WO2020005113A1 - Agent à effet anti-acv - Google Patents
Agent à effet anti-acv Download PDFInfo
- Publication number
- WO2020005113A1 WO2020005113A1 PCT/RU2019/050067 RU2019050067W WO2020005113A1 WO 2020005113 A1 WO2020005113 A1 WO 2020005113A1 RU 2019050067 W RU2019050067 W RU 2019050067W WO 2020005113 A1 WO2020005113 A1 WO 2020005113A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- stroke
- brain
- ischemic
- lithium ascorbate
- experimental
- Prior art date
Links
- 230000000320 anti-stroke effect Effects 0.000 title claims abstract description 17
- IHAQDFLGBNNAEH-RXSVEWSESA-M lithium (2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate Chemical compound O=C1C(O)=C([O-])[C@H](O1)[C@@H](O)CO.[Li+] IHAQDFLGBNNAEH-RXSVEWSESA-M 0.000 claims abstract description 15
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 3
- 241000700159 Rattus Species 0.000 description 11
- 210000004556 brain Anatomy 0.000 description 9
- 208000032382 Ischaemic stroke Diseases 0.000 description 8
- 206010008118 cerebral infarction Diseases 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 7
- 208000026106 cerebrovascular disease Diseases 0.000 description 7
- 208000006011 Stroke Diseases 0.000 description 5
- 230000006931 brain damage Effects 0.000 description 4
- 231100000874 brain damage Toxicity 0.000 description 4
- 208000029028 brain injury Diseases 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- 208000028867 ischemia Diseases 0.000 description 3
- 230000000302 ischemic effect Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 102220240796 rs553605556 Human genes 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- PKDBCJSWQUOKDO-UHFFFAOYSA-M 2,3,5-triphenyltetrazolium chloride Chemical compound [Cl-].C1=CC=CC=C1C(N=[N+]1C=2C=CC=CC=2)=NN1C1=CC=CC=C1 PKDBCJSWQUOKDO-UHFFFAOYSA-M 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 210000000269 carotid artery external Anatomy 0.000 description 2
- 210000004004 carotid artery internal Anatomy 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 210000003657 middle cerebral artery Anatomy 0.000 description 2
- 230000010410 reperfusion Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010048962 Brain oedema Diseases 0.000 description 1
- 206010008088 Cerebral artery embolism Diseases 0.000 description 1
- 206010015548 Euthanasia Diseases 0.000 description 1
- 102000034615 Glial cell line-derived neurotrophic factor Human genes 0.000 description 1
- 108091010837 Glial cell line-derived neurotrophic factor Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- 206010060840 Ischaemic cerebral infarction Diseases 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- 206010028851 Necrosis Diseases 0.000 description 1
- 102000001068 Neural Cell Adhesion Molecules Human genes 0.000 description 1
- 108010069196 Neural Cell Adhesion Molecules Proteins 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 208000006752 brain edema Diseases 0.000 description 1
- 201000008247 brain infarction Diseases 0.000 description 1
- 210000005013 brain tissue Anatomy 0.000 description 1
- OLBBKQREWLVXDO-UHFFFAOYSA-N butanedioic acid;2,4,6-trimethylpyridin-3-ol Chemical compound OC(=O)CCC(O)=O.CC1=CC(C)=C(O)C(C)=N1 OLBBKQREWLVXDO-UHFFFAOYSA-N 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 210000001168 carotid artery common Anatomy 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 238000005474 detonation Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 230000002518 glial effect Effects 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 201000010849 intracranial embolism Diseases 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- QHIJANTUHTWLCS-UHFFFAOYSA-N lithium;dihydrate Chemical compound [Li].O.O QHIJANTUHTWLCS-UHFFFAOYSA-N 0.000 description 1
- 229920002529 medical grade silicone Polymers 0.000 description 1
- 239000012907 medicinal substance Substances 0.000 description 1
- 238000002406 microsurgery Methods 0.000 description 1
- 239000002113 nanodiamond Substances 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 230000016273 neuron death Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- AFEHBIGDWIGTEH-AQRCPPRCSA-N semax Chemical compound C([C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CCSC)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)NCC(=O)N1[C@@H](CCC1)C(O)=O)C1=CNC=N1 AFEHBIGDWIGTEH-AQRCPPRCSA-N 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
Images
Classifications
-
- 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
-
- 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
- A61K31/365—Lactones
- A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
Definitions
- the invention relates to the pharmaceutical industry, namely to a medicinal substance with anti-stroke action.
- the proposed tool has an anti-stroke effect and helps to reduce the volume of the zone of brain damage in strokes.
- the invention relates to medicine, namely to medicinal substances with anti-stroke action.
- 2,4,6-trimethyl-3-hydroxypyridine succinate is known as an anti-stroke agent [RU 2326665 C1, IPC (2006.01) A61K31 / 4412, A61P 9/10, A61P 25/00, A61P 7/00, publ. . 06/20/2008].
- a means is known that has an anti-stroke effect and is an amino acid glycine immobilized on detonation nanodiamond particles of 2-10 nm in size [RU 2521404 C1, IPC (2006.01) A61K31 / 195, B82B3 / 00, B82Y5 / 00, publ. 06/27/2014].
- the invention consists in the use of lithium ascorbate dihydrate as an anti-stroke agent.
- the anti-stroke effect of lithium ascorbate was established for the first time.
- the combination of the well-known psychostabilizing and antioxidant and immunostimulating properties of lithium ascorbate with its new property of reducing the area of brain infarction in ischemic stroke is promising for practical use.
- An object of the present invention is to expand the arsenal of anti-stroke agents.
- the technical result is achieved by the use of lithium ascorbate dihydrate with the formula Li ⁇ 6 ⁇ 7 ⁇ 6 ⁇ 2 ⁇ 2 O for a new purpose as an anti-stroke agent.
- Lithium ascorbate has an anti-stroke effect, expressed in the ability to reduce the volume of the zone of brain damage during strokes.
- rat brain sections are shown after administration of lithium ascorbate.
- On successive sections of the brain there is a significant decrease in the size of foci of cerebral infarction. Zones of the brain without ischemic damage turn bright pink.
- the decrease in white necrosis zones is a consequence of the protective effect of lithium ascorbate in ischemia.
- the filament was passed through the external and common into the internal carotid artery to a level corresponding to the discharge of the middle cerebral artery, which leads to its occlusion and ischemia of the corresponding part of the brain.
- the filament was left in the vascular system for 1 hour, then gradually removed, first from the intracranial section (partial reperfusion), and after 15 minutes completely, tearing off blood flow through the system of general-internal carotid arteries (complete reperfusion).
- This methodology corresponds to the chronology of generally accepted tactics for providing emergency medical care to patients with ischemic stroke.
- mice were placed under normal conditions with unlimited access to food and drink. Experimental animals were observed during the day after the experimental intervention, and survival was assessed.
- the volume of ischemic cerebral infarction was determined according to the classical method with staining of brain sections of 2,3,5-triphenyltetrazolium chloride [Mishima K, Ikeda T, Yoshikawa T. Brain & development. 1997; 19: 326.].
- Brain sections were placed in a 1% solution of 2,3,5-triphenyltetrazolium chloride and incubated for 15 min at 37 ° C.
- Indicator ⁇ Group Mortality of animals within 24 hours after a stroke,% of the total The volume of the zone of cerebral infarction, mm cube The first (experimental rats) 0% 62 ⁇ 27 Second (control rats) thirty% 248 ⁇ 41
- the anti-stroke effect of lithium dihydrate ascorbate has reduced the area of brain damage by more than four times (Fig. 1, 2).
- the invention can be used to create new drugs in various dosage forms, including in the form of a solution for intravenous use and in the form of tablets for oral administration.
- Lithium ascorbate can be used as an active substance in the creation of new combination preparations for the treatment and prevention of strokes and to reduce the degree of brain damage in ischemia. It is possible to use lithium ascorbate as an individual anti-stroke drug, as well as its inclusion in existing treatment and prophylaxis of ischemic stroke.
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- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Epidemiology (AREA)
- Cardiology (AREA)
- 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)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
L'invention porte sur l'utilisation d'ascorbate de dihydrate de lithium en tant que produit possédant une action anti-ACV. L'agent se présente comme un dihydrate de lithium cristallin correspondant à la formule LiС 6Н 7О 6·2Н 2O ; l'invention permet d'élargir la gamme des moyens possédant uen action ancti-ACBV et peut être utilisée en médecine.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| RU2018123138A RU2675601C1 (ru) | 2018-06-26 | 2018-06-26 | Средство, обладающее противоинсультным действием |
| RU2018123138 | 2018-06-26 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2020005113A1 true WO2020005113A1 (fr) | 2020-01-02 |
Family
ID=64753509
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/RU2019/050067 WO2020005113A1 (fr) | 2018-06-26 | 2019-05-28 | Agent à effet anti-acv |
Country Status (2)
| Country | Link |
|---|---|
| RU (1) | RU2675601C1 (fr) |
| WO (1) | WO2020005113A1 (fr) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2699039C1 (ru) * | 2019-03-25 | 2019-09-03 | Федеральное государственное автономное образовательное учреждение высшего образования "Национальный исследовательский Томский политехнический университет" | Средство, обладающее кардиопротекторной активностью |
| RU2720455C1 (ru) * | 2019-11-06 | 2020-04-30 | федеральное государственное автономное образовательное учреждение высшего образования «Национальный исследовательский Томский политехнический университет» | Радиосенсибилизирующее средство |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070049565A1 (en) * | 2005-08-24 | 2007-03-01 | Neurotech Pharmaceuticals Co., Ltd. | Combination of cell necrosis inhibitor and lithium for treating neuronal death or neurological dysfunction |
| US20070298129A1 (en) * | 2005-08-24 | 2007-12-27 | Neurotech Pharmaceuticals Co., Ltd. | Compounds and compositions for treating neuronal death or neurological dysfunction |
| RU2521404C1 (ru) * | 2013-01-25 | 2014-06-27 | Николай Борисович Леонидов | Средство, обладающее противоинсулитным действием, и способ его получения |
| RU2614697C1 (ru) * | 2016-04-12 | 2017-03-28 | Общество с ограниченной ответственностью "Нормофарм" | Нейропротекторное средство |
-
2018
- 2018-06-26 RU RU2018123138A patent/RU2675601C1/ru active
-
2019
- 2019-05-28 WO PCT/RU2019/050067 patent/WO2020005113A1/fr active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070049565A1 (en) * | 2005-08-24 | 2007-03-01 | Neurotech Pharmaceuticals Co., Ltd. | Combination of cell necrosis inhibitor and lithium for treating neuronal death or neurological dysfunction |
| US20070298129A1 (en) * | 2005-08-24 | 2007-12-27 | Neurotech Pharmaceuticals Co., Ltd. | Compounds and compositions for treating neuronal death or neurological dysfunction |
| RU2521404C1 (ru) * | 2013-01-25 | 2014-06-27 | Николай Борисович Леонидов | Средство, обладающее противоинсулитным действием, и способ его получения |
| RU2614697C1 (ru) * | 2016-04-12 | 2017-03-28 | Общество с ограниченной ответственностью "Нормофарм" | Нейропротекторное средство |
Also Published As
| Publication number | Publication date |
|---|---|
| RU2675601C1 (ru) | 2018-12-20 |
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