CN116392486A - Pharmaceutical composition for preventing and treating ischemic cerebral apoplexy and application thereof - Google Patents

Pharmaceutical composition for preventing and treating ischemic cerebral apoplexy and application thereof Download PDF

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CN116392486A
CN116392486A CN202310614537.6A CN202310614537A CN116392486A CN 116392486 A CN116392486 A CN 116392486A CN 202310614537 A CN202310614537 A CN 202310614537A CN 116392486 A CN116392486 A CN 116392486A
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cerebral apoplexy
pharmaceutical composition
preventing
ischemic cerebral
pharmaceutical
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何亚荣
曹钰
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West China Hospital of Sichuan University
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West China Hospital of Sichuan University
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34Heterocyclic 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
    • A61K31/341Heterocyclic 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • A61K31/195Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197Carboxylic 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
    • A61K31/198Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs 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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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
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  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Urology & Nephrology (AREA)
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  • Heart & Thoracic Surgery (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)

Abstract

The invention discloses a pharmaceutical composition for preventing and treating ischemic 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 ischemic cerebral apoplexy and clinical prevention and treatment effects are limited in the prior art. The invention relates to a pharmaceutical composition for preventing and treating ischemic cerebral apoplexy, which consists of the following compounds or salts thereof: sulfoxylamine, deferiprone and MCC950; the weight ratio of the sulfoxylamine, the deferiprone and the MCC950 is 10-40:10-40:1-4. The pharmaceutical composition for preventing and treating ischemic cerebral apoplexy can obviously reduce the death rate, infarct area, nerve injury and inflammatory factor level of a mouse model of the ischemic cerebral apoplexy, can provide a new medicine source for treating the ischemic cerebral apoplexy, and has potential significant economic and social benefits.

Description

Pharmaceutical composition for preventing and treating ischemic cerebral apoplexy and application thereof
Technical Field
The invention relates to the technical field of medicines, in particular to a pharmaceutical composition for preventing and treating ischemic cerebral apoplexy and application thereof.
Background
Ischemic cerebral apoplexy is a sudden onset brain blood circulation disorder refractory disease, has the characteristics of high morbidity, disability rate and mortality rate, and seriously endangers the health of human beings. At present, no specific method is available for clinically treating the serious disease, and the clinical prevention and treatment effects are limited, so that serious challenges are faced. Development of a novel medicine for improving ischemic cerebral apoplexy and reduction of the death rate of cerebral apoplexy are very necessary and urgent.
Disclosure of Invention
The invention discloses a pharmaceutical composition for preventing and treating ischemic cerebral apoplexy and application thereof, and solves the technical problems that no specific method exists for the ischemic 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 ischemic cerebral apoplexy.
The invention relates to a pharmaceutical composition for preventing and treating ischemic cerebral apoplexy, which consists of the following compounds or salts thereof:
sulfoxylamine, deferiprone and MCC950;
the weight ratio of the sulfoxylamine, the deferiprone and the MCC950 is 10-40:10-40:1-4.
MCC950 is NLRP3 inhibitor with the molecular formula: c (C) 20 H 24 N 2 O 5 S, english name is: n- (1, 2,3,5,6, 7-Hexahydro-s-indacen-4-ylcarbamoyl) -4- (2-hydroxy-2-process) -2-furansulfonamide.
Preferably, the weight ratio of the sulfoxylamine-butyl-thiamine to the deferiprone to the MCC950 is 10-20:10-20:1-2.
Preferably, the pharmaceutical composition for preventing and treating ischemic cerebral apoplexy also comprises pharmaceutically acceptable auxiliary materials or auxiliary components.
Preferably, the pharmaceutical composition for preventing and treating ischemic cerebral apoplexy is a preparation prepared by adding pharmaceutically acceptable auxiliary materials or auxiliary components into active ingredients of sulfoxylamine or salts thereof, deferiprone or salts thereof and MCC950 or salts thereof.
The second aspect of the invention provides application of a pharmaceutical composition for preventing and treating ischemic cerebral apoplexy.
The invention relates to an application of a pharmaceutical composition for preventing and treating ischemic cerebral apoplexy in preparing a medicine for preventing and treating ischemic cerebral apoplexy.
The technical scheme adopted by the invention can achieve the following beneficial effects:
the invention relates to a pharmaceutical composition for preventing and treating ischemic cerebral apoplexy, which consists of the following compounds or salts thereof: the composition comprises the following components of the butafenamide sulfoxide amine, deferiprone and MCC950, wherein the butafenamide sulfoxide amine can obviously reduce copper death of tissues in an ischemic cerebral apoplexy model, deferiprone can obviously reduce iron death of the tissues in the ischemic cerebral apoplexy model, the NLRP3 inhibitor MCC950 can obviously reduce cell apoptosis of the tissues in the ischemic cerebral apoplexy model, and the combination of the butafenamide sulfoxide amine, deferiprone and MCC950 can obviously reduce the death rate, the infarct area, the nerve injury and the inflammatory factor level of a mouse model in the ischemic cerebral apoplexy; the antiplatelet drugs commonly used in the prior art, such as methotrexate, rifampicin, clopidogrel and the like, are easy to cause thrombocytopenia, and most patients have drug resistance to the currently used drugs, compared with the existing antiplatelet drugs, the NLRP3 inhibitor MCC950 used in the invention can reduce the risk of thrombocytopenia and solve the problem of drug resistance of the current users to the existing antiplatelet drugs.
On the other hand, the invention provides the optimal ratio of the components of the pharmaceutical composition, and the invention can better improve ischemic cerebral apoplexy under the ratio. Specifically, the optimal ratio of the butamine sulfoxide amine, the deferiprone and the MCC950 is that the weight ratio of the butamine sulfoxide amine to the deferiprone to the MCC950 is 10-40:10-40:1-4, and particularly preferred ratio is: the weight ratio of the sulfoxylamine, the deferiprone and the MCC950 is 10-20:10-20:1-2.
The application of the pharmaceutical composition can provide a new medicine source for treating cerebral arterial thrombosis, and has potential significant economic and social benefits. The preparation prepared by taking the sulfoxylamine-butyl-thiamine, deferiprone and MCC950 as active ingredients has application prospect as an ischemic cerebral apoplexy prevention and treatment drug, is developed according to a national innovation drug approval method, is hopeful to become an innovation drug for high-efficiency low-toxicity ischemic cerebral apoplexy prevention and treatment, and has wide industrialization prospect.
Namely, the pharmaceutical composition for preventing and treating ischemic cerebral apoplexy and the application thereof solve the technical problems that no specific method exists for preventing and treating ischemic 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
The influence of the pharmaceutical composition of the present invention on the ischemic stroke model will be described in detail in this example.
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. And performing drug combination gastric lavage intervention on the drug intervention group 1-the drug intervention group 7, wherein the drug intervention is performed once a day in the morning and evening for 21 days.
Molding and collecting samples: after the last administration for 1h, C57BL/6 mice were anesthetized with sodium pentobarbital and fixed on a stereotactic apparatus in prone position, local sterilization with iodine was performed using an ophthalmic surgical scissors, incisions were made along the right side of the median line of the mouse neck, the right common carotid artery and external carotid artery of the mice were blunt-separated, then the near common carotid artery and external carotid artery of the mice were ligated, the carotid artery was rapidly inserted into a model-dedicated plug by a special hook, the plug was taken out after 1 hour, after one day of modeling was completed, bederson injury and mNSS injury scores were performed, the brains of the mice were taken out after sodium pentobarbital anesthesia, 2,3, 5-triphenyltetrazolium chloride (TTC) staining was performed, brain infarction areas were quantified with Image J software, relevant sample detection factors, platelet data and aggregation were detected, and the values are shown in tables 1 to 6, and the test results are shown as mean value.+ -. SED. n=10 and,P<0.05 was statistically different.
The pharmaceutical intervention group 1-7 comprises the following pharmaceutical components in parts by weight:
drug intervention group 1: 200 mg/kg of sulfoxylamine-b-butyl-thiamine; deferiprone 125 mg/kg; MCC950 sodium salt 10 mg/kg;
drug intervention group 2: 100 mg/kg of sulfoxylamine-b-butyl-thiamine; deferiprone 400/mg/kg; MCC950 sodium salt 40 mg/kg;
drug intervention group 3: 400 mg/kg of sulfoxylamine-b-butyl-thiamine; deferiprone 100 mg/kg; MCC950 sodium salt 10 mg/kg;
drug intervention group 4: 100 mg/kg of sulfoxylamine-b-butyl-thiamine; deferiprone 400/mg/kg; MCC950 sodium salt 10 mg/kg;
drug intervention group 5: 500 mg/kg of sulfoxylamine-b-butyl-thiamine; deferiprone 100 mg/kg; MCC950 sodium salt 50 mg/kg;
drug intervention group 6: 500 mg/kg of sulfoxylamine-b-butyl-thiamine; deferiprone 100 mg/kg; MCC950 sodium salt 10 mg/kg.
Drug intervention group 7: 100 mg/kg of sulfoxylamine-b-butyl-thiamine; deferiprone 500 mg/kg; MCC950 sodium salt 50 mg/kg.
TABLE 1 influence of pharmaceutical combinations on mortality in ischemic stroke modes
Grouping Mortality (%)
False operation group 0
Model group 30
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 ischemic 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 reduce the death rate of ischemic 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.
TABLE 2 influence of pharmaceutical combinations on ischemic stroke model infarct size
Grouping Infarct size (%)
False operation group 0
ModelGroup of 39 ± 5
Pharmaceutical intervention group 1 7 ± 3
Pharmaceutical intervention group 2 13 ± 2
Pharmaceutical intervention group 3 12 ± 4
Pharmaceutical intervention group 4 11 ± 3
Pharmaceutical intervention group 5 22 ± 5
Pharmaceutical intervention group 6 23 ± 4
Pharmaceutical intervention group 7 20 ± 4
Table 2 shows the effect of the pharmaceutical composition on the infarct size in ischemic stroke. From the data in table 2, it can be seen that: the pharmaceutical composition used in the pharmaceutical intervention groups 1-7 can reduce the infarct size of ischemic 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.
TABLE 3 influence of pharmaceutical combinations on ischemic stroke-type nerve injury
Grouping Neurological score (Bederson score) Neurological score (mNSS score)
False operation group 0 18
Model group 2.4 ± 0.3 6.1 ± 1.2
Pharmaceutical intervention group 1 0.8 ± 0.3 15.9 ± 0.2
Pharmaceutical intervention group 2 1.3± 0.2 13.2± 0.4
Pharmaceutical intervention group 3 1.2± 0.2 12.1± 0.5
Pharmaceutical intervention group 4 1.3± 0.3 13.5± 0.3
Pharmaceutical intervention group 5 1.4± 0.2 10.2± 0.2
Pharmaceutical intervention group 6 1.5± 0.3 10.5± 0.2
Pharmaceutical intervention group 7 1.6± 0.3 9.5± 0.3
Table 3 shows the effect of the pharmaceutical composition on ischemic stroke type nerve injury. 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 ischemic 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.
TABLE 4 influence of pharmaceutical combinations on serum inflammatory factors of the cerebral arterial thrombosis type
Grouping Serum IL-1 beta level (ng/mL)
False operation group 0.24 ± 0.1
Model group 2.61 ± 0.2
Pharmaceutical intervention group 1 0.29 ± 0.1
Pharmaceutical intervention group 2 0.45± 0.2
Pharmaceutical intervention group 3 0.51± 0.1
Pharmaceutical intervention group 4 0.43± 0.1
Pharmaceutical intervention group 5 0.99± 0.1
Pharmaceutical intervention group 6 1.1± 0.3
Pharmaceutical intervention group 7 1.2± 0.2
Table 4 shows the effect of the pharmaceutical composition on serum inflammatory factors of the ischemic stroke type. 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 of ischemic 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.
TABLE 5 influence of pharmaceutical combinations on platelet count in ischemic stroke modes
Grouping Platelet count (10) 3 /mL)
False operation group 1150 ± 120
Model group 1157 ± 125
Pharmaceutical intervention group 1 1160 ±125
Pharmaceutical intervention group 2 1158 ± 120
Pharmaceutical intervention group 3 1153 ± 119
Pharmaceutical intervention group 4 1169 ± 124
Pharmaceutical intervention group 5 1173 ± 145
Pharmaceutical intervention group 6 1165 ± 135
Pharmaceutical intervention group 7 1176 ± 145
Table 5 shows the effect of the pharmaceutical composition on the number of plasma platelets in the ischemic stroke mode. From the data in table 5, it can be seen that: the pharmaceutical compositions used in the pharmaceutical intervention groups 1-7 have no obvious influence on the number of the platelets, which indicates that the pharmaceutical composition is not easy to cause thrombocytopenia.
TABLE 6 influence of pharmaceutical combinations on platelet aggregation induced by ischemic stroke model thrombin
Grouping Platelet aggregation (%)
False operation group 30 ± 6
Model group 75 ± 12
Pharmaceutical intervention group 1 32 ± 7
Pharmaceutical intervention group 2 38 ± 7
Pharmaceutical intervention group 3 43 ± 5
Pharmaceutical intervention group 4 45 ±4
Pharmaceutical intervention group 5 53 ± 7
Pharmaceutical intervention group 6 55 ± 6
Pharmaceutical intervention group 7 52 ± 7
Table 6 shows the effect of the pharmaceutical composition on the degree of platelet aggregation in the ischemic stroke mode. From the data in table 6, it can be seen that: the pharmaceutical composition used in the pharmaceutical intervention groups 1-7 can reduce the platelet aggregation degree induced by ischemic cerebral apoplexy type thrombin (0.01U/mL, 5 min), 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, namely the sulfoxylamine, the deferiprone and the MCC950, can obviously reduce the death rate, the infarct area, the neurological damage and the inflammatory factor secretion of an ischemic cerebral apoplexy model, reduce the high reactivity of platelets, do not influence the number of platelets, reduce the platelet aggregation degree induced by thrombin and have excellent effect of preventing and treating the ischemic cerebral apoplexy; the above data also demonstrate that the optimum ratios of sulfoxylamine, deferiprone and MCC950 are: the weight ratio is 10-40:10-40:1-4, and particularly preferred ratios are: the weight ratio of the sulfoxylamine, the deferiprone and the MCC950 is 10-20:10-20:1-2.
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 ischemic cerebral apoplexy, which is characterized by comprising the following compounds or salts thereof:
sulfoxylamine, deferiprone and MCC950;
the weight ratio of the sulfoxylamine, the deferiprone and the MCC950 is 10-40:10-40:1-4.
2. The pharmaceutical composition for preventing and treating ischemic stroke according to claim 1, wherein the weight ratio of the sulfoxylamine-busulfan to the deferiprone to the MCC950 is 10-20:10-20:1-2.
3. The pharmaceutical composition for preventing and treating ischemic stroke according to claim 1 or 2, further comprising pharmaceutically acceptable auxiliary materials or auxiliary components.
4. The pharmaceutical composition for preventing and treating ischemic stroke according to claim 3, wherein the preparation is prepared by adding pharmaceutically acceptable auxiliary materials or auxiliary components into active ingredients such as sulfoxylamine butoxide or salts thereof, deferiprone or salts thereof, MCC950 or salts thereof.
5. Use of the pharmaceutical composition for preventing and treating ischemic stroke according to any one of claims 1 to 4 in the preparation of a medicament for preventing and treating ischemic stroke.
CN202310614537.6A 2023-05-29 2023-05-29 Pharmaceutical composition for preventing and treating ischemic cerebral apoplexy and application thereof Pending CN116392486A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1939895A (en) * 2000-04-19 2007-04-04 纽若泰克有限公司 Compound, composition and method for preventing from neurodegeneration in injury of central nervous system
US20170172958A1 (en) * 2014-03-06 2017-06-22 Helga Refsum Compounds for Use in Controlling Body Fat
CN113244241A (en) * 2021-04-04 2021-08-13 四川大学华西医院 Pharmaceutical composition for preventing and treating hemorrhagic stroke and application thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1939895A (en) * 2000-04-19 2007-04-04 纽若泰克有限公司 Compound, composition and method for preventing from neurodegeneration in injury of central nervous system
US20170172958A1 (en) * 2014-03-06 2017-06-22 Helga Refsum Compounds for Use in Controlling Body Fat
CN113244241A (en) * 2021-04-04 2021-08-13 四川大学华西医院 Pharmaceutical composition for preventing and treating hemorrhagic stroke and application thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
SAIFUDEEN ISMAEL等: "Inhibition of the NLRP3-inflammasome as a potential approach for neuroprotection after stroke", 《SCIENTIFIC REPORTS》, vol. 08 *
饶政清等: "脑泰方调控细胞铁转运抑制铁死亡保护脑卒中缺血损伤的机制研究", 《中草药》, vol. 52, no. 21, pages 1 *

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