Application of nucleoside analogue in preparation of anti-aging drugs or health care products

Abstract

The invention relates to the technical field of medicines, in particular to application of nucleoside analogues in preparation of anti-aging medicines or health-care products. The nucleoside analogues are specifically acyclovir and telbivudine, aging is specifically adriamycin-induced aging, acyclovir and telbivudine can enhance the balance capacity and limb muscle strength of a mouse, meanwhile, the number of survival days of animals can be remarkably prolonged, and the nucleoside analogues have an anti-aging effect and are expected to be clinically applied.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to the application of nucleoside analogs in the preparation of anti-aging drugs or health products. Background Art

[0002] Aging refers to the natural phenomenon that after an organism matures under normal conditions, as the age increases, its own tissue structure gradually undergoes degenerative changes, the function of the body's organs decreases, the ability of the internal environment to stabilize itself weakens, the resistance to internal and external environmental damage factors decreases, and it tends to die. With the increase of age, the incidence of aging-related diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), hypertension, gout, diabetes and other diseases will also increase, causing great harm to the body and psychology of the elderly. With the aging of the population increasing year by year, the pressure of elderly care is getting greater and greater. With the improvement of people's quality of life, how to delay aging has become a technical problem that people urgently need to solve. In response to the above technical problems, technicians in this field have done a lot of research, and the research found that metformin, rapamycin, β-nicotinamide mononucleotide and dasatinib have anti-aging effects, but the current anti-aging effects can only act on the skin surface, which can significantly delay skin aging, and the effects on the body and life extension are unknown.

[0003] Acyclovir is a synthetic purine nucleoside analog, mainly used as a first-line clinical drug for the treatment of herpes zoster virus infection, genital infection, cold sores and chickenpox. Telbivudine is a nucleoside analog antiviral drug that can prevent viral replication. At the same time, Telbivudine also has good safety. It is a pregnancy class B drug approved by the US FDA and is clinically used to treat adult patients with chronic hepatitis B. Patent CN116510017A discloses the use of Telbivudine in the treatment of chronic hepatitis B, liver fibrosis, and liver cancer; Patent CN116754538A discloses the use of acyclovir for topical treatment of chickenpox and herpes zoster skin diseases, and Patent CN116440138A discloses the use of acyclovir in the preparation of tumor immunotherapy drugs. However, there is currently no report on the application of the analogs Telbivudine and acyclovir to anti-aging, and there is no literature suggesting that technicians in the field prove that Telbivudine has anti-aging effects. Summary of the invention

[0004] The primary purpose of the present invention is to provide the use of nucleoside analogs and pharmaceutically acceptable salts thereof in the preparation of anti-aging drugs.

[0005] Preferably, the nucleoside analogue is acyclovir and / or telbivudine.

[0006] The second object of the present invention is to provide the use of nucleoside analogs and pharmaceutically acceptable salts thereof in the preparation of anti-aging health products.

[0007] Preferably, the nucleoside analogue is acyclovir and / or telbivudine.

[0008] Preferably, the nucleoside analog is added to a pharmaceutically acceptable carrier and / or excipient, as well as other drugs and / or health products, to prepare any pharmaceutically acceptable dosage form.

[0009] Preferably, the dosage form includes any one of tablets, sprays, granules, capsules, oral solutions and injections.

[0010] The beneficial effects of the present invention are as follows: the present invention provides a new use of nucleoside analogs in the preparation of anti-aging drugs, the nucleoside analogs are specifically acyclovir and telbivudine, the aging is specifically an aging model induced by doxorubicin, acyclovir and telbivudine can enhance the balance ability and limb muscle strength of mice, and can significantly prolong the survival days of animals, have anti-aging effects, and are expected to be used clinically. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Figure 1 Schematic diagram of drug administration and dosage for mice

[0012] Figure 2 Figure 3. Body weight changes of mice after administration of telbivudine;

[0013] Figure 3 Survival curve of mice after telbivudine administration;

[0014] Figure 4 Statistics of the rotarod fatigue test in mice after telbivudine administration;

[0015] Figure 5 Statistics of the mouse net-grabbing experiment after telbivudine administration;

[0016] Note: Compared with the blank control group, **p<0.01, the "Model" group was compared with the "Control" group; **p<0.01, the "Model" group was compared with the "Model+T1" group; **p<0.01, the "Model" group was compared with the "Model+T2" group;

[0017] Figure 6 Figure 3. Changes in body weight of mice after administration of acyclovir;

[0018] Figure 7 Survival curve of mice after acyclovir administration;

[0019] Figure 8 Statistics of the rotarod fatigue test in mice after acyclovir administration;

[0020] Fig. 9 Statistics of the mouse net-grabbing experiment after acyclovir administration;

[0021] Note: Compared with the blank control group, **p<0.01, the "Model" group was compared with the "Control" group; *p<0.05, the "Model" group was compared with the "Model+A1" group; **p<0.01, the "Model" group was compared with the "Model+A2" group; DETAILED DESCRIPTION

[0022] The following will be combined with the drawings in the examples of the present invention to clearly and completely describe the technical solutions in the examples of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments, and at the same time protect the therapeutic effects of telbivudine and acyclovir in all aging and aging-related diseases, including different dosage forms, dosages, etc. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative labor are within the scope of protection of the present invention.

[0023] It should be understood that the above brief description and the following detailed description are exemplary and are only used for explanation, and do not limit the subject matter of the invention herein. In this application, it must be noted that unless otherwise clearly stated in the text, the singular forms used in this specification and claims include the plural forms of the referred things. It should also be noted that unless otherwise stated, the use of "or" and "or" means "and / or". In addition, the use of the term "including" and other forms, such as "including", "containing" and "containing" are not restrictive.

[0024] The telbivudine and acyclovir used are in the form of pharmaceutically acceptable salts, solvates such as hydrates, lipids, or prodrugs.

[0025] Balance ability evaluation: During the aging process, balance ability will gradually decline. In order to evaluate the balance ability of mice and predict the life span of mice, each group of experimental mice was trained 3 times before the formal experiment. At the beginning of the formal experiment, the mice were placed on the rotating rod of the mouse rotating rod fatigue instrument (purchased from Shanghai Xinruan Information Technology Co., Ltd.), and the software was used to set the speeds of each level as follows: blank speed: 5 laps / min, initial speed: 10 laps / min, first speed: 20 laps / min, second speed: 30 laps / min, and then the time the mice persisted on the rotating wooden rod was recorded.

[0026] Muscle strength evaluation: During the aging process, the strength of the animal's limbs will weaken. In order to evaluate the limb strength of mice, a grid experiment was used to evaluate the strength of mice. The grid device is composed of a 50×50cm grid with a grid opening of 1×1cm. The grid is 20 cm above the ground to prevent the mouse from jumping out of the grid. At the beginning of the experiment, the mouse is placed in the center of the grid. When the mouse grabs the grid with all four paws, the grid is then inverted and the time the mouse persists on the grid is recorded.

[0027] Example 1: Study on the anti-aging effect of telbivudine

[0028] 1. Experimental Animals

[0029] Male Kunming mice aged 6-8 weeks were selected, with a body weight of 25±2g. They were provided by the Lanzhou Veterinary Research Institute of the Chinese Academy of Agricultural Sciences. No drugs were used before the experiment. The experimental animals were acclimatized for one week in an environment with a temperature of 24-26°C and a 12h / 12h day-night cycle. The animals were given diet and free access to water, and then divided into groups for the experiment.

[0030] 2. Drugs and reagents

[0031] Doxorubicin hydrochloride was purchased from Shanghai Aladdin Biosynthesis Technology Co., Ltd., batch number: S17092, molecular weight: 579.5;

[0032] Telbivudine tablets were purchased from Pfizer Pharmaceuticals Co., Ltd., batch number: H20070028;

[0033] 3. Experimental groups and intraperitoneal injection dose

[0034] Male 6-8 week old Kunming mice were randomly divided into 4 groups, 3 Kunming mice in each group, and the grouping and drug dosage were as follows:

[0035] “Control” group: blank control group, intraperitoneally injected with an equal volume of normal saline;

[0036] “Model” group: Model group, intraperitoneal injection of an equal volume of 3 mg / kg doxorubicin hydrochloride;

[0037] "Model+T1" group: drug administration group, intraperitoneal injection of an equal volume of 3 mg / kg doxorubicin hydrochloride and an equal volume of 5 mg / kg telbivudine;

[0038] "Model+T2" group: drug administration group, intraperitoneal injection of an equal volume of 3 mg / kg doxorubicin hydrochloride and an equal volume of 10 mg / kg telbivudine;

[0039] The drug administration time was 3 days after adaptive feeding. All Kunming mice were administered the drug 24 hours before modeling and again 24 hours after modeling.

[0040] 4. Establishment of Aging Model

[0041] After 3 days of adaptive feeding, the mice were weighed and intraperitoneally injected with 3 mg / kg of doxorubicin hydrochloride (dissolved in saline) at 0.1 mL / 10 g. Doxorubicin hydrochloride was intraperitoneally injected twice a week (with an interval of 1 day). Figure 1 shown.

[0042] After each administration of doxorubicin hydrochloride, relevant indicators were tested, including the mouse rotating wooden rod fatigue test to evaluate the mouse balance ability and the net grabbing test to evaluate the mouse limb muscle strength. The administration method of the "Control" group was the same as that of the modeling group.

[0043] 5. Experimental Methods

[0044] (1) Daily weight changes of mice

[0045] After one week of adaptive feeding of the purchased mice, the aging model was established after continuous intraperitoneal injection of telbivudine for 5 days, and the weight changes of the mice were detected daily.

[0046] (2) Number of days mice survived

[0047] After one week of adaptive feeding, the purchased mice were intraperitoneally injected with telbivudine for 5 consecutive days, and then intraperitoneally injected with doxorubicin hydrochloride to establish a mouse aging model.

[0048] (3) Balance ability of mice

[0049] The purchased mice were adaptively fed for one week and given telbivudine intraperitoneally for 5 consecutive days. Then, doxorubicin hydrochloride was intraperitoneally injected once. The mice were subjected to a rotating wooden rod fatigue test. The time each group of mice could persist on the rotating wooden rod was recorded to evaluate the mice's balance ability.

[0050] (4) Mouse muscle strength

[0051] After one week of adaptive feeding, the purchased mice were given telbivudine intraperitoneally for 5 consecutive days, followed by a single intraperitoneal injection of doxorubicin hydrochloride. On the second day, a net-grabbing experiment was conducted on the mice. The length of time each group of mice spent grasping the net was recorded to evaluate the muscle strength of the mice's limbs and draw a statistical graph.

[0052] 6. Experimental Results

[0053] (1) Daily weight changes of mice

[0054] The weight changes of mice were detected daily. Figure 2 As shown, compared with the blank control group, the body weight of mice in the model group decreased significantly, indicating that the model was successfully established; the body weight of the groups using different doses of telbivudine increased significantly compared with the model group, but there was no significant change compared with the blank control group.

[0055] (2) Number of days mice survived

[0056] The survival curve of mice is as follows Figure 3 The movement speed and fur color of mice were observed every day. Compared with the blank control group, the mice in the model group had slow movement, dark fur, and significantly shortened lifespan. The lifespan of mice in the drug-treated group was significantly prolonged compared with the model group, and it was dose-dependent and statistically significant.

[0057] (3) Balance ability of mice

[0058] The time for the mouse to rotate the wooden stick Figure 4 As shown, compared with the blank control group, the rotating wooden rod time of the mice in the model group was significantly shortened; compared with the model group, the rotating wooden rod time of the mice in the drug-treated group was significantly prolonged, which was statistically significant.

[0059] (4) Mouse muscle strength

[0060] The time it takes for mice to catch the net is Figure 5 As shown, compared with the blank control group, the net-grasping time of mice in the model group was significantly decreased, indicating that the model was successfully established; compared with the model group, the net-grasping time of mice in the drug-treated group was significantly prolonged, which was statistically significant.

[0061] Example 2: Study on the anti-aging effect of acyclovir

[0062] 1. Experimental Animals

[0063] Male Kunming mice aged 6-8 weeks were selected, with a body weight of 25±2g. They were provided by the Lanzhou Veterinary Research Institute of the Chinese Academy of Agricultural Sciences. No drugs were used before the experiment. The experimental animals were acclimatized for one week in an environment with a temperature of 24-26°C and a 12h / 12h day-night cycle. The animals were given diet and free access to water, and then divided into groups for the experiment.

[0064] 2. Drugs and reagents

[0065] Doxorubicin hydrochloride was purchased from Shanghai Aladdin Biosynthesis Technology Co., Ltd., batch number: S17092, molecular weight: 579.5;

[0066] Acyclovir was purchased from Shanghai MacLean Biochemical Technology Co., Ltd., batch number: C10465165, molecular weight: 225.20;

[0067] 3. Experimental groups and intraperitoneal injection dose

[0068] Male 6-8 week old Kunming mice were randomly divided into 4 groups, 3 Kunming mice in each group, and the grouping and drug dosage were as follows:

[0069] “Control” group: blank control group, intraperitoneally injected with an equal volume of normal saline;

[0070] “Model” group: Model group, intraperitoneal injection of an equal volume of 3 mg / kg doxorubicin hydrochloride;

[0071] "Model+A1" group: drug administration group, intraperitoneal injection of an equal volume of 3 mg / kg doxorubicin hydrochloride and an equal volume of 5 mg / kg acyclovir;

[0072] "Model+A2" group: drug administration group, intraperitoneal injection of an equal volume of 3 mg / kg doxorubicin hydrochloride and an equal volume of 10 mg / kg acyclovir;

[0073] The drug administration time was 3 days after adaptive feeding. All Kunming mice were administered the drug 24 hours before modeling and again 24 hours after modeling.

[0074] 4. Establishment of Aging Model

[0075] After the mice were adaptively fed for 3 days, they were weighed and intraperitoneally injected with 3 mg / kg of doxorubicin hydrochloride (dissolved in physiological saline) at 0.1 mL / 10 g. Doxorubicin hydrochloride was intraperitoneally injected twice a week (with an interval of 1 day). The specific administration conditions were the same as those in Example 1.

[0076] The drug administration method of the “Control” group was the same as that of the modeling group.

[0077] 5. Experimental Methods

[0078] (1) Daily weight changes of mice

[0079] After one week of adaptive feeding of the purchased mice, an aging model was established after continuous intraperitoneal injection of acyclovir for 5 days, and the weight changes of the mice were detected daily.

[0080] (2) Number of days mice survived

[0081] After one week of adaptive feeding, the purchased mice were intraperitoneally injected with acyclovir for 5 consecutive days, and then intraperitoneally injected with doxorubicin hydrochloride to establish a mouse aging model.

[0082] (3) Balance ability of mice

[0083] After one week of adaptive feeding of the purchased mice, acyclovir was continuously injected intraperitoneally for 5 days, and then doxorubicin hydrochloride was injected intraperitoneally once. The mice were subjected to a rotating wooden rod fatigue test. The time each group of mice could persist on the rotating wooden rod was recorded to evaluate the mice's balance ability.

[0084] (4) Mouse muscle strength

[0085] After one week of adaptive feeding of the purchased mice, they were given intraperitoneal injections of acyclovir for 5 consecutive days, followed by an intraperitoneal injection of doxorubicin hydrochloride once a day. On the second day, a net-grabbing experiment was conducted on the mice. The length of time each group of mice spent grasping the net was recorded to evaluate the muscle strength of the mice's limbs and draw statistical graphs.

[0086] 6. Experimental Results

[0087] (1) Daily weight changes of mice

[0088] The weight changes of mice were detected daily. Figure 6 As shown, after modeling with doxorubicin hydrochloride, the weight curves of mice in each group were flat, and the weight curves of mice in the "Model" group and "Model+A1" group decreased after death.

[0089] (2) Evaluation of mouse survival days

[0090] The survival curve of mice is as follows Figure 7 The movement speed and fur color of mice were observed every day. Compared with the blank control group, the mice in the model group had slow movement, dark fur, and significantly shortened lifespan. The lifespan of mice in the drug-treated group was significantly prolonged compared with the model group, and it was dose-dependent and statistically significant.

[0091] (3) Evaluation of mouse balance ability

[0092] The time for the mouse to rotate the wooden stick Figure 8 As shown, compared with the blank control group, the rotating wooden rod time of the mice in the model group was significantly shortened; compared with the model group, the rotating wooden rod time of the mice in the drug-treated group was significantly prolonged, which was statistically significant.

[0093] (4) Evaluation of mouse muscle strength

[0094] The time it takes for mice to catch the net is Fig. 9 As shown, compared with the blank control group, the net-grasping time of mice in the model group was significantly decreased, indicating that the model was successfully established; compared with the model group, the net-grasping time of mice in the drug-treated group was significantly prolonged, which was statistically significant.

[0095] In summary, the present invention established a mouse aging model by intraperitoneal injection of doxorubicin hydrochloride twice a week to evaluate the therapeutic effects of acyclovir and telbivudine on aging mice. The results showed that acyclovir and telbivudine could enhance the balance ability and limb muscle strength of mice, and significantly prolong the survival days of animals, showing anti-aging effects, and are expected to be used clinically.

[0096] Any technical solutions obtained by technicians through logical analysis, inference and experiments on the prior art according to the ideas of the present invention shall fall within the scope of protection in the claims.

Claims

1. Use of nucleoside analogs and pharmaceutically acceptable salts thereof in the preparation of anti-aging drugs.

2. The use according to claim 1, characterized in that The nucleoside analogs are acyclovir and / or telbivudine.

3. Application of nucleoside analogs and pharmaceutically acceptable salts thereof in the preparation of anti-aging health products.

4. The use according to claim 1, characterized in that The nucleoside analogs are acyclovir and / or telbivudine.

5. The use according to any one of claims 1 to 4, characterized in that: The nucleoside analogs are added with pharmaceutically acceptable carriers and / or excipients, as well as other drugs and / or health products, to prepare any pharmaceutically acceptable dosage form.

6. The use according to claim 5, characterized in that The dosage form includes any one of tablets, sprays, granules, capsules, oral liquids and injections.

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