Application of nucleoside analogs in the preparation of anti-aging drugs

Abstract

This invention relates to the field of pharmaceutical technology, specifically to the application of nucleoside analogs in the preparation of anti-aging drugs. The nucleoside analogs are specifically acyclovir and telbivudine, and the aging is specifically doxorubicin-induced aging. Acyclovir and telbivudine can enhance the balance and limb muscle strength of mice, and significantly prolong the survival time of animals, exhibiting anti-aging effects and showing promise for clinical application.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to the application of nucleoside analogs in the preparation of anti-aging drugs. Background Technology

[0002] Aging refers to the natural phenomenon that, under normal circumstances, after an organism has reached maturity, its tissue structure gradually undergoes degenerative changes with increasing age, leading to a decline in organ function, a weakening of the body's homeostasis, and a decrease in resistance to damaging factors from both internal and external environments, ultimately resulting in death. With increasing age, the incidence of age-related diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), hypertension, gout, and diabetes also increases, causing significant harm to the physical and mental health of the elderly. As the aging population increases year by year, the pressure on elderly care is growing. With the improvement of people's quality of life, how to delay aging has become an urgent technical problem to be solved. To address these technical problems, those skilled in the art have conducted numerous studies. Research has found that metformin, rapamycin, β-nicotinamide mononucleotide, and dasatinib have anti-aging effects; however, current anti-aging effects are only effective on the skin surface, significantly delaying skin aging, while their effects on overall health and lifespan extension remain unknown.

[0003] Acyclovir is a synthetic purine nucleoside analogue, primarily used as a first-line clinical treatment for herpes zoster virus infection, genital infections, cold sores, and chickenpox. Telbivudine is a nucleoside analogue antiviral drug that inhibits viral replication. Telbivudine also has a good safety profile and is approved by the US FDA as a pregnancy category B drug, 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 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 are currently no reports of using the hepatitis B analogues telbivudine and acyclovir for anti-aging purposes, nor is there any literature suggesting that those skilled in the art can prove that telbivudine has anti-aging effects. Summary of the Invention

[0004] The primary objective of this invention is to provide the use of nucleoside analogs and their pharmaceutically acceptable salts in the preparation of anti-aging drugs, wherein the nucleoside analogs are acyclovir and / or telbivudine, and the aging is doxorubicin-induced aging.

[0005] Preferably, the nucleoside analogue is formulated into any pharmaceutically acceptable dosage form by adding pharmaceutically acceptable excipients and other drugs.

[0006] Preferably, the dosage form is any one of tablets, sprays, granules, capsules, oral liquids, or injections.

[0007] The beneficial effects of this invention are: This invention provides a new use of nucleoside analogs in the preparation of anti-aging drugs. The specific nucleoside analogs are acyclovir and telbivudine, and the aging is specifically an doxorubicin-induced aging model. Acyclovir and telbivudine can enhance the balance ability and limb muscle strength of mice, and can also significantly prolong the survival days of animals, thus having an anti-aging effect and showing promise for clinical application. Attached Figure Description

[0008] Figure 1 Diagram showing the administration method and dosage for mice.

[0009] Figure 2 Figure showing the change in body weight of mice after telbivudine administration;

[0010] Figure 3 Survival curves of mice after telbivudine administration;

[0011] Figure 4 Statistical analysis of fatigue test on rotating wooden sticks in mice after telbivudine administration;

[0012] Figure 5 Statistical analysis of mouse net-grabbing experiment after telbivudine administration;

[0013] Note: Compared with the "Control" blank control group, the "Model" group showed **p < 0.01; compared with the "Model+T1" drug treatment group, the "Model" group showed **p < 0.01; compared with the "Model+T2" drug treatment group, the "Model" group showed **p < 0.01.

[0014] Figure 6 Figure showing changes in mouse body weight after acyclovir administration;

[0015] Figure 7 Survival curves of mice after acyclovir administration;

[0016] Figure 8 Statistics of fatigue test of rotating wooden stick in mice after acyclovir administration;

[0017] Figure 9 Statistics of mouse net-catching experiments after acyclovir administration;

[0018] Note: Compared with the "Control" blank control group, the "Model" group showed **p < 0.01; compared with the "Model+A1" drug treatment group, the "Model" group showed *p < 0.05; compared with the "Model+A2" drug treatment group, the "Model" group showed **p < 0.01. Detailed Implementation

[0019] The technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only a part of the embodiments of the present invention, not all of them, and protect the therapeutic effects of telbivudine and acyclovir in all aging and age-related diseases, including different dosage forms and dosages. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention.

[0020] It should be understood that the above brief description and the following detailed description are exemplary and for illustrative purposes only, and do not limit the subject matter of the invention herein. In this application, it must be noted that, unless clearly stated otherwise, the singular form used in this specification and claims includes the plural form of the referred to. It should also be noted that, unless otherwise stated, the use of “or” or “or” means “and / or”. Furthermore, the use of the term “comprising” and other forms such as “including,” “containing,” and “comprising” are not limiting.

[0021] The telbivudine and acyclovir used are pharmaceutically acceptable salts, solvates such as hydrates, lipids, and prodrugs.

[0022] Balance Ability Assessment: Balance ability gradually declines during aging. To evaluate the balance ability of mice and thus predict their lifespan, each group of mice underwent three training sessions before the formal experiment. At the start of the formal experiment, mice were placed on a rotundus fatigue tester (purchased from Shanghai Xinruan Information Technology Co., Ltd.). The software was used to set the speeds at each level as follows: blank speed: 5 rotations / min, initial speed: 10 rotations / min, first-level speed: 20 rotations / min, and second-level speed: 30 rotations / min. The time the mice could maintain their balance on the rotating rod was then recorded.

[0023] Muscle strength assessment: During aging, the limb strength of animals weakens. To assess the limb strength of mice, a grid test was used. The grid apparatus consisted of a 50×50cm grid with a 1×1cm opening, and the grid was 20cm above the ground to prevent the mouse from jumping out. At the start of the experiment, the mouse was placed in the center of the grid. When all four paws of the mouse gripped the grid, the grid was inverted, and the time the mouse remained on the grid was recorded.

[0024] Example 1: Study on the anti-aging effects of telbivudine

[0025] 1. Laboratory animals

[0026] Male Kunming mice aged 6-8 weeks, weighing 25±2g, were used. They were provided by the Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences. No drugs were administered prior to the experiment. The animals were acclimatized for one week in an environment with a temperature of 24–26℃ and a 12h / 12h day / night cycle, provided with food and free access to water, and then divided into groups for the experiment.

[0027] 2. Drugs and reagents

[0028] Doxorubicin hydrochloride, purchased from Shanghai Aladdin Biosynthesis Technology Co., Ltd., batch number: S17092, molecular weight: 579.5;

[0029] Telbivudine tablets, purchased from Pfizer Pharmaceuticals Ltd., batch number: H20070028;

[0030] 3. Experimental grouping and intraperitoneal injection dosage

[0031] Male Kunming mice aged 6-8 weeks were randomly divided into 4 groups, with 3 Kunming mice in each group. The grouping and drug dosage are as follows:

[0032] "Control" group: blank control group, which received an equal volume of normal saline via intraperitoneal injection;

[0033] "Model" group: The model group received an equal volume of 3 mg / kg of doxorubicin hydrochloride via intraperitoneal injection;

[0034] “Model+T1” group: The drug administration group received an equal volume of 3 mg / kg doxorubicin hydrochloride and an equal volume of 5 mg / kg telbivudine via intraperitoneal injection;

[0035] “Model+T2” group: The drug administration group received an equal volume of 3 mg / kg doxorubicin hydrochloride via intraperitoneal injection and an equal volume of 10 mg / kg telbivudine via intraperitoneal injection;

[0036] The administration time was 3 days after acclimatization. All Kunming mice were given the drug 24 hours before modeling and again 24 hours after modeling.

[0037] 4. Establishment of an aging model

[0038] After acclimatizing mice for 3 days, their body weight was measured. Doxorubicin hydrochloride (0.1 mL / 10 g) at a dose of 3 mg / kg was administered intraperitoneally twice weekly (one day apart). The process of establishing the doxorubicin hydrochloride aging model is as follows: Figure 1 As shown.

[0039] After each administration of doxorubicin hydrochloride, relevant indicators were measured, including the mouse rotating wooden stick fatigue test to evaluate the balance ability of mice and the net grab test to evaluate the muscle strength of the limbs of mice. The administration method for the "Control" group was the same as that for the model group.

[0040] 5. Experimental Methods

[0041] (1) Daily weight changes in mice

[0042] After purchasing mice and acclimating them for one week, an aging model was established by intraperitoneal injection of telbivudine for five consecutive days, with daily monitoring of mouse weight changes.

[0043] (2) Number of days the mice survived

[0044] After purchasing mice and acclimating them for one week, they were injected intraperitoneally with telbivudine for five consecutive days, followed by intraperitoneal injection of doxorubicin hydrochloride to establish a mouse aging model.

[0045] (3) Mouse balance ability

[0046] After purchasing mice and acclimating them for one week, they were injected intraperitoneally with telbivudine for 5 consecutive days, followed by an intraperitoneal injection of doxorubicin hydrochloride. The mice were then subjected to a rotating wooden stick fatigue test, and the duration of each group of mice on the rotating wooden stick was recorded to evaluate their balance ability.

[0047] (4) Mouse muscle strength

[0048] After purchasing mice and acclimating them for one week, they were injected intraperitoneally with telbivudine for five consecutive days, followed by an intraperitoneal injection of doxorubicin hydrochloride once a day. The mice were then subjected to a net-grabbing test on the second day. The duration of net-grabbing time for each group of mice was recorded to evaluate the muscle strength of the mice's limbs and to create a statistical graph.

[0049] 6. Experimental Results

[0050] (1) Daily weight changes in mice

[0051] Daily monitoring of mouse weight changes, results as follows 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 mice in the different doses of telbivudine group increased significantly compared with the model group, but there was no significant change compared with the blank control group.

[0052] (2) Number of days the mice survived

[0053] The survival curve of mice is as follows Figure 3 As shown in the figure. Daily observations of movement speed and fur color changes in mice revealed that, compared to the blank control group, the model group mice exhibited sluggish movement, darkened fur, and significantly shortened lifespan; the drug-treated group mice showed a significantly longer lifespan compared to the model group, with a dose-dependent effect that was statistically significant.

[0054] (3) Mouse balance ability

[0055] The time it takes for the mouse to rotate the wooden stick is as follows Figure 4 As shown, compared with the blank control group, the time for the model group mice to rotate the wooden stick was significantly shortened; compared with the model group, the time for the drug-treated group mice to rotate the wooden stick was significantly prolonged, which was statistically significant.

[0056] (4) Mouse muscle strength

[0057] The time it takes for the mouse to catch the net is as follows Figure 5 As shown, compared with the blank control group, the net-grabbing time of mice in the model group was significantly reduced, indicating that the model was successfully established; compared with the model group, the net-grabbing time of mice in the drug-treated group was significantly prolonged, which was statistically significant.

[0058] Example 2: Study on the anti-aging effects of acyclovir

[0059] 1. Laboratory animals

[0060] Male Kunming mice aged 6-8 weeks, weighing 25±2g, were used. They were provided by the Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences. No drugs were administered prior to the experiment. The animals were acclimatized for one week in an environment with a temperature of 24–26℃ and a 12h / 12h day / night cycle, provided with food and free access to water, and then divided into groups for the experiment.

[0061] 2. Drugs and reagents

[0062] Doxorubicin hydrochloride, purchased from Shanghai Aladdin Biosynthesis Technology Co., Ltd., batch number: S17092, molecular weight: 579.5;

[0063] Acyclovir, purchased from Shanghai Maclean Biochemical Technology Co., Ltd., batch number: C10465165, molecular weight: 225.20;

[0064] 3. Experimental grouping and intraperitoneal injection dosage

[0065] Male Kunming mice aged 6-8 weeks were randomly divided into 4 groups, with 3 Kunming mice in each group. The grouping and drug dosage are as follows:

[0066] "Control" group: blank control group, which received an equal volume of normal saline via intraperitoneal injection;

[0067] "Model" group: The model group received an equal volume of 3 mg / kg of doxorubicin hydrochloride via intraperitoneal injection;

[0068] “Model+A1” group: The drug administration group received an equal volume of 3 mg / kg doxorubicin hydrochloride and an equal volume of 5 mg / kg acyclovir via intraperitoneal injection.

[0069] “Model+A2” group: The drug administration group received an equal volume of 3 mg / kg doxorubicin hydrochloride and an equal volume of 10 mg / kg acyclovir via intraperitoneal injection.

[0070] The administration time was 3 days after acclimatization. All Kunming mice were given the drug 24 hours before modeling and again 24 hours after modeling.

[0071] 4. Establishment of an aging model

[0072] After acclimatizing the mice for 3 days, weigh them and administer 0.1 mL / 10 g of 3 mg / kg doxorubicin hydrochloride (dissolved in physiological saline) intraperitoneally twice a week (one day apart). The specific administration procedure is the same as in Example 1.

[0073] The administration method for the “Control” group was the same as that for the model group.

[0074] 5. Experimental Methods

[0075] (1) Daily weight changes in mice

[0076] After purchasing mice and acclimating them for one week, an aging model was established by intraperitoneal injection of acyclovir for five consecutive days, with daily monitoring of mouse weight changes.

[0077] (2) Number of days the mice survived

[0078] After purchasing mice and acclimating them for one week, they were injected intraperitoneally with acyclovir for five consecutive days, followed by intraperitoneal injection of doxorubicin hydrochloride to establish a mouse aging model.

[0079] (3) Mouse balance ability

[0080] After purchasing mice and acclimating them for one week, they were given intraperitoneal injections of acyclovir for 5 consecutive days, followed by intraperitoneal injections of doxorubicin hydrochloride. The mice were then subjected to a rotating wooden stick fatigue test, and the duration of each group of mice on the rotating wooden stick was recorded to evaluate their balance ability.

[0081] (4) Mouse muscle strength

[0082] After purchasing mice and acclimating them for one week, they were given intraperitoneal injections of acyclovir for five consecutive days, followed by an intraperitoneal injection of doxorubicin hydrochloride. The mice were then subjected to a net-grabbing test on the second day. The duration of net-grabbing time for each group of mice was recorded to evaluate the limb muscle strength of the mice, and statistical graphs were plotted.

[0083] 6. Experimental Results

[0084] (1) Daily weight changes in mice

[0085] Daily monitoring of mouse weight changes, results as follows Figure 6 As shown, after modeling with doxorubicin hydrochloride, the weight gain curves of mice in each group were flat, while the weight gain curves of mice in the "Model" group and the "Model+A1" group decreased after death.

[0086] (2) Evaluation of mouse survival days

[0087] The survival curve of mice is as follows Figure 7 As shown in the figure. Daily observations of movement speed and fur color changes in mice revealed that, compared to the blank control group, the model group mice exhibited sluggish movement, darkened fur, and significantly shortened lifespan; the drug-treated group mice showed a significantly longer lifespan compared to the model group, with a dose-dependent effect that was statistically significant.

[0088] (3) Evaluation of mouse balance ability

[0089] The time it takes for the mouse to rotate the wooden stick is as follows Figure 8 As shown, compared with the blank control group, the time for the model group mice to rotate the wooden stick was significantly shortened; compared with the model group, the time for the drug-treated group mice to rotate the wooden stick was significantly prolonged, which was statistically significant.

[0090] (4) Evaluation of mouse muscle strength

[0091] The time it takes for the mouse to catch the net is as follows Figure 9 As shown, compared with the blank control group, the net-grabbing time of mice in the model group was significantly reduced, indicating that the model was successfully established; compared with the model group, the net-grabbing time of mice in the drug-treated group was significantly prolonged, which was statistically significant.

[0092] In summary, this 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 and limb muscle strength of mice, and significantly prolong the survival days of the animals, thus exhibiting anti-aging effects and showing promise for clinical application.

[0093] Any technical solution derived by those skilled in the art based on the concept of this invention through logical analysis, deduction, and experimentation within the existing technology falls within the scope of protection of the claims.

Claims

1. The use of nucleoside analogues and their pharmaceutically acceptable salts in the preparation of anti-aging drugs, wherein the nucleoside analogues are acyclovir and / or telbivudine, and the aging is doxorubicin-induced aging.

2. The application as described in claim 1, characterized in that, The nucleoside analogues are added to pharmaceutically acceptable excipients and other drugs to form any pharmaceutically acceptable dosage form.

3. The application as described in claim 2, characterized in that, The dosage form is any one of the following: tablets, sprays, granules, capsules, oral liquids, and injections.

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