data, the combined medicines of the sulfoxylamine, the deferiprone, the furosemide, the disulfiram and the sodium nitroprusside are found to be capable of remarkably reducing the mortality, the bleeding amount, the neurological damage and the inflammatory factor secretion of a hemorrhagic stroke model, and have excellent effect of preventing and treating the hemorrhagic stroke; the above data also demonstrate that the optimum ratios of sulfoxylamine, deferiprone, furosemide, disulfiram, and sodium nitroprusside are: the weight ratio of the sulfoxylamine, the deferiprone, the furosemide, the disulfiram and the sodium nitroprusside is 100-400:100-400:50-200:1-4, and particularly preferred proportions are as follows: the weight ratio of the sulfoxylamine, the deferiprone, the furosemide, the disulfiram and the sodium nitroprusside is 100-200:100-200:50-100:1-2.
Example 2
This example describes in detail the evaluation of drug toxicity of the pharmaceutical composition of the present invention.
Grouping and administration: the C57BL/6 mice were randomly divided into 3 groups, namely a sham operation group, a model group, a drug combination group 1 (200 mg/kg of sulfoxylamine-busulfan; 125 mg/kg of deferiprone; 100 mg/kg of furosemide; 50 mg/kg of disulfiram; 1 mg/kg of sodium nitroprusside) and a drug combination group 2 (200 mg/kg of sulfoxylamine-busulfan; 125 mg/kg of deferiprone; 50 mg/kg of disulfiram), each group of 10 animals. Drug combination group 1 and drug combination group 2 were subjected to drug combination gastric lavage intervention (drug combination group 1: butafenamic acid sulfoxide amine, deferiprone, furosemide and disulfiram; drug combination group 2: butafenamic acid sulfoxide amine, deferiprone, disulfiram) and tail vein injection intervention (drug combination group 1: sodium nitroprusside; drug combination group 2: none), once a day, and drug administration was started one day before molding.
Molding and collecting samples: the mice were anesthetized by intraperitoneal injection of 3.5% pentobarbital sodium and fixed on a stereotactic apparatus in prone position, which was fixed on the stereotactic apparatus, iodine was sterilized locally and the skull bore was exposed, then 0.3 μl of type VII collagenase (0.35U) was injected using a microsyringe, the needle was slowly withdrawn after 5 split charging, and the bone cement covered the skull bore and the skin was sutured. The sham group was injected with collagenase-free vehicle in the same way.
Nerve function measurement was performed 24 hours after the construction of the hemorrhagic stroke model. Its neurological function was scored using the Zea-Longa scoring criteria. The more severe the hemorrhagic stroke, the more pronounced the symptoms of impaired neurological function, and the higher the neurological score.
4, the following steps: mice have disturbance of consciousness and cannot walk autonomously.
3, the method comprises the following steps: the body of the mouse was inclined to the undamaged side when walking.
2, the method comprises the following steps: the body of the mouse turns towards the undamaged side and is shaped like a tail.
1, the method comprises the following steps: the intact lateral forelimbs of the mice were not fully extended.
Measurement of cerebral hemorrhage: after model 24 h, pentobarbital sodium is anesthetized, after PBS heart perfusion, brain tissues are immediately taken, the brain on the bleeding side of the mice is cut off, blood on the surface of the brain tissues is removed by washing with normal saline, then the brain tissues are homogenized, the supernatant is taken, the content of hemoglobin is detected by using a hemoglobin detection kit, the inflammatory factor level of the brain tissues is detected by using an IL-1 beta kit, and the death rate of each group of mice is detected within 24 hours.
TABLE 5 influence of drug combination group 1 and drug combination group 2 on mortality of the cerebral arterial thrombosis
| Grouping | Mortality (%) |
| False operation group | 0 |
| Model group | 40 |
| Pharmaceutical combination group 1 | 0 |
| Pharmaceutical combination group 2 | 10 |
Table 5 shows the effect of drug combination group 1 and drug combination group 2 on mortality in the hemorrhagic stroke pattern. From the data in table 5, it can be seen that: the medicine combination used in the medicine combination group 1 and the medicine combination group 2 can obviously reduce the death rate of the cerebral arterial thrombosis, and especially the medicine combination used in the medicine combination group 1 has better effect. Values are expressed as mean ± SED. n= 10,p<0.05 vs Model.
TABLE 6 influence of drug combination group 1 and drug combination group 2 on the bleeding amount of the cerebral arterial thrombosis
| Grouping | Brain tissue hemoglobin content (μg/mL) |
| False operation group | 232 ± 32 |
| Model group | 980 ± 81 |
| Pharmaceutical combination group 1 | 311 ± 31 |
| Pharmaceutical combination group 2 | 458 ± 42 |
Table 6 shows the effect of drug combination group 1 and drug combination group 2 on the amount of hemorrhagic stroke pattern. From the data in table 6, it can be seen that: the pharmaceutical compositions used in the pharmaceutical combination group 1 and the pharmaceutical combination group 2 can obviously reduce the bleeding amount of a cerebral arterial thrombosis model, and especially the pharmaceutical composition used in the pharmaceutical intervention group 1 has the optimal effect. Specifically, the bleeding volume in the model group increased 748 μg/mL and decreased 89% after treatment with the pharmaceutical intervention group 1 composition. Values are expressed as mean ± SED. n= 10,p<0.05 vs Model.
TABLE 7 influence of drug combination group 1 and drug combination group 2 on hemorrhagic stroke model neural injury
| Grouping | Neurological score (Zea-Longa score) |
| False operation group | 0 |
| Model group | 2.9 ± 0.4 |
| Pharmaceutical combination group 1 | 0.8 ± 0.2 |
| Pharmaceutical combination group 2 | 1.2 ± 0.2 |
Table 7 shows the effect of the pharmaceutical composition on hemorrhagic stroke-type nerve damage. From the data in table 7, it can be seen that: the pharmaceutical compositions used in the pharmaceutical combination group 1 and the pharmaceutical combination group 2 can reduce nerve injury of cerebral arterial thrombosis, and especially the pharmaceutical composition used in the pharmaceutical intervention group 1 has the optimal effect. Values are expressed as mean ± SED. n= 10,p<0.05 vs Model.
From the above data, it was found that the combination drugs, butafenamide sulfoxide, deferiprone, furosemide, disulfiram and sodium nitroprusside, significantly reduced mortality, bleeding volume and neurological damage in the hemorrhagic stroke model compared to the combination drugs, butafenamide sulfoxide, deferiprone and disulfiram. Specifically, the disulfiram is a perforating protein GSDMD inhibitor, excessive use of hemorrhagic cerebral apoplexy has off-target effect, toxic and side effects possibly occur, the sodium nitroprusside is a vasodilator, the furosemide is a diuretic, and the sodium nitroprusside can promote copper ion-chelating sulfoxylamine and iron ion-chelating deferiprone speed to play a role in removing toxins in vitro, so that the combined use of the sodium nitroprusside and the furosemide can reduce the toxins in vivo, increase the survival rate of the hemorrhagic cerebral apoplexy and reduce cerebral hemorrhage and nerve injury.
The foregoing is merely illustrative of the present invention, and the present invention is not limited thereto, and any person skilled in the art will readily recognize that variations or substitutions are within the scope of the present invention.
Claims (5)
1. A pharmaceutical composition for preventing and treating cerebral arterial thrombosis, which is characterized by comprising a compound or salt thereof as shown in the following formula:
sulfoxylamine, deferiprone, furosemide, disulfiram, and sodium nitroprusside;
the weight ratio of the sulfoxylamine, the deferiprone, the furosemide, the disulfiram and the sodium nitroprusside is 100-400:100-400:50-200:1-4.
2. The pharmaceutical composition for preventing and treating cerebral arterial thrombosis according to claim 1, wherein the weight ratio of the sulfoxylamine-busulfan, the deferiprone, the furosemide, the disulfiram and the sodium nitroprusside is 100-200:100-200:50-100:1-2.
3. The pharmaceutical composition for preventing and treating cerebral arterial thrombosis according to claim 1 or 2, characterized in that it also consists of pharmaceutically acceptable auxiliary materials or auxiliary components.
4. The pharmaceutical composition for preventing and treating cerebral arterial thrombosis according to claim 3, which is a preparation prepared by adding pharmaceutically acceptable auxiliary materials or auxiliary components to active ingredients such as sulfoxylamine, deferiprone, furosemide, disulfiram and sodium nitroprusside or salts thereof.
5. Use of the pharmaceutical composition for preventing and treating hemorrhagic stroke according to any one of claims 1 to 4 in the preparation of a medicament for preventing and treating hemorrhagic stroke.
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