CN113116900B - Application of nucleoside analogs in preparation of drugs for preventing and/or treating cerebrovascular diseases - Google Patents
Application of nucleoside analogs in preparation of drugs for preventing and/or treating cerebrovascular diseases Download PDFInfo
- Publication number
- CN113116900B CN113116900B CN202110398882.1A CN202110398882A CN113116900B CN 113116900 B CN113116900 B CN 113116900B CN 202110398882 A CN202110398882 A CN 202110398882A CN 113116900 B CN113116900 B CN 113116900B
- Authority
- CN
- China
- Prior art keywords
- cerebral
- treating
- lamivudine
- application
- nucleoside
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- 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
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- 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
-
- 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)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Cardiology (AREA)
- Molecular Biology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the technical field of medicines, in particular to application of nucleoside analogues in preparation of medicines for preventing or treating cerebrovascular diseases. The structural general formula of the nucleoside analogue is shown as a formula (I), wherein X and Y are respectively selected from S, O, NH or any one of alkoxy, R is defined as any one of cytosine, thymine, adenine and guanine, and R1Is OH, NH2、CH3、CH3O, halogen, C1‑C6Alkyl, metal ions, etc.; r2Is OH, NH2、CH3、CH3O, halogen, C1‑C6Alkyl, metal ions, etc.; n is more than or equal to 0 and less than or equal to 3. The nucleoside analogue has obvious curative effect on cerebral arterial thrombosis, can obviously improve nerve function damage and reduce infarction area, and has good clinical application prospect in clinic.
Description
Technical Field
The invention relates to the technical field of medicines, and also relates to a novel small molecular compound for treating cerebrovascular diseases, in particular to application of nucleoside analogues such as lamivudine, zidovudine and acyclovir in preparation of medicines for treating cerebrovascular diseases.
Background
Cerebrovascular diseases (cerebravicular disease), which generally refer to various diseases of cerebral vessels, including atherosclerosis, thrombosis, stenosis, occlusion, cerebral arteritis, cerebral artery injury, cerebral aneurysm, intracranial vascular malformation, cerebral arteriovenous fistula, etc., have common characteristics of causing ischemia or hemorrhagic accident of brain tissues. Typical cerebrovascular diseases include cerebral thrombosis, cerebral ischemia, cerebral infarction, etc.
Cerebral thrombosis is characterized in that on the basis of cerebral atherosclerosis and plaques, under the conditions of slow blood flow and low blood pressure, effective components of blood are attached to intima of arteries to form thrombus, and become cerebral thrombosis, and hemiplegia is clinically used as a main clinical manifestation. Stroke is an acute cerebrovascular disease, a group of diseases that causes damage to brain tissue due to sudden rupture of cerebral vessels or failure of blood to flow into the brain due to vessel occlusion, including ischemic stroke and hemorrhagic stroke. Thrombosis can cause the formation of cerebral infarction, also known as ischemic stroke; cerebral thrombosis and cerebral infarction can be finally attributed to stroke. And the stroke is a serious chronic non-infectious disease seriously harming the health of China, and has five characteristics of high morbidity, high disability rate, high mortality, high recurrence rate and high economic burden. With the aging of the population, the epidemic trend of risk factors of cerebrovascular diseases is more obvious, and the number of the patients suffering from cerebrovascular diseases is continuously increased. At present, no effective treatment method exists in the clinic for the serious disease. Therefore, how to develop a new drug capable of significantly treating ischemic stroke is a problem to be solved urgently.
Common clinical nucleoside analogue drugs mainly comprise lamivudine, acyclovir, adefovir dipivoxil, famciclovir, entecavir, gemcitabine, zidovudine, cytarabine, azacitidine, emtricitabine, telbivudine, clevudine, emtricitabine and the like, and the functions of the nucleoside analogue drugs mainly comprise antivirus, antitumor, immunity improvement and liver function recovery. Wherein. Lamivudine is a cytosine nucleoside analogue, has competitive inhibiting effect on synthesis and extension of virus DNA chain, is mainly used for treating hepatitis B and liver and gall diseases, and is the most representative nucleoside analogue in clinical application at present; cytarabine acts mainly on pyrimidine antimetabolites in the cell S proliferation stage, interferes with cell proliferation by inhibiting the synthesis of cell DNA, is mainly used for treating acute leukemia, has the best curative effect on acute granulocyte leukemia, and also has the effect on acute monocytic leukemia and acute lymphocytic leukemia. Has certain curative effect on malignant lymphoma, lung cancer, digestive tract cancer, head and neck cancer, viral keratitis, epidemic conjunctivitis, etc. Gemcitabine is a novel cytosine nucleoside derivative, has the same action mechanism as cytarabine, and the main metabolite of gemcitabine is incorporated into DNA in cells and mainly acts on G1/S phase. Clinically, gemcitabine and cytarabine have different anti-tumor spectra and are effective to various solid tumors, and the composition is used for second-line medication of patients with advanced pancreatic cancer and can improve the life quality of the patients; as a first-line drug for locally advanced and metastatic non-small cell lung cancer. Zidovudine is a thymine nucleoside analogue used for treating AIDS patients or AIDS-related syndromes and immunodeficiency virus HIV infection, is the first anti-AIDS drug approved and produced by the American FDA in the world, becomes the most basic composition component of a 'cocktail' therapy due to definite curative effect, and has high activity on retroviruses including human immunodeficiency virus in vitro. Acyclovir is a synthetic guanine nucleoside analogue, is mainly used for various infections caused by herpes simplex virus, and can be used for initial or recurrent skin, mucous membrane and external genitalia infections and Herpes Simplex Virus (HSV) infections caused by immunodeficiency. The drug is the first choice drug for treating HSV encephalitis, and is superior to vidarabine in reducing morbidity and mortality. It can also be used for treating herpes zoster, EB virus, and immunodeficiency complicated with varicella infection. It is only applied topically to the skin because it is less absorbed by the skin.
Currently, researchers have been studying nucleosides and nucleoside analogues, and more about the dosage forms, detection methods, preparation methods, structural modifications, etc. thereof, for example, patent CN101511375B discloses the use of L-cytosine nucleoside analogues in the preparation of drugs for treating cancers and other disorders or disease states, which is mainly structural modification of nucleoside analogues, and the modified compounds are used for treating colon cancer, pancreatic cancer and liver cancer. Patent CN111741967A discloses nucleotide analogs, preparation methods and their applications in nucleic acid sequencing and the like, which mainly relates to the preparation methods of nucleoside analogs and the like; patent CN109790196A discloses a method for nucleic acid detection using reversibly blocked nucleoside analogues; patent CN108671235A discloses a functional nucleic acid of skeleton-integrated nucleoside analogue drug and its derivatives, and their preparation method, and their application in treating diseases by gene therapy and chemotherapy; patent CN104211742A discloses phosphoric acid N-fatty acid modified by a cyclophosphylated group and connected with a fatty chain for treating viral hepatitis and liver cancer; patent CN110643609A discloses a drug aptamer constructed by nucleoside analogue drug molecules, a preparation method and application thereof, and the like; however, there is no literature on the application of nucleoside analogs to cerebrovascular diseases, and there is no literature on the application of nucleoside analogs to cerebrovascular diseases.
The inventor unexpectedly discovers that the nucleoside analogue has obvious curative effect on cerebrovascular diseases in the research process, and provides a new application of the nucleoside analogue.
Disclosure of Invention
Aiming at the technical problems, the invention discloses a nucleoside analogue shown as a formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer and a mixture form thereof, and an application of a medicinal salt thereof in preparing a medicament for treating and/or preventing cerebrovascular diseases;
wherein, X and Y in the structural formula are respectively selected from any one of S, O, NH or alkoxy;
r is any one of cytosine, thymine, adenine and guanine;
R1is OH, NH2、CH3、CH3O, halogen, C1-C6Alkyl, metal ions, etc.;
R2is OH, NH2、CH3、CH3O, halogen, C1-C6Alkyl, metal ions, etc.;
0≤n≤3。
preferably, the nucleoside analogue is one of lamivudine, acyclovir, adefovir dipivoxil, famciclovir, entecavir, gemcitabine, zidovudine, cytarabine, azacitidine, emtricitabine, telbivudine, cladribine or emtricitabine.
Preferably, the nucleoside analogue is lamivudine, zidovudine and acyclovir.
Preferably, the cerebrovascular disease is cerebral thrombosis, cerebral ischemia and cerebral apoplexy.
Preferably, the stroke includes hemorrhagic stroke and ischemic stroke.
Preferably, the stroke is ischemic stroke.
The second purpose of the invention is to disclose the application of the nucleoside analogue shown in the formula (I) or the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer and the mixture form thereof, and the pharmaceutically acceptable salt thereof in preparing the medicine for treating and/or preventing the nerve function damage;
wherein, in the structural formula, X and Y are respectively selected from any one of S, O, NH or alkoxy;
r is any one of cytosine, thymine, adenine and guanine;
R1is OH, NH2、CH3、CH3O, halogen, C1-C6Alkyl, metal ions, etc.;
R2is OH, NH2、CH3、CH3O、Halogen, C1-C6Alkyl, metal ions, etc.;
0≤n≤3。
the third purpose of the invention is to disclose the nucleoside analogue shown in the formula (I) or the tautomer, mesomer, racemate, enantiomer, diastereoisomer and mixture form thereof, and the application of the pharmaceutically acceptable salt thereof in preparing the medicine for treating and/or preventing cerebral ischemia-reperfusion injury;
wherein, X and Y in the structural formula are respectively selected from any one of S, O, NH or alkoxy;
r is any one of cytosine, thymine, adenine and guanine;
R1is OH or NH2、CH3、CH3O, halogen, C1-C6Alkyl, metal ions, etc.;
R2is OH, NH2、CH3、CH3O, halogen, C1-C6Alkyl, metal ions, etc.;
0≤n≤3。
the fourth purpose of the invention is to disclose the nucleoside analogue shown in formula (I) or the tautomer, mesomer, racemate, enantiomer, diastereomer and mixture form thereof, and the pharmaceutically acceptable salt and one or more pharmaceutically acceptable carriers to form the pharmaceutical composition, wherein the pharmaceutical composition is in the dosage form of injection, tablet, capsule, granule and pill.
The invention has the beneficial effects that: the invention provides a new application of nucleoside analogues, in particular to an application of nucleoside analogues such as lamivudine, zidovudine and acyclovir in preparation of drugs for treating cerebrovascular diseases, especially for treating ischemic stroke.
Drawings
FIG. 1 Lamivudine rat MCAO model test results
In contrast to the "SHAM", the method of the present invention,###p < 0.001; compared with "IR". about.p<0.05 and x p<0.001
Wherein "A" is a brain slice TTC staining pattern; "B" is a neurological deficit scoring chart; and C is a cerebral infarction volume ratio graph. FIG. 2 results of rat MCAO model test of zidovudine and acyclovir
In contrast to the "SHAM", the method of the present invention,###p < 0.001; compared with "IR". about.p<0.05 and x p<0.001
Wherein "A" is a brain slice TTC staining pattern; "B" is a neurological deficit scoring chart; and C is a cerebral infarction volume ratio graph.
Detailed Description
The scope of the present invention will be described in detail with reference to the following examples, but it should be understood that the scope of the present invention is not limited to the following examples, and the therapeutic effects of a class of compounds that protect nucleoside analogs in all cerebrovascular diseases, especially stroke diseases, include various dosage forms, dosages, combinations, etc. All technical solutions which can be derived from a technical solution by a person skilled in the art through logical analysis, inference and experiment according to the technical solutions of the present invention are within the scope of the claimed invention.
In the following examples of the present invention, lamivudine is a drug for inhibiting virus and cannot eliminate hepatitis B virus because lamivudine has no effect on cccDNA of hepatitis B virus, the half-life of cccDNA in human body is about 3-4 years, if cccDNA exists continuously, virus cannot be eliminated, and the virus will relapse after drug withdrawal. Therefore, when the lamivudine is applied, the curative effect of the lamivudine is not completely dependent on the medicament, and is closely related to the specific immunoreaction state of a patient to HBV and virus virulence, the lamivudine is independently applied to the patient with weak specific immunoreaction, so that the purpose of eliminating the virus is difficult to achieve, a method for improving the specific immunoreaction of an organism to the HBV is also needed, and the combined application of thymosin, therapeutic vaccine, high-titer hepatitis B immunoglobulin and the like can be considered.
In the following examples of the invention zidovudine is a thymidine analog used in aids or aids-related syndrome patients and in the treatment of HIV infection, the first anti-aids drug to be approved by the FDA in the united states worldwide, and because of its precise therapeutic effect, it is the most basic combination of "cocktail" therapy and is highly active against retroviruses including human immunodeficiency virus in vitro.
In the following examples of the invention, acyclovir is a synthetic guanosine analogue, is mainly used for various infections caused by herpes simplex virus, and can be used for primary or recurrent skin, mucous membrane and external genitalia infections and HSV infections caused by immunodeficiency. Acyclovir is used as a first choice drug for treating HSV encephalitis, and is superior to vidarabine in reducing morbidity and mortality. Acyclovir is also used in the treatment of herpes zoster, EB virus, and varicella concurrent with immunodeficiency.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the subject matter herein. In this application, it must be noted that, unless the context clearly dictates otherwise, as used in this specification and the claims, the singular forms "a," "an," and "the" include plural referents. It should also be noted that the use of "or", "or" means "and/or" unless stated otherwise. Furthermore, the term "comprising" as well as other forms, such as "includes," "including," and "containing," are used without limitation.
In the following examples of the present invention, butylphthalide is mainly used for treating mild and moderate acute ischemic stroke. In the embodiment of the invention, butylphthalide is used as a positive drug.
In the following examples of the invention, MCAO is Middle Cerebral Artery ischemia, Middle Cerebral Artery ischemia.
Example I therapeutic Effect of Lamivudine on ischemic Stroke
1. Laboratory animals and drugs
SPF grade healthy male SD rats with the weight of 200-.
Drugs and reagents: lamivudine (Lamivudine, 3-TC, HPLC ≥ 98%), available from McClin Biotech, Inc.; butylphthalide soft capsules (NBP), available from stone pharmaceutical group embiop pharmaceutical ltd; 2, 3, 5-Triphenyltetrazolium chloride (TTC), available from Solarbio.
Preparation and dosing time of MCAO model: one week after acclimation, all SD rats were randomly divided into 4 groups, and the groups and doses were as follows:
SHAM group (SHAM, gavage given an equal volume of 0.5% CMC-Na);
model group (IR, gavage given equal volume of 0.5% CMC-Na);
butylphthalide group (NBP, 20mg/kg/day for gavage)
Lamivudine group (C1, Lamivudine gavage, 2mg/kg/day),
the animal model of right middle artery occlusion in rats was prepared by a method of embolization using Longa et al (see, Reversible middle artery occlusion with thrombus in rats).
Model group: the anesthetized rats were fixed, prepped, disinfected with iodophor, and disinfected with surgical instruments, ready for ligation with No. 5 thread, and a longitudinal incision of about 1.5cm was made along the right midline of the neck. After the right carotid artery and vagus nerve were carefully isolated, the common carotid artery and internal carotid artery were ligated with surgical sutures, the common carotid artery was ligated at the position of 10mm from the bifurcation, and then a 0.32mm diameter plug was inserted into the internal carotid artery through the incision at the position of 5mm from the bifurcation of the common carotid artery, and when the depth of the plug was about 18-20mm, the plugging was stopped and the ligation was tied. After cleaning, layered sewing is performed. And removing the wire bolt after the animal is ischemic for 2h, naturally reviving the animal, and then perfusing the animal for 24h to perform related index detection. Different from permanent cerebral ischemia, the nylon wire plug is pulled out after blocking for 2 hours, the artery stump is tied tightly, and subcutaneous tissues and skin are sutured layer by layer after disinfection.
The sham operation group: the same model set was operated except that no wire plug was inserted. After the experimental animal is awake, the drug intervention is carried out, and the materials are sacrificed and taken 24h after the drug administration.
3. Detecting the index
3.1 neurological deficit score
Score according to Zea Longa grade 5: 0 minute: no neurological deficit; 1 minute: the front paw at the opposite side of the focus can not be fully extended; and 2, dividing: spontaneous rotation to the opposite side of the lesion; and 3, dividing: pouring to the opposite side of the focus; and 4, dividing: there was no spontaneous walking and loss of consciousness occurred.
3.2TTC staining
Taking each group of rats, cutting off heads, separating brain tissues on ice, removing olfactory bulbs and brainstems, washing with normal saline, immediately freezing at-20 ℃ for 15min, taking out, coronal-cutting the brains along a visual cross plane to a pituitary plane uniformly into 4 coronal slices, immersing into 1.5% TTC solution, incubating and staining (shading) in 37 ℃ constant temperature water bath for 45min, turning over every 15min to make the staining uniform, reacting with deoxyenzyme in normal tissues to be red, enabling ischemic areas to be white, namely, enabling unstained areas to be dead areas, and determining the animal brain tissue infarction volume according to the percentage of the sum of the infarction volumes of all coronal slices of the brain tissue in the whole brain volume.
Volume of cerebral infarction (sum of ischemic side area average value-sum of contralateral area average value) x thickness of infarcted brain tissue
4. Results of the experiment
Neurological deficit assessment, TTC staining and cerebral infarct volume results are shown in figure 1. As can be seen from fig. 1A and 1B, the neurological scores of the model group were significantly increased compared to the sham group (a)###p < 0.001), the brain tissue TTC is stained uniformly red, no white infarction focus of ischemia is seen, and the white infarction focus of a large area can be seen in the MCAO model group, which indicates that the rat MCAO model is successfully made. Compared with the IR model group, the positive drugs of butylphthalide and lamivudine can obviously reduce the neurological deficit score ([ p ])<0.05, fig. 1B), improving infarct focus (. about.p)<0.001, FIG. 1C), indicating that lamivudine has a nerve of stroke like butylphthalideThe protective effect is that the nerve protective effect (80.38%) of lamivudine is stronger than the nerve protective effect (60.71%) of clinical butylphthalide, namely the lamivudine has better effect of treating cerebral arterial thrombosis nerve injury.
Since lamivudine belongs to the classical nucleoside analogue drugs, the inventors speculate that other nucleoside analogues besides lamivudine also have the effect of treating ischemic stroke, and in order to verify the speculation, the inventors evaluated the therapeutic effect of zidovudine and acyclovir on ischemic stroke, and the specific experimental process is as follows.
EXAMPLE II therapeutic Effect of Zidovudine and Acyclovir on ischemic Stroke
1. Laboratory animal
SPF healthy male SD rats with the weight of 200-.
2. Reagent and experimental method
Drugs and reagents: zidovudine (Zidovudine, AZT, HPLC. gtoreq.98%) purchased from Aladdin Biotechnology Ltd; acyclovir (Acylovir, ACV, HPLC ≥ 98%), available from McClin Biotech limited; butylphthalide soft capsules (NBP), available from stone pharmaceutical group embiop pharmaceutical ltd; 2, 3, 5-Triphenyltetrazolium chloride (TTC), available from Solarbio.
3. The preparation and detection index method of the animal model are the same as the first embodiment
The experimental groups were as follows:
SHAM group (SHAM, gavage given equal volume of 0.9% NaCl);
model group (IR, gavage given equal volume of 0.9% NaCl);
butylphthalide group (NBP, 20mg/kg/day for gavage)
Zidovudine group (AZT, gavage for zidovudine, 20mg/kg/day)
Acyclovir group (ACV, gavage for Acyclovir, 20mg/kg/day)
Experimental results
Neurological deficit assessment, TTC staining and cerebral infarct volume results are shown in figure 2. As can be seen from fig. 2A and 2B, the neurological scores of the model group were significantly increased compared to the sham group (a)###p < 0.001), the brain tissue TTC is stained uniformly red, no white infarction focus of ischemia is seen, and the white infarction focus of a large area can be seen in the MCAO model group, which indicates that the rat MCAO model is successfully made. Compared with the IR model group, the positive drug butylphthalide, zidovudine and acyclovir can obviously reduce the neurological deficit score (. p)<0.05, fig. 2B), reduction of infarct focus (. about.p)<0.001 and fig. 2C), indicating that zidovudine, acyclovir and butylphthalide have the same neuroprotective effect on cerebral apoplexy, and that the neuroprotective effect (72.96%) of zidovudine is stronger than the neuroprotective effect (59.44%) of clinical butylphthalide, and the neuroprotective effect (61.80%) of acyclovir is slightly stronger than the neuroprotective effect (59.44%) of clinical butylphthalide, i.e. zidovudine and acyclovir of the present invention have better effect of treating cerebral apoplexy nerve injury.
In conclusion, the invention adopts MCAO cerebral ischemia reperfusion injury animal model to evaluate the treatment effect of lamivudine, zidovudine and acyclovir on cerebral ischemic stroke, and the experimental result shows that lamivudine, zidovudine and acyclovir have the effect of treating cerebral ischemic stroke, and the treatment effect of lamivudine is better than that of zidovudine and acyclovir. Therefore, the nucleoside analogs have the effect of treating cerebral arterial thrombosis and have wide clinical application prospect.
The scope of protection of the invention is not limited to the embodiments. All technical solutions which can be derived by a person skilled in the art through logical analysis, inference and experiments according to the idea of the invention are within the scope of protection of the claims.
Claims (2)
1. Application of lamivudine in preparing medicine for treating and/or preventing cerebral arterial thrombosis is provided.
2. The use according to claim 1, wherein the lamivudine is in the form of injection, tablet, capsule, granule, pill.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110398882.1A CN113116900B (en) | 2021-04-14 | 2021-04-14 | Application of nucleoside analogs in preparation of drugs for preventing and/or treating cerebrovascular diseases |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110398882.1A CN113116900B (en) | 2021-04-14 | 2021-04-14 | Application of nucleoside analogs in preparation of drugs for preventing and/or treating cerebrovascular diseases |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113116900A CN113116900A (en) | 2021-07-16 |
| CN113116900B true CN113116900B (en) | 2022-07-08 |
Family
ID=76776216
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110398882.1A Active CN113116900B (en) | 2021-04-14 | 2021-04-14 | Application of nucleoside analogs in preparation of drugs for preventing and/or treating cerebrovascular diseases |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113116900B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004098627A1 (en) * | 2003-05-06 | 2004-11-18 | Royal College Of Surgeons In Ireland | Inhibition of platelet aggregation through acyclovir and two peptide antagonists |
| CN1626107A (en) * | 1999-02-23 | 2005-06-15 | 加利福尼亚大学董事会 | Pyrimidine nucleoside and pharmacy usage of pyrimidine nucleotide precursor |
| CN102058614A (en) * | 2003-03-07 | 2011-05-18 | Cbt发展有限公司 | Use of adenosine receptor agonists in therapy |
| CN111569075A (en) * | 2020-05-13 | 2020-08-25 | 四川大学华西医院 | Application of nucleoside antiviral drug in preparation of drug for treating infarct disease |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040014648A1 (en) * | 2002-05-17 | 2004-01-22 | Faust Pharmaceuticals | Methods for the prevention and/or the treatment of neurological disorders |
| ES2358089T3 (en) * | 2004-11-01 | 2011-05-05 | Seo Hong Yoo | METHODS AND COMPOSITIONS TO REDUCE NEURODEGENERATION IN AMIOTROPHIC SIDE STERHERISIS. |
| WO2006060382A2 (en) * | 2004-11-30 | 2006-06-08 | Trustees Of The University Of Pennsylvania | Use of hdac and/or dnmt inhibitors for treatment of ischemic injury |
-
2021
- 2021-04-14 CN CN202110398882.1A patent/CN113116900B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1626107A (en) * | 1999-02-23 | 2005-06-15 | 加利福尼亚大学董事会 | Pyrimidine nucleoside and pharmacy usage of pyrimidine nucleotide precursor |
| CN102058614A (en) * | 2003-03-07 | 2011-05-18 | Cbt发展有限公司 | Use of adenosine receptor agonists in therapy |
| WO2004098627A1 (en) * | 2003-05-06 | 2004-11-18 | Royal College Of Surgeons In Ireland | Inhibition of platelet aggregation through acyclovir and two peptide antagonists |
| CN111569075A (en) * | 2020-05-13 | 2020-08-25 | 四川大学华西医院 | Application of nucleoside antiviral drug in preparation of drug for treating infarct disease |
Non-Patent Citations (2)
| Title |
|---|
| A pharmacological screening approach for discovery of neuroprotective compounds in ischemic stroke;Simret Beraki等;《PLoS ONE》;20130718;第8卷(第7期);e69233 * |
| State of Astrocytes in the Mice Brain under Conditions of Herpes Viral Infection and Modeled Stroke;A.V.Gumenyuk等;《Neurophysiology》;20181031;第50卷(第5期);326-331 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113116900A (en) | 2021-07-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2640582C2 (en) | Derivatives of vitamine b6 nucleotides, acyclic nucleotides and acyclic nucleoside phosphonates | |
| KR100256144B1 (en) | Composition of chemotherapeutic agent or antiviral agent with acylated pyrimidine nucleosides | |
| JP4959900B2 (en) | Antiviral pyrimidine nucleosides | |
| US20080139496A1 (en) | Combination therapy for reduction of toxicity of chemotherapeutic agents | |
| JPH10511682A (en) | Synergistic combination of zidovudine, 1592U89 and 3TC or FTC | |
| RU2005114018A (en) | EPOTHYLON D + FLUORORACIL / HEMCITABINE | |
| WO1997023230A1 (en) | Method of treating disorders characterized by overexpression of cytidine deaminase or deoxycytidine deaminase | |
| WO2016014527A2 (en) | Stabilized nucleotides for medical treatment | |
| CN111655691B (en) | Liver delivery entecavir prodrug nucleoside cyclic phosphate ester compound and application thereof | |
| CN113116900B (en) | Application of nucleoside analogs in preparation of drugs for preventing and/or treating cerebrovascular diseases | |
| WO2022217481A1 (en) | Application of nucleoside analogues in preparation of drugs for preventing and/or treating cerebrovascular diseases | |
| JP5204943B2 (en) | Use of pyrimidine nucleotides for the treatment of diseases of the peripheral nervous system | |
| WO2021058021A1 (en) | Drug combination containing tlr7 agonist | |
| CN114533739B (en) | Application of nucleoside analogue in preparing medicament for preventing or treating gastrointestinal diseases | |
| CN115028594A (en) | Emotitabine medicinal precursor compound and preparation method and medical application thereof | |
| CN114621156A (en) | Entifovir pharmaceutical precursor compound, preparation method and medical application thereof | |
| CN110354168A (en) | A kind of pharmaceutical composition and preparation method thereof for treating clear cell carcinoma of kidney | |
| US8586561B2 (en) | Anti-tumor agent comprising cytidine derivative and carboplatin | |
| CN115634228A (en) | Application of purine synthesis inhibitor in preparation of medicine for treating ischemia and ischemia reperfusion injury | |
| ES2203692T3 (en) | USE OF (R) -PENCICLOVIR TRYPHOSPHATE FOR THE MANUFACTURE OF A MEDICINAL PRODUCT FOR THE TREATMENT OF VIRIC DISEASES. | |
| CN116407640A (en) | Antitumor pharmaceutical composition comprising Azvudine and a chemotherapeutic agent | |
| CN1131040C (en) | Application of double-stranded ribonucleic acid in preparing medicine for treating human coxsackie virus infection | |
| RU2007136996A (en) | APPLICATION OF THIOPHOSPHONIC ACID AND NRTIs FOR THE TREATMENT OF VIRAL INFECTIONS | |
| MXPA98005083A (en) | Method of treatment of disorders characterizopopor the over-expression of citidina deaminasa or deoxicitidina deamin | |
| JP2002104972A (en) | Topoisomerase inhibitor |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |