Preparation of Drug for Treating Alzheimer's Disease (AD)

Abstract

The present disclosure provides use of a combination of acyclovir and dexamethasone (DXMT) in preparation of a drug for treating Alzheimer's disease (AD); where the use includes all symptoms of a patient with the AD, especially following symptoms: cognitive impairment and neuroinflammation. Combination of the acyclovir and the DXMT has a synergistic effect, to exert anti-inflammatory and immunoregulation effects to achieve a therapeutic effect.

Claims

1. Use of acyclovir and dexamethasone (DXMT) in preparation of a drug for treating Alzheimer's disease (AD).

2. The use according to claim 1, wherein the drug is capable of treating cognitive impairment in a patient with the AD.

3. The use according to claim 1, wherein the drug is capable of treating neuroinflammation in a patient with the AD.

4. The use according to claim 1, wherein the drug is capable of promoting an immunoregulation effect in a patient with the AD.

5. The use according to claim 1, wherein the acyclovir and the DXMT in the drug are used simultaneously or successively.

6. The use according to claim 4, wherein the drug is capable of alleviating a digestive problem possibly caused by the acyclovir.

7. The use according to claim 1, wherein the acyclovir and the DXMT are prepared into a compound pharmaceutical composition.

8. The use according to claim 7, wherein a weight ratio of the acyclovir to the DXMT in the compound pharmaceutical composition is (3000-200):(10-0.1).

9. The use according to claim 8, wherein the weight ratio is 500:(1-5).

10. The use according to claim 8, wherein the weight ratio is 500:(1.5-2).

11. The use according to claim 1, wherein an administration route of the drug is selected from the group consisting of a gastrointestinal administration, an intravenous administration, an intramuscular administration, a subcutaneous administration, an oral mucosa administration, a sublingual administration, an oral spray administration, and a nasal spray administration.

12. The use according to claim 1, wherein the drug is prepared into an oral preparation selected from the group consisting of a tablet, a capsule, a granule, an oral liquid, and a spray.

13. The use according to claim 12, wherein the oral preparation comprises 500 mg of the acyclovir and 1.5 mg of the DXMT.

14. The use according to claim 13, wherein the oral preparation is taken twice per day.

15. The use according to claim 1, wherein the drug is a balance regulator of an immune system, and relieves brain inflammation and autoimmune hyperfunction; therefore, the drug has a certain therapeutic resistance to invasion of the brain by protozoa, bacteria, viruses, fungi, and parasites, and has a certain ability to protect and repair endogenous nerves, blood vessels and cranium.

16. The use according to claim 1, wherein the acyclovir and the DXMT are combined to reduce side effects caused by using either the acyclovir or the DXMT alone, and the acyclovir and the DXMT are used as supportive components in a regular ratio of 500:2 or 600:3, such that the drug has a high efficacy, a shortened treatment period, and an increased safety.

17. The use according to claim 1, wherein the drug is capable of being combined with a target therapy for senile dementia and the AD based on immune balance, to achieve synergistic treatment and repair, and synergistic treatment and repair through natural regulation of immune system cells and factors, thereby shortening a time required for treatment with more safety and less sequelae.

18. The use according to claim 1, wherein the drug is used in pregnant women, newborn infants, infants, children, adults, and elderly, especially in fatal brain infections caused by a human herpes simplex virus and near-derived varicella virus infections, with post-treatment immune memory protection.

19. The use according to claim 1, wherein the drug has an immunity and repair ability to direct or indirect brain trauma, comprising stroke, forced oscillations, accidental trauma, and headache and amnesia sequelae, due to a sudden increase in pTau caused by surgery.

20. The use according to claim 1, wherein the drug is selected from the group consisting of derivatives and prodrugs of the acyclovir, and derivatives and prodrugs of the DXMT, comprising famciclovir, ganciclovir, fluocinonide, and salts thereof.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0092] FIG. 1 shows an experimental design of the whole behavioral tests; where briefly, on day 1, A13 is injected into mouse hippocampus; the mice are let recover for 3 d; on day 4, the mice are given the drug for 13 d; on day 17, a motor function of the mice is examined by the open field test; on days 18-24, the spatial cognition is tested by the Morris water maze test; the body weight is measured every 2 d to 3 d; on day 25, the mice are sacrificed for biochemical studies;

[0093] FIG. 2 shows that a body weight of mice was significantly lower in acyclovir and acyclovir+DXMT groups than the control groups; during the experiment, the body weight of mice is measured every 2 d to 3 d; data represents mean±standard deviation (n=10); .sup.#p<0.05 and .sup.###p<0.001 compared to the control group on day 25 (one-way ANOVA and Tukey's test);

[0094] FIGS. 3A-3B show that the motor function of mice was not significantly altered among groups; in an open field experiment, the number of standing and the number of crossing lines in each group are shown in FIG. 3A and FIG. 3B, separately; data is presented as mean±standard deviation (n=10);

[0095] FIGS. 4A-4D show that a combination of acyclovir and DXMT significantly attenuates A13 oligomer-induced impairments of spatial cognition as demonstrated by the Morris water maze test; FIG. 4A shows that a latency of the acyclovir group and the acyclovir+DXMT group after training is significantly shorter than that of an A13 group; FIG. 4B shows that in the trail, a duration of the mice in a target area of the acyclovir+DXMT group is significantly longer than that in a low A13 group; representative swimming trajectories of mice in the trial are shown in FIG. 4C to FIG. 4D; data represents mean±SD (n=10); .sup.##p<0.01 and .sup.###p<0.001 compared to the control group; *p<0.05 and ***p<0.001 compared to the A13 group (one-way ANOVA and Tukey's test); FIG. 4C shows a representative swimming trajectory of the mice during a training period; FIG. 4D shows a representative swimming trajectory of the mice during a latency period;

[0096] FIGS. 5A-5D show that the combination of acyclovir and DXMT significantly attenuates A13 oligomer-induced over-expression of pro-inflammatory cytokines; contents of TNF-α in FIG. 5A and IL-6 in FIG. 5B in hippocampal extracts of each group are determined by ELISA, separately; FIG. 5C shows expressions of IL-17 and β-actin in mouse hippocampal extracts detected by Western blotting; a quantitative analysis of an IL-17 level is shown in FIG. 5D; data represents mean±standard deviation (n=4 in FIG. 5A and FIG. 5B, and n=3 in FIG. 5D); .sup.##p<0.01 and .sup.###p<0.001 compared to the control group; and *p<0.05 and **p<0.01 compared to the A13 group (one-way ANOVA and Tukey's test);

[0097] FIGS. 6A-6B show that the combination of acyclovir and DXMT significantly attenuates A13 oligomer-induced over-activation of astrocytes in the hippocampal region of mice; FIG. 6A shows a typical image of GFAP staining in the hippocampus of each group; a quantitative analysis of a mean OD of the GFAP staining is shown in FIG. 6B; data represents mean±standard deviation (n=3); .sup.###p<0.001 for the control group, and ***p<0.001 for the A13 group (one-way ANOVA and Tukey's test); scale bar is: 30 microns;

[0098] FIGS. 7A-7B show that the combination of acyclovir and DXMT significantly attenuates A13 oligomer-induced over-activation of microglia in the hippocampal region of mice; FIG. 7A shows a typical image of CD45 staining in the hippocampus of each group; a quantitative analysis of a mean OD of the CD45 staining is shown in FIG. 7B; data represents mean±standard deviation (n=3); .sup.###p<0.001 relative to the control group; **p<0.01 and ***p<0.001 relative to the A13 group (one-way ANOVA and Tukey's test); scale bar is: 30 microns;

[0099] FIGS. 8A-8B show that the combination of acyclovir and DXMT attenuates A13 oligomer-induced decrease of PSD-95 expression in the hippocampal region of mice; FIG. 8A shows expressions of PSD-95 and β-actin detected by Western blotting; a quantitative analysis of PSD-95 expression is shown in FIG. 8B; data represents mean±standard deviation (n=4); .sup.##p<0.01 for the control group, and *p<0.05 for the A13 group (one-way ANOVA and Tukey's test);

[0100] FIGS. 9A-9B show that the combination of acyclovir and DXMT attenuates A13 oligomer-induced increase expression of pTau in the hippocampal region of mice; FIG. 9A shows expressions of Tau and pTau determined by Western blotting; a quantitative analysis of pTau expression is shown in FIG. 9B; data represents mean±SD (n=4); .sup.###p<0.001 for the control group, and *p<0.05 and ***p<0.001 for the A13 group (one-way ANOVA and Tukey's test).

DETAILED DESCRIPTION OF THE EMBODIMENTS

[0101] The present disclosure is further illustrated through the following examples, but the examples are not intended to limit the present disclosure.

Example 1

[0102] Acyclovir and DXMT Granules

[0103] 100 g of acyclovir and 0.75 g of DXMT, lactose, starch, and low-substituted hydroxypropyl cellulose were sieved through a 60-mesh sieve, separately, weighed according to a formula, and mixed in a mixer for 30 min; an appropriate amount of a binder was added to prepare a soft material, granulated by 20 mesh, dried, and sieved by 18 mesh to obtain a mixed powder; a prescribed amount of magnesium stearate was added to the granulated mixed powder for mixing, and a resulting product was divided to obtain the granules.

Example 2

[0104] Acyclovir and DXMT Capsules

[0105] 100 g of acyclovir and 0.75 g of DXMT, lactose, starch, and low-substituted hydroxypropyl cellulose were sieved through a 60-mesh sieve, separately, weighed according to a formula, and mixed in a mixer for 30 min; an appropriate amount of a binder was added to prepare a soft material, granulated by 20 mesh, dried, and sieved by 18 mesh to obtain a mixed powder; a prescribed amount of magnesium stearate was added to the granulated mixed powder for mixing, and a resulting product was placed in a capsule filling machine for filling into the capsules.

Example 3

[0106] Acyclovir and DXMT Tablets

[0107] 100 g of acyclovir and 0.75 g of DXMT, lactose, starch, and low-substituted hydroxypropyl cellulose were sieved through a 60-mesh sieve, separately, weighed according to a formula, and mixed in a mixer for 30 min; an appropriate amount of a binder was added to prepare a soft material, granulated by 20 mesh, dried, and sieved by 18 mesh to obtain a mixed powder; a prescribed amount of magnesium stearate was added to the granulated mixed powder for mixing evenly, and an appropriate amount of a resulting product was sampled for content measurement; a tablet weight was calculated according to a measured content, tabletting was conducted, followed by film coating on obtained tablets.

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