CN111569075A - Application of nucleoside antiviral drug in preparation of drug for treating infarct disease - Google Patents
Application of nucleoside antiviral drug in preparation of drug for treating infarct disease Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- 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
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- 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
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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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Abstract
The invention discloses an application of nucleoside antiviral drugs in preparation of drugs for treating infarct diseases, relates to the technical field of medicines, and provides a new direction for researching and developing drugs for treating the infarct diseases. The nucleoside antiviral drug provided by the invention can be used for preparing the drug for treating the infarct disease, and not only can reduce the severity and frequency of herpes simplex virus infection, but also has the obvious activity of improving the infarct complication. Research shows that in infarct diseases, platelet adhesion, activation and aggregation play a key role in regulation, and nucleoside antiviral drugs, such as famciclovir, can inhibit platelet aggregation, GPIIb/IIIa activation, P-selectin expression and/or arteriovenous thrombosis and cerebral infarction formation, and simultaneously, the research does not influence the blood coagulation system, and provides a new idea for researching and developing drugs for treating infarct diseases.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to application of a nucleoside antiviral drug in preparing a drug for treating infarct diseases.
Background
Thrombosis plays a promoting role in the development and progression of infarct diseases such as unstable angina, myocardial infarction, transient ischemic attacks, atherosclerosis, and the like. In the process of thrombosis, platelet adhesion, activation and aggregation play a key regulatory role. Platelets will adhere to the damaged exposed collagen surface of the vascular endothelium, in which case they are rapidly activated by binding to thrombosis related substrates, thereby locally releasing or generating agonists, including Adenosine Diphosphate (ADP), Thromboxane (TX) a and thrombin, which respectively interact with corresponding receptors on the platelet surface, thereby promoting more platelet adhesion and aggregation. While platelet aggregation mainly involves the process of binding fibrinogen to exposed platelet membrane glycoprotein IIb/IIIa (GP IIb/IIIa) receptors on platelets, the formation of fibrin network further consolidates platelet aggregation, leading to platelet mutual adhesion, thrombosis and local blood flow stoppage.
With the continuous research and understanding of the pathogenesis of thrombus, various new antithrombotic drugs appear successively, such as Adenosine Diphosphate (ADP) receptor blockers, factor Xa (FXa) inhibitors, thrombin inhibitors, cyclooxygenase-1 inhibitors, GPIIb/IIIa receptor antagonists, etc. Among them, aspirin, clopidogrel, rivaroxaban, dabigatran etexilate, apixaban, and the like have been developed and marketed.
Herpes simplex viruses are classified into herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2), and have wide popularity in China and even all over the world, high infectivity and incurability. A retrospective cohort study of the population indicated that herpes virus infection was positively correlated with increased risk of cardiovascular disease. Cardiovascular diseases include hypertension, hyperlipidemia, atherosclerosis, myocardial infarction, coronary heart disease, acute ischemic stroke, etc. For the association of viral infections and cardiovascular disease, studies have shown that HSV-1 alters the phenotype of endothelial cells, allowing them to exert procoagulant activity, thereby promoting the adhesion of neutrophils and platelets to the endothelium. HSV infection of endothelial cells may also promote the assembly of prothrombinase, thereby producing thrombin more efficiently. Excessive thrombin generation leads to translocation of P-selectin, ultimately leading to increased risk of thrombosis.
It follows that the antiplatelet effect of antiviral drugs may slow the risk of formation of HSV-related infarct disease. Therefore, research on the application of antiviral drugs in the preparation of drugs for treating infarct diseases is urgently needed, so as to provide a new direction for the research and development of drugs for treating infarct diseases.
Disclosure of Invention
One of the purposes of the invention is to provide the application of nucleoside antiviral drugs in preparing drugs for treating infarct diseases, so as to provide a new direction for developing drugs for treating infarct diseases. The various technical effects that can be produced by the preferred technical solution of the present invention are described in detail below.
In order to achieve the purpose, the invention provides the following technical scheme:
the invention provides an application of nucleoside antiviral drugs in preparation of drugs for treating infarct diseases.
According to a preferred embodiment, the nucleoside antiviral agent is famciclovir.
According to a preferred embodiment, the drug for treating an infarct disease comprises an antiplatelet drug and/or an antithrombotic drug.
According to a preferred embodiment, the administration dosage of the nucleoside antiviral drug is 60 mg/kg-120 mg/kg.
According to a preferred embodiment, the infarct disease comprises one or more of unstable angina, myocardial infarction, transient ischemia and atherosclerosis.
According to a preferred embodiment, the nucleoside antiviral agents have an inhibitory effect on platelet activity.
According to a preferred embodiment, said inhibition of platelet activity is one or more of inhibition of platelet aggregation, inhibition of platelet GPIIb/IIIa activation, inhibition of platelet P-selectin expression.
According to a preferred embodiment, the nucleoside antiviral agents have an antithrombotic effect.
According to a preferred embodiment, the thrombus is one or more of an arterial thrombus, a venous thrombus and a cerebral infarction.
According to a preferred embodiment, the nucleoside antiviral agents have an effect on the prevention and treatment of cardiovascular diseases.
The application of the nucleoside antiviral drug in preparing the drug for treating the infarct disease at least has the following beneficial technical effects:
the nucleoside antiviral drug provided by the invention can be used for preparing the drug for treating the infarct disease, and not only can reduce the severity and frequency of herpes simplex virus infection, but also has the obvious activity of improving the infarct complication. Research shows that in infarct diseases, platelet adhesion, activation and aggregation play a key role in regulation, and nucleoside antiviral drugs, such as famciclovir, can inhibit platelet aggregation, GPIIb/IIIa activation, P-selectin expression and/or arteriovenous thrombosis and cerebral infarction formation, and simultaneously, the research does not influence the blood coagulation system, and provides a new idea for researching and developing drugs for treating infarct diseases.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts.
FIG. 1 is a graph of experimental results of the effect of famciclovir on platelet aggregation;
FIG. 2 is a graph of experimental results of the effect of famciclovir on GPIIb/IIIa activation;
FIG. 3 is a graph of experimental results of the effect of famciclovir on P-selectin expression;
FIG. 4 is a graph of the results of a first experiment demonstrating the effect of famciclovir on arteriovenous thrombosis;
FIG. 5 is a graph of the results of a second experiment demonstrating the effect of famciclovir on arteriovenous thrombosis;
FIG. 6 is a graph of the results of a third experiment demonstrating the effect of famciclovir on arteriovenous thrombosis;
fig. 7 is a graph of experimental results of the effect of famciclovir on cerebral infarction.
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 is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be derived by a person skilled in the art from the examples given herein without any inventive step, are within the scope of the present invention.
The application of the nucleoside antiviral agent in the present embodiment in the preparation of a drug for treating an infarct disease is described in detail below with reference to the accompanying drawings of the specification 1 to 7 and examples 1 to 3.
The embodiment provides application of nucleoside antiviral drugs in preparation of drugs for treating infarct diseases. Preferably, the nucleoside antiviral drug is famciclovir.
The incidence of the infarction complications of patients infected by herpes simplex virus is increased, and famciclovir, as a commonly used antiviral drug, not only can reduce the severity and frequency of herpes simplex virus infection, but also has significant activity of improving the infarction complications. A number of studies have shown that platelet adhesion, activation and aggregation play a key regulatory role in infarct disease. Famciclovir can inhibit platelet aggregation, GPIIb/IIIa activation, P-selectin expression and/or arteriovenous thrombus and cerebral infarction, does not affect the blood coagulation system, and provides a new idea for researching and developing medicaments for treating infarct diseases.
Preferably, the medicament for treating the infarct disease comprises an antiplatelet medicament and/or an antithrombotic medicament.
Preferably, the administration dosage of the nucleoside antiviral drug is 60 mg/kg-120 mg/kg.
Preferably, the infarct disease includes one or more of unstable angina, myocardial infarction, transient ischemia, and atherosclerosis.
Preferably, the nucleoside antiviral agent has the function of inhibiting platelet activity. More preferably, the platelet activity inhibition is one or more of platelet aggregation inhibition, platelet GPIIb/IIIa activation inhibition and platelet P-selectin expression inhibition.
Preferably, the nucleoside antiviral agent has an antithrombotic effect. More preferably, the thrombus is one or more of an arterial thrombus, a venous thrombus and a cerebral infarction.
Preferably, the nucleoside antiviral drugs have the effect of preventing and treating cardiovascular diseases.
Example 1
The effect of famciclovir on platelet aggregation, platelet GPIIb/IIIa activation, and P-selectin expression is described in this example with reference to FIGS. 1-3.
(1) The experimental method for studying the effect of famciclovir on platelet aggregation is as follows:
male C57BL/6 mice (25-30g) were randomized (N-6) into model control, model, famciclovir low (LFCV, 60mg/kg) and famciclovir high (HFCV, 120mg/kg) groups, administered 1 time daily for seven consecutive days. The model control group was given an equal volume of vehicle medium saline in the same manner. C57BL/6 mice were fasted overnight on the seventh day without water deprivation.
On the day of experiment, 3.5% sodium pentobarbital solution is injected into abdominal cavity to anesthetize the mouse, blood is taken through cardiac puncture, and is immediately mixed with 3.8% sodium citrate anticoagulant in a volume ratio of 9: 1, the mixed plasma sample is centrifuged for 10min at 100g to obtain supernatant, Platelet Rich Plasma (PRP) is obtained, the rest blood sample is centrifuged for 5min at 1000g to obtain supernatant, Platelet Poor Plasma (PPP) is obtained, and finally the PRP is diluted and adjusted by the PPP to ensure that the number of platelets is 2 × l06Platelets/. mu.L. The platelet aggregation degree was determined by means of LBY-NJ4 platelet aggregation apparatus, 20. mu.L of ADP was added to a final concentration of 20. mu.M by means of a microsyringe, and the platelet aggregation profile and the maximum aggregation degree within 5min were observed and recorded。
(2) The experimental method for studying the effect of famciclovir on platelet GPIIb/IIIa activation and P-selectin expression is as follows:
male C57BL/6 mice (25-30g) were randomized (N-6) into model control, model, famciclovir low (LFCV, 60mg/kg) and famciclovir high (HFCV, 120mg/kg) groups, administered 1 time daily for seven consecutive days. The model control group was given an equal volume of vehicle medium saline in the same manner. C57BL/6 mice were fasted overnight on the seventh day without water deprivation.
On the day of the experiment, mice were anesthetized by intraperitoneal injection of a 3.5% sodium pentobarbital solution, blood was taken by cardiac puncture, and immediately mixed with a 3.8% sodium citrate anticoagulant in a volume ratio of 9: 1. Centrifuging the plasma sample for 10min at 100g to obtain PRP, collecting PRP, centrifuging at 100g for 6 min, discarding red precipitate, and collecting supernatant. Centrifuging the collected PRP blood sample for 5min at 1000g, discarding the supernatant, taking the white precipitate as platelet, washing the white precipitate twice with a desktop liquid, and resuspending for later use. Platelet purity was detected and quantified using platelet-specific fluorescently labeled antibody (CD41 antibody). In each of the other groups except the model control group, platelet activator ADP (final concentration: 20. mu.M) was added and incubated at 37 ℃ for 30 min. After the incubation is finished, 20 mu LPAC-1 stain antibody or CD62P stain antibody (see the kit specification for details) is added, the incubation is carried out for 30min at 37 ℃ in the dark, then the fluorescence is detected by a flow cytometer, and the data is collected and collated.
The experimental results are as follows: FIGS. 1-3 show experimental results of the effect of famciclovir on platelet aggregation, GPIIb/IIIa activation, and P-selectin expression, respectively. In FIGS. 1 to 3, the values are expressed as the mean. + -. SED. n 8-10, p <0.05 vsscontrol, p # <0.05 vsModel. As can be seen from fig. 1: famciclovir can reduce ADP-induced elevation in platelet aggregation. As can be seen from fig. 2 and 3: famciclovir can inhibit GPIIb/IIIa activation and P-selectin expression.
Example 2
The present example describes the effect of famciclovir on arterial and venous thrombosis with reference to FIGS. 4-6.
(1) The experimental method for studying the effect of famciclovir on arterial thrombosis is as follows:
administration pretreatment: male C57BL/6 mice (25-30g) were randomly assigned (N ═ 6) to model control, model, famciclovir low dose (LFCV, 60mg/kg), and famciclovir high dose (HFCV, 120mg/kg), administered 1 time daily for seven consecutive days. The model control group was given an equal volume of vehicle medium saline in the same manner. C57BL/6 mice were fasted overnight on the seventh day without water deprivation.
On the eighth day, 1h after the last administration, C57BL/6 mice were intraperitoneally injected with 3.5% sodium pentobarbital solution, anesthetized, cut open the skin along the median line of the mouse neck with surgical scissors, then blunt-dissected the left common carotid artery of the mice to expose it, place a mini-Doppler blood flow probe on the carotid artery, and then soaked with 10 μ L15% FeCl3A strip of filter paper of the solution was wrapped around the isolated common carotid artery, and after 5min the strip was removed and the carotid artery was flushed with saline at 37 ℃ and recorded for 30 min. The vessel occlusion time is set to be no occlusion after stopping blood flow for 30 seconds or 30 minutes.
(2) The experimental method for studying the effect of famciclovir on venous thrombosis is as follows:
administration pretreatment: male C57BL/6 mice (25-30g) were randomly assigned (N ═ 6) to model control, model, famciclovir low dose (LFCV, 60mg/kg), and famciclovir high dose (HFCV, 120mg/kg), administered 1 time daily for seven consecutive days. The model control group was given an equal volume of vehicle medium saline in the same manner. C57BL/6 mice were fasted overnight on the seventh day without water deprivation.
Molding: on the eighth day, 1h after the last administration, C57BL/6 mice were injected intraperitoneally with 3.5% pentobarbital sodium solution. After anesthesia, the mouse is made to be in a supine position, a towel is laid, the mouse is disinfected and prepared with skin, an incision is longitudinally made in the middle of the lower abdomen by using a surgical instrument, the abdominal cavity is exposed, after the lower renal inferior vena cava of the mouse is separated, the lower vena cava is ligated below the left renal inferior vena cava by using a surgical ligature, after the ligation is completed, whether the abdominal cavity of the mouse has hemorrhage or not is checked, then an intestinal canal is brought back into the abdominal cavity, the abdomen is closed layer by layer, and the peritoneum is sutured. After the operation is finished, the warm lamp is used for keeping the mouse warm until the mouse is clear. C57BL/6 mice were operated 24h postoperatively, abdominated, and the inferior vena cava below the ligature was dissected, the vein was washed with Phosphate Buffered Saline (PBS), the thrombus was collected, and its weight and length were measured, and blood was taken to detect biochemical markers.
The experimental results are as follows: FIGS. 4-6 show graphs of the results of first to third experiments, respectively, showing the effect of famciclovir on arteriovenous thrombosis. In FIGS. 4-6, the values are expressed as means. + -. SED. n 8-10, p # <0.05 vsModel. As can be seen in fig. 4, famciclovir can reduce ferric chloride induced arterial thrombosis. As can be seen from fig. 5 and 6, famciclovir can reduce the weight and length of venous thrombosis induced by inferior vena cava ligation.
Therefore, famciclovir can inhibit venous thrombosis caused by inferior vena cava ligation, has obvious antithrombotic effect, and can also obviously prolong the occlusion time of arterial thrombosis.
Example 3
This example illustrates the effect of famciclovir on cerebral infarction in conjunction with fig. 7.
The experimental method for studying the influence of famciclovir on cerebral infarction is as follows:
administration pretreatment: male C57BL/6 mice (25-30g) were randomly assigned (N ═ 6) to model control, model, famciclovir low dose (LFCV, 60mg/kg), and famciclovir high dose (HFCV, 120mg/kg), administered 1 time daily for seven consecutive days. The model control group was given an equal volume of vehicle medium saline in the same manner. C57BL/6 mice were fasted overnight on the seventh day without water deprivation.
Molding: on the eighth day, 1h after the last administration, C57BL/6 mice were injected intraperitoneally with 3.5% pentobarbital sodium solution. After anaesthesia, the animals were fixed on the operating table in supine position, the neck hair was shaved off and the operating area was disinfected. A median incision was made in the neck, and the neck muscles were isolated bluntly to free the bilateral Common Carotid Artery (CCA) and the left External Carotid Artery (ECA). Separating, ligating and cutting off the left ECA branch, ligating and cutting off the ECA with 5-0 nylon thread at the position 7-10 mm away from the distal end of the carotid bifurcation, and keeping the distal thread head to pull down to enable the ECA to be close to a straight line with an Internal Carotid Artery (ICA). The left ICA was isolated, the vagus nerve was gently dissected until ICA was visible at the inferior border of the tympanic bone, but only the extracranial branch pterygopalatine artery was visible, and the artery was ligated, making ICA the only extracranial remaining artery for CCA. The ICA and CCA were closed by micro-motion clip removal, a loose knot was tied with a nylon wire at the beginning of the ECA, a small opening was cut in the ECA about 3mm from the carotid bifurcation, from which the tether was inserted into the lumen of the ECA and into the ICA, and the nylon wire at the beginning of the ECA was tied tight to prevent the tether from moving and bleeding. The arteriolar clamp on the ICA was removed and the tether continued to be inserted to the black marker point, at which time the tip of the tether was 2-3mm from the start of the MCA. Remove the arteriolar clamp on the right CCA 5min later, ligate the proximal ECA; after 15min, the arteriolar clamp on the left CCA was removed, the skin was sutured and raised in a single cage.
The experimental results are as follows: figure 7 shows a graph of experimental results of the effect of famciclovir on cerebral infarction. In fig. 7, the values are expressed as means ± SED. n 8-10, p # <0.05 vsModel. As can be seen in fig. 7, famciclovir reduced infarct size in brain infarction.
The above description is only for the specific embodiments of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can easily conceive of the changes or substitutions within the technical scope of the present invention, and all the changes or substitutions should be covered within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the appended claims.
Claims (10)
1. An application of nucleoside antiviral agent in preparing medicine for treating infarct disease is disclosed.
2. The use of a nucleoside antiviral agent according to claim 1, in the preparation of a medicament for the treatment of an infarct disease, wherein said nucleoside antiviral agent is famciclovir.
3. Use of a nucleoside antiviral agent according to claim 1 or 2, for the preparation of a medicament for the treatment of an infarct disease, wherein the medicament for the treatment of an infarct disease comprises an antiplatelet agent and/or an antithrombotic agent.
4. The use of a nucleoside antiviral agent as in claim 3, wherein the dose of said nucleoside antiviral agent is 60mg/kg to 120 mg/kg.
5. Use of a nucleoside antiviral agent according to claim 3, in the manufacture of a medicament for the treatment of an infarct disease, wherein the infarct disease comprises one or more of unstable angina, myocardial infarction, transient ischemia and atherosclerosis.
6. The use of a nucleoside antiviral agent according to claim 3, in the preparation of a medicament for the treatment of infarct disease, wherein said nucleoside antiviral agent has an effect of inhibiting platelet activity.
7. The use of a nucleoside antiviral agent according to claim 6, in the preparation of a medicament for the treatment of infarct disease, wherein the platelet inhibiting activity is one or more of platelet aggregation inhibition, platelet GPIIb/IIIa activation inhibition, and platelet P-selectin expression inhibition.
8. The use of a nucleoside antiviral agent according to claim 3, in the preparation of a medicament for the treatment of infarct disease, wherein said nucleoside antiviral agent has an antithrombotic effect.
9. The use of a nucleoside antiviral agent according to claim 8, in the preparation of a medicament for the treatment of an infarct disease, wherein the thrombus is one or more of an arterial thrombus, a venous thrombus and a cerebral infarction.
10. The use of a nucleoside antiviral agent according to claim 3, in the preparation of a medicament for the treatment of infarct disease, wherein said nucleoside antiviral agent has an effect on the prevention and treatment of cardiovascular disease.
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CN112168829A (en) * | 2020-09-24 | 2021-01-05 | 华南理工大学 | Application of antiviral drug in preparation of drug for treating myelodysplastic syndrome and prepared myelodysplastic syndrome drug |
CN113116900A (en) * | 2021-04-14 | 2021-07-16 | 兰州大学 | Application of nucleoside analogs in preparation of drugs for preventing and/or treating cerebrovascular diseases |
WO2022217481A1 (en) * | 2021-04-14 | 2022-10-20 | 兰州大学 | Application of nucleoside analogues in preparation of drugs for preventing and/or treating cerebrovascular diseases |
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US20140271923A1 (en) * | 2013-03-14 | 2014-09-18 | Christopher Brian Reid | Compositions & formulations for preventing and treating chronic diseases that cluster in patients such as cardiovascular disease, diabetes, obesity, polycystic ovary syndrome, hyperlipidemia and hypertension, as well as for preventing and treating other diseases and conditions |
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CN101765424A (en) * | 2007-05-30 | 2010-06-30 | 伯明翰大学 | Use of antivirals in the treatment of medical disorders |
US20140271923A1 (en) * | 2013-03-14 | 2014-09-18 | Christopher Brian Reid | Compositions & formulations for preventing and treating chronic diseases that cluster in patients such as cardiovascular disease, diabetes, obesity, polycystic ovary syndrome, hyperlipidemia and hypertension, as well as for preventing and treating other diseases and conditions |
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CN113116900A (en) * | 2021-04-14 | 2021-07-16 | 兰州大学 | Application of nucleoside analogs in preparation of drugs for preventing and/or treating cerebrovascular diseases |
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