CN111569075A - Application of a nucleoside antiviral drug in the preparation of a drug for the treatment of infarct disease - Google Patents

Abstract

The invention discloses the application of a nucleoside antiviral drug in the preparation of a drug for treating infarct diseases, relates to the field of medical technology, and provides a new direction for developing drugs for treating infarct diseases. The application of the nucleoside antiviral drug provided in the present invention in the preparation of a drug for treating infarct disease, the nucleoside antiviral drug can not only reduce the severity and frequency of herpes simplex virus infection, but also have significant activity of improving infarct complications . Studies have shown that platelet adhesion, activation and aggregation play a key regulatory role in infarct disease, and nucleoside antiviral drugs, such as famciclovir, can inhibit platelet aggregation, inhibit GPIIb/IIIa activation, inhibit P-selectin expression and / or inhibiting the formation of arterial and venous thrombosis and cerebral infarction without affecting the coagulation system, which provides a new idea for the development of drugs for the treatment of infarct diseases.

Description

Application of a nucleoside antiviral drug in the preparation of a drug for the treatment of infarct disease

technical field

The invention relates to the technical field of medicine, in particular to the application of a nucleoside antiviral drug in the preparation of a drug for treating infarct diseases.

Background technique

Thrombosis plays a promoting role in the occurrence and development of infarct diseases such as unstable angina, myocardial infarction, transient ischemic attack and atherosclerosis. In the process of thrombosis, platelet adhesion, activation and aggregation play key regulatory roles. Platelets will adhere to the exposed collagen surface of the damaged vascular endothelium, in which case platelets are rapidly activated by binding to thrombosis-related substrates to locally release or produce agonists, including adenosine diphosphate (ADP), Thromboxane (TX)A and thrombin, these agonists interact with corresponding receptors on the platelet surface, respectively, thereby promoting more platelet adhesion and aggregation. Platelet aggregation mainly involves the process of fibrinogen binding to the exposed platelet membrane glycoprotein IIb/IIIa (GP IIb/IIIa) receptors on platelets. The formation of fibrin network further consolidates platelet aggregation, resulting in platelet adhesion and thrombosis. Local blood flow stops.

With the continuous research and understanding of the pathogenesis of thrombosis, various new antithrombotic drugs have appeared one after another, such as adenosine diphosphate (ADP) receptor blockers, factor Xa (FXa) inhibitors, thrombin inhibitors, Oxygenase-1 inhibitors, GPIIb/IIIa receptor antagonists, etc. Among them, aspirin, clopidogrel, rivaroxaban, dabigatran etexilate and apixaban have been developed and marketed.

Herpes simplex virus is divided into herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2). Population retrospective cohort studies have shown that herpesvirus infection is positively associated with an increased risk of cardiovascular disease. Cardiovascular diseases include hypertension, hyperlipidemia, atherosclerosis, myocardial infarction, coronary heart disease and acute ischemic stroke. In relation to viral infection and cardiovascular disease, studies have shown that HSV-1 alters the phenotype of endothelial cells to exert procoagulant activity that promotes neutrophil and platelet adhesion to the endothelium. HSV infection of endothelial cells also promotes the assembly of prothrombinase for more efficient thrombin production. Excessive thrombin production leads to the translocation of P-selectin, which ultimately leads to an increased risk of thrombosis.

CONCLUSIONS: The antiplatelet effect of antiviral drugs may reduce the risk of developing HSV-related infarct disease. Therefore, it is urgent to study the application of antiviral drugs in the preparation of drugs for the treatment of infarct diseases, so as to provide a new direction for the development of drugs for the treatment of infarct diseases.

SUMMARY OF THE INVENTION

One of the purposes of the present invention is to propose the application of a nucleoside antiviral drug in the preparation of a drug for the treatment of infarct diseases, so as to provide a new direction for the research and development of drugs for the treatment of infarct diseases. The technical effects that can be produced by the preferred technical solutions of the present invention are described in detail below.

For achieving the above object, the invention provides the following technical solutions:

The invention provides the application of a nucleoside antiviral drug in the preparation of a drug for treating infarct diseases.

According to a preferred embodiment, the nucleoside antiviral drug is famciclovir.

According to a preferred embodiment, the drugs for treating infarct diseases include antiplatelet drugs and/or antithrombotic drugs.

According to a preferred embodiment, the dosage of the nucleoside antiviral drug is 60 mg/kg to 120 mg/kg.

According to a preferred embodiment, the infarct disease includes one or more of unstable angina, myocardial infarction, transient ischemia and atherosclerosis.

According to a preferred embodiment, the nucleoside antiviral drug has the effect of inhibiting platelet activity.

According to a preferred embodiment, the inhibition of platelet activity is one or more of inhibition of platelet aggregation, inhibition of platelet GPIIb/IIIa activation, and inhibition of platelet P-selectin expression.

According to a preferred embodiment, the nucleoside antiviral drug has an antithrombotic effect.

According to a preferred embodiment, the thrombus is one or more of arterial thrombus, venous thrombus and cerebral infarction.

According to a preferred embodiment, the nucleoside antiviral drug has the effect of preventing and treating cardiovascular disease.

The application of the nucleoside antiviral drug provided by the present invention in the preparation of a drug for treating infarct disease has at least the following beneficial technical effects:

The application of the nucleoside antiviral drug provided in the present invention in the preparation of a drug for treating infarct disease, the nucleoside antiviral drug can not only reduce the severity and frequency of herpes simplex virus infection, but also have significant activity of improving infarct complications . Studies have shown that platelet adhesion, activation and aggregation play a key regulatory role in infarct disease, and nucleoside antiviral drugs, such as famciclovir, can inhibit platelet aggregation, inhibit GPIIb/IIIa activation, inhibit P-selectin expression and / or inhibiting the formation of arterial and venous thrombosis and cerebral infarction without affecting the coagulation system, which provides a new idea for the development of drugs for the treatment of infarct diseases.

Description of drawings

In order to explain the embodiments of the present invention or the technical solutions in the prior art more clearly, the following briefly introduces the accompanying drawings that need to be used in the description of the embodiments or the prior art. Obviously, the accompanying drawings in the following description are only These are some embodiments of the present invention. For those of ordinary skill in the art, other drawings can also be obtained according to these drawings without creative efforts.

Fig. 1 is the experimental result graph of the effect of famciclovir on platelet aggregation;

Figure 2 is a graph of the experimental results of the effect of famciclovir on the activation of GPIIb/IIIa;

Figure 3 is a graph showing the experimental results of the effect of famciclovir on the expression of P-selectin;

Fig. 4 is the first experimental result graph of the effect of famciclovir on arterial and venous thrombosis;

Fig. 5 is the second experiment result graph of the effect of famciclovir on arteriovenous thrombosis;

Fig. 6 is the third experiment result diagram of the effect of famciclovir on arteriovenous thrombosis;

Figure 7 is a graph showing the experimental results of the effect of famciclovir on cerebral infarction.

Detailed ways

In order to make the objectives, technical solutions and advantages of the present invention clearer, the technical solutions of the present invention will be described in detail below. Obviously, the described embodiments are only some, but not all, embodiments of the present invention. Based on the embodiments of the present invention, all other implementations obtained by those of ordinary skill in the art without creative work fall within the protection scope of the present invention.

The application of the nucleoside antiviral drug of this embodiment in the preparation of a drug for treating infarct diseases will be described in detail below with reference to Figures 1 to 7 and Examples 1 to 3 of the description.

This embodiment provides the application of a nucleoside antiviral drug in the preparation of a drug for treating infarct diseases. Preferably, the nucleoside antiviral drug is famciclovir.

Patients with herpes simplex virus infection have an increased incidence of infarct complications, and famciclovir, a commonly used antiviral drug, not only reduces the severity and frequency of herpes simplex virus infection, but also has significant activity in improving infarct complications. Numerous studies have shown that platelet adhesion, activation and aggregation play a key regulatory role in infarct disease. Famciclovir can inhibit platelet aggregation, inhibit the activation of GPIIb/IIIa, inhibit the expression of P-selectin and/or inhibit the formation of arterial and venous thrombosis and cerebral infarction without affecting the coagulation system, which provides a new idea for the development of drugs for the treatment of infarct diseases.

Preferably, the drugs for treating infarct diseases include antiplatelet drugs and/or antithrombotic drugs.

Preferably, the dosage of the nucleoside antiviral drug is 60 mg/kg to 120 mg/kg.

Preferably, the infarct disease includes one or more of unstable angina, myocardial infarction, transient ischemia and atherosclerosis.

Preferably, the nucleoside antiviral drug has the effect of inhibiting platelet activity. More preferably, the inhibition of platelet activity is one or more of inhibition of platelet aggregation, inhibition of platelet GPIIb/IIIa activation, and inhibition of platelet P-selectin expression.

Preferably, the nucleoside antiviral drug has an antithrombotic effect. More preferably, the thrombus is one or more of arterial thrombus, venous thrombus and cerebral infarction.

Preferably, the nucleoside antiviral drug has the effect of preventing and treating cardiovascular disease.

Example 1

In this example, the effects of famciclovir on platelet aggregation, platelet GPIIb/IIIa activation, and P-selectin expression are described with reference to Figures 1 to 3 .

(1) The experimental method to study the effect of famciclovir on platelet aggregation is as follows:

Male C57BL/6 mice (25-30g) were randomly divided into groups (N=6), model control group, model group, famciclovir low-dose group (LFCV, 60mg/kg), famciclovir high-dose group (HFCV, 120mg/kg) kg), administered once a day for seven consecutive days. In the same way, the model control group was given an equal volume of normal saline as a vehicle. On the seventh night, C57BL/6 mice were fasted without food and water.

On the day of the experiment, mice were anesthetized by intraperitoneal injection of 3.5% sodium pentobarbital solution, blood was collected by cardiac puncture, and immediately mixed with 3.8% sodium citrate anticoagulant in a volume ratio of 9:1. The mixed plasma samples were centrifuged at 100 g for 10 min to obtain the supernatant to obtain platelet-rich plasma (PRP). The remaining blood samples were centrifuged at 1000 g for 5 min to obtain the supernatant to obtain platelet-poor plasma (PPP). Finally, the PRP was diluted with PPP to adjust the number of platelets to 2×10 ⁶ platelets/μL. LBY-NJ4 platelet aggregator was used to measure the degree of platelet aggregation, and 20 μL of ADP with a final concentration of 20 μM was added with a microsyringe to observe and record the platelet aggregation curve and the maximum degree of aggregation within 5 min.

(2) The experimental method to study the effect of famciclovir on platelet GPIIb/IIIa activation and P-selectin expression is as follows:

Male C57BL/6 mice (25-30g) were randomly divided into groups (N=6), model control group, model group, famciclovir low-dose group (LFCV, 60mg/kg), famciclovir high-dose group (HFCV, 120mg/kg) kg), administered once a day for seven consecutive days. In the same way, the model control group was given an equal volume of normal saline as a vehicle. On the seventh night, C57BL/6 mice were fasted without food and water.

On the day of the experiment, mice were anesthetized by intraperitoneal injection of 3.5% sodium pentobarbital solution, blood was collected by cardiac puncture, and immediately mixed with 3.8% sodium citrate anticoagulant in a volume ratio of 9:1. The plasma samples were centrifuged at 100 g for 10 min to take the supernatant to obtain PRP, the PRP was collected and centrifuged at 100 g for 6 min, the red precipitate was discarded, and the supernatant was taken. The collected PRP blood samples were centrifuged at 1000g for 5 min, the supernatant was discarded, the white precipitate was taken as platelets, and the white precipitate was washed twice with benchtop solution and resuspended for use. Platelet purity was detected and quantified with platelet-specific fluorescently labeled antibody (CD41 antibody). Except for the model control group, platelet activator ADP (final concentration 20 μM) was added to the other groups and incubated at 37°C for 30 min. After the incubation, add 20 μL of PAC-1 stain antibody or CD62P stain antibody (see the kit instructions for details), incubate at 37°C for 30 minutes in the dark, and then detect the fluorescence by flow cytometry to collect and organize the data.

Experimental results: Figures 1 to 3 show the experimental results of the effects of famciclovir on platelet aggregation, GPIIb/IIIa activation, and P-selectin expression, respectively. In Figs. 1 to 3, the numerical values are represented by the mean ± SED. n=8-10, p*<0.05vscontrol, p#<0.05vsModel. It can be seen from Figure 1 that famciclovir can reduce the increase in platelet aggregation induced by ADP. It can be seen from Figures 2 and 3 that famciclovir can inhibit the activation of GPIIb/IIIa and the expression of P-selectin.

Example 2

In this embodiment, the effects of famciclovir on arterial thrombosis and venous thrombosis are described with reference to FIGS. 4 to 6 .

(1) The experimental method to study the effect of famciclovir on arterial thrombosis is as follows:

Pretreatment of administration: Male C57BL/6 mice (25-30g) were randomly divided into groups (N=6), model control group, model group, famciclovir low-dose group (LFCV, 60 mg/kg), famciclovir high-dose group ( HFCV, 120 mg/kg), administered once a day for seven consecutive days. In the same way, the model control group was given an equal volume of normal saline as a vehicle. On the seventh night, C57BL/6 mice were fasted without food and water.

On the eighth day, 1 hour after the last administration, C57BL/6 mice were intraperitoneally injected with 3.5% sodium pentobarbital solution, and after anesthesia, the skin was incised along the midline of the mouse neck with surgical scissors, and then the left side of the mouse was bluntly separated. The common carotid artery was exposed, a miniature Doppler flow probe was placed on the carotid artery, and a filter paper strip dipped in 10 μL of 15% FeCl ₃ solution was used to wrap the isolated common carotid artery, and the filter was removed after 5 minutes. For paper strips, the carotid artery was flushed with saline at 37°C and recorded for 30 min. Vessel occlusion time was set as no occlusion after 30 seconds of cessation of blood flow or 30 minutes.

(2) The experimental method to study the effect of famciclovir on venous thrombosis is as follows:

Pretreatment of administration: Male C57BL/6 mice (25-30g) were randomly divided into groups (N=6), model control group, model group, famciclovir low-dose group (LFCV, 60 mg/kg), famciclovir high-dose group ( HFCV, 120 mg/kg), administered once a day for seven consecutive days. In the same way, the model control group was given an equal volume of normal saline as a vehicle. On the seventh night, C57BL/6 mice were fasted without food and water.

Modeling: On the eighth day, 1 hour after the last administration, C57BL/6 mice were injected with 3.5% sodium pentobarbital solution by intraperitoneal injection. After anesthesia, the mice were placed in a supine position, covered with towels, sterilized, and skin prepared. A longitudinal incision was made in the middle of the lower abdomen with surgical instruments to expose the abdominal cavity. The inferior vena cava was ligated with surgical ligatures. After the ligation was completed, the abdominal cavity of the mice was checked for hemorrhage, and then the intestinal tube was put back into the abdominal cavity, the abdomen was closed layer by layer, and the peritoneum was sutured. Mice were kept warm with a warm lamp until awake after surgery. 24 hours after the operation of C57BL/6 mice, the laparotomy was performed, and the inferior vena cava below the ligature was cut, the vein was flushed with phosphate buffered saline (PBS), the thrombus was collected, and its weight and length were measured, and blood was taken for biochemical testing index.

Experimental results: Figures 4 to 6 respectively show the first to third experimental results of the effect of famciclovir on arteriovenous thrombosis. In Figs. 4 to 6, the numerical values are represented by the mean ± SED. n=8-10, p#<0.05 vs Model. It can be seen from Figure 4 that famciclovir can reduce ferric chloride-induced arterial thrombosis. It can be seen from Figures 5 and 6 that famciclovir can reduce the weight and length of venous thrombosis induced by inferior vena cava ligation.

It can be seen that famciclovir can inhibit venous thrombosis caused by inferior vena cava ligation, and has obvious antithrombotic effect, and famciclovir can also significantly prolong the occlusion time of arterial thrombosis.

Example 3

In this example, the effect of famciclovir on cerebral infarction is described with reference to FIG. 7 .

The experimental method to study the effect of famciclovir on cerebral infarction is as follows:

Pretreatment of administration: Male C57BL/6 mice (25-30g) were randomly divided into groups (N=6), model control group, model group, famciclovir low-dose group (LFCV, 60 mg/kg), famciclovir high-dose group ( HFCV, 120 mg/kg), administered once a day for seven consecutive days. In the same way, the model control group was given an equal volume of normal saline as a vehicle. On the seventh night, C57BL/6 mice were fasted without food and water.

Modeling: On the eighth day, 1 hour after the last administration, C57BL/6 mice were injected with 3.5% sodium pentobarbital solution by intraperitoneal injection. After anesthesia, the animals were fixed on the operating table in a supine position, the neck hair was shaved, and the surgical area was sterilized. A midline incision was made in the neck, the neck muscles were bluntly separated, and the bilateral common carotid arteries (CCA) and the left external carotid arteries (ECA) were dissociated. Separate, ligate and cut off the left ECA branch, ligate and cut off the ECA with 5-0 nylon thread at the distal end of the carotid artery bifurcation 7-10mm, leave the distal end of the thread and pull it down to make it connect with the internal carotid artery (ICA). ) close to a straight line. The left ICA was separated, and the vagus nerve was gently dissected, and the only extracranial branch of the pterygopalatine artery of the ICA was seen to the lower edge of the tympanic bone. The ICA and CCA were clamped with a micro-movement clip, a nylon thread was used to tie a loose knot at the beginning of the ECA, and a small incision was cut about 3 mm from the carotid artery bifurcation on the ECA. To enter the ICA, tie the nylon thread at the beginning of the ECA tightly to prevent thread movement and bleeding. Remove the capillary clip on the ICA, and continue to insert the tethering line to the black mark. At this time, the front end of the tethering line is 2-3mm away from the start of the MCA. After 5 min, the capillary clip on the right CCA was removed, and the proximal end of the ECA was ligated; 15 min later, the capillary clip on the left CCA was removed, the skin was sutured, and the animals were reared in a single cage.

Experimental results: Figure 7 shows the experimental results of the effect of famciclovir on cerebral infarction. In Fig. 7, values are expressed as mean ± SED. n=8-10, p#<0.05 vs Model. It can be seen from Figure 7 that famciclovir can reduce the infarct size of cerebral infarction.

The above are only specific embodiments of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art can easily think of changes or substitutions within the technical scope disclosed by the present invention. should be included within the protection scope of the present invention. Therefore, the protection scope of the present invention should be based on the protection scope of the 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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