TW201932103A - Pharmaceutical compositions for preventions and managements of dementia, infectious diseases, and cancers, diabetes, obesity, metabolic syndromes, periodontitis, dental caries, osteoporosis and chronic pain and methods thereof - Google Patents

Abstract

A series of pharmaceutical compositions(PTM) containing phyto-polyphenols(P), clinical drugs with selective targets(T) and metal ions(M)(Cu<SP>2+</SP>, SeO3<SP>2-</SP>, Ag<SP>+</SP>, Mn<SP>2+</SP>, VO4<SP>2+</SP>, Zn<SP>2+</SP> and Sr<SP>2+</SP>) for use in prevention and therapy of infectious diseases, neurodegenerative diseases, dementia, diabetes, obesity, metabolic syndromes, periodontitis, dental caries, osteoporosis, cancers and/or chronic pain.

Description

Medicinal composition for preventing dementia, infectious diseases, diabetes, obesity, metabolic syndrome, periodontitis, dental caries, osteoporosis, chronic pain and anticancer effects and methods thereof

The invention provides a series of pharmaceutical compositions (having a broad-spectrum neuroprotective, antibacterial and anti-cancer effect, and can be applied to the prevention and treatment of amnesia and infectious diseases, diabetes, obesity, metabolic syndrome and osteoporosis, especially oral periodontal disease , caries and oral cancer. The invention especially refers to the use and operation methods of broad-acting antibacterial, anti-cancer, prevention and treatment of osteoporosis, metabolic syndrome and neuroprotection.

The prevalence of many chronic diseases such as aging amnesia, obesity, diabetes, osteoporosis and cancer in the world is increasing, and most of these diseases are currently not fully cured [1, 2]. Recent studies have shown that the common causes of amnesia, diabetes, obesity and cancer are [2-6] (1) inflammation, (2) oxidative stress, (3) abnormal glandular dysfunction, (4) infection, (5) ) immune dysfunction. The key point is that the oral to intestinal bacteria phase is closely related to these incurable diseases [5-12]. At present, due to the abuse of antibiotics, not only the bacterial phase is changed, but also the drug-resistant infection is caused, and no drug can be cured. The development of new antibacterial agents is the most pressing problem in the medical field and needs to be resolved urgently.

More than 30 years of research in our laboratory has proven that polyphenols have multifunctional pharmacological properties, especially tea polyphenols (EGCG), curcumin (C) and other flavonoids (flavonoids such as apigenin, quercetin). Etc., they all have multifunctional pharmacological properties such as anti-inflammatory, anti-oxidation, anti-cancer, anti-diabetes, slimming and weight loss, prevention and treatment of osteoporosis and chronic diseases, neuroprotection and antibacterial, etc. [13-18]. In addition, divalent metal ions such as copper ions, manganese ions, zinc ions, strontium ions, and selenium oxide have been shown to have regulatory effects on cell membrane calcium ion permeability, ion channels, ATPases, and granulocytes, and thus The release of conductive substances has a great regulatory effect and has a wide regulatory effect on cell function.

Among the treatments for amnesia, Memantine is approved by the US FDA, but there are side effects such as illusion and dizziness. We have published new use of tea polyphenol EGCG and Memantine, which has the effect of enhancing Memantine efficacy (including amnesia, etc.). Therapy [23-25], and obtained the relevant US patent (Pub. No.: US 2014/0094513).

For the increasingly serious and incurable chronic diseases (aging amnesia, diabetes, obesity, osteoporosis and cancer), especially infectious diseases with multiple drug resistance, our response strategy is to develop pleiotropic effects medicine. New treatments for the composition.

The present invention provides for inhibiting pathogenic bacteria and/or preventing and/or treating infectious diseases, neurodegenerative diseases, dementia, diabetes, obesity, metabolic syndrome, periodontitis, caries, osteoporosis, cancer And/or a chronic pain pharmaceutical composition (PTM) comprising a polyphenolic compound (P), a selective target clinical drug (T), and a metal ion (M).

According to the above concept, the polyphenolic compound (P) comprises at least one polyphenol selected from the group consisting of tea polyphenols, curcumin, theaflavins, apigenin, quercetin, tannic acid, catechins, chlorogenic acids, isoflavones. a group consisting of anthocyanins, cocoa polyphenols, citrose, rutin, ligustrazine and resveratrol.

According to the above concept, the selective target clinical drug (T) comprises at least one drug selected from the group consisting of a receptor agonist, a receptor antagonist, a membrane ion channel modulator, a membrane ion transporter, a granulocyte function regulator, and an antibiotic. The group consisting of.

According to the above concept, the selective target clinical drug comprises at least one drug selected from the group consisting of NaF (sodium fluoride), memantine, metformin, Thioridazine, chlorpromazine, Tobramycin, rifampin, streptomycin, isoniazide, verapamil, diltiazem, dithiothreitol (dithiothreitol), dibucaine, digitonin, polymycin B, cisplatin, dequalinium, 4-hexyl resorcinol ( 4-hexylresorcinol), ursodeoxycholic acid, etidronate, glibenclamide, and 3,4-diaminopyridine .

According to the above concept, the metal ion comprises at least one metal ion selected from the group consisting of copper ions, manganese ions, zinc ions, vanadium ions, strontium ions, selenium oxide, silver ions, and ruthenium red (RuR).

According to the above concept, the pathogenic bacteria comprise at least one pathogen selected from the group consisting of Porphyromonas gingivalis , Streptococcus mutans , E. coli , Pseudomonas aeruginosa , Bacillus subtilis. ( Bacillus subtilis ) and a group consisting of Staphylococcus aureus and the like.

According to the above concept, the concentration ratio of the polyphenolic compound to the clinical target of the selective target is 1:0.1-3.

According to the above concept, the polyphenolic compound, the selective target clinical drug, and the metal ion interaction have a synergistic (synergism) effect.

In one aspect, the invention provides an anti-microbial action against pathogens and/or for the prevention and treatment of infectious diseases, neurodegenerative diseases, dementia, diabetes, obesity, metabolic syndrome, osteoporosis, teeth A method of periarthritis, caries, cancer, and/or chronic pain comprising administering to a subject a therapeutically effective amount of a polyphenolic compound, a selective target clinical drug, and a metal ion, wherein the polyphenolic compound, the selective target Synergistic (potentiating) effects of clinical drugs and metal ions.

According to the above concept, the polyphenolic compound comprises at least one polyphenol selected from the group consisting of tea polyphenols, curcumin, theaflavins, apigenin, quercetin, tannic acid, catechin, chlorogenic acid, isoflavones, and cyanine. a group consisting of vegetarian, cocoa polyphenols, taraxanthin, rutin and resveratrol.

According to the above concept, the selective target clinical drug comprises at least one drug selected from the group consisting of a receptor agonist, a receptor antagonist, a membrane ion channel modulator, a membrane ion transporter, and a mitochondrial function modulator.

According to the above concept, the selective target clinical drug comprises at least one drug selected from the group consisting of NaF (sodium fluoride), memantine, metformin, Thioridazine, chlorpromazine, Tobramycin, rifampin, streptomycin, isoniazide, verapamil, diltiazem, dithiothreitol (dithiothreitol), dibucaine, digitonin, polymycin B, cisplatin, dequalinium, 4-hexyl resorcinol ( 4-hexylresorcinol), ursodeoxycholic acid, etidronate, glibenclamide, and 3,4-diaminopyridine .

According to the above concept, the metal ion comprises at least one metal ion selected from the group consisting of copper ions, manganese ions, zinc ions, vanadium ions, strontium ions, selenium oxide, silver ions, and ruthenium.

According to the above concept, the pathogenic bacteria comprise at least one pathogen selected from the group consisting of Porphyromonas gingivalis , Streptococcus mutans , E. coli , Pseudomonas aeruginosa , Bacillus subtilis. ( Bacillus subtilis ) and a group consisting of Staphylococcus aureus .

According to the above concept, the concentration ratio of the polyphenolic compound to the clinical target of the selective target is 1:0.1-3.

The present invention, as well as the advantages of the present invention, will be more readily understood by those of ordinary skill in the art.

Methods and compositions for providing a range of pharmaceutical compositions and uses thereof are disclosed. Those skilled in the art will be able to practice the invention with reference to the following embodiments and description.

Based on the major common pathogenic factors involved in the pathogenesis of these diseases (inflammation, oxidative stress, mitochondrial metabolic dysfunction, immune dysfunction and infection) [1-6], we have developed a new prevention program "PTM". It has the advantages of chemical (complex combination of polyphenols and metal ions) and pharmacological interactions, resulting in synergistic gain between them (antioxidation, anti-inflammatory, anti-microbial and neuroprotective) [23-25]; P: plant polyphenols; T: clinical drugs with selective targeting, such as receptor agonists or antagonists, ion channel modulators, membrane ion transporters, mitochondrial function regulators, antibiotics, etc.; M: Cu , Mn, Zn, VO ₄ , Sr, SeO ₃ ^-2 , Ag, Ge132, ruthenium red (RuR) and other metals.

Pathogen culture

Anaerobic Streptococcus (Sm, UA159) and Porphyromonas gingivalis (Pg) were cultured in BHI medium (BHI, Becton Dickinson, Sparks, MD) and Wilkins-Chalgren Anaerobe medium, respectively, anaerobic incubator The temperature was 37 ± 0.5 ° C and contained 10% H 2 , 5% CO 2 and 85% N 2 (Forma Scientific Inc., Marietta, OH, USA) [26].

The other four pathogens include E. coli , Pseudomonas aeruginosa ( Pa ), Bacillus subtilis ( Bs ), Staphylococcus aureus ( Sa ), and probiotic L. lactis ( Lr ) at 37 ± 0.5 ° C. Oxygen culture.

Antibacterial effect of drugs on pathogenic bacteria proliferation

In one embodiment, the rate of proliferation of the cultured pathogen is read by an enzyme immunoassay reader with an optical density of 600 nm (OD600). After 16 hours of incubation, the OD600 value of the cultured pathogen was adjusted to about 0.55, at which time the bacterial concentration was about 1.7 x ¹⁰⁹ CFU/ml. Then, dilute 10 ⁶ times of the bacterial solution with the culture medium to 1.7×10 ³ CFU/ml, and add different concentrations of the drug (10 μl/well) to 90 μl/well of the diluted pathogen in the 96-well microplate, and evaluate the change of the OD600 value. The effect of this drug on bacterial proliferation. The control group was treated with vehicle saline, and the OD600 value of the drug-treated group was calculated as the percentage of the OD600 value of the control [26].

This experiment was carried out in a triple repeat. The inhibitory effect of a drug is quantified through the inhibition concentration curve was calculated for each drug by 50% inhibitory concentration (IC ₅₀₎ of.

Cell culture

Cell culture medium (RPMI) and supplements were purchased from Sigma (St. Louise, USA). All media were supplemented with heat-sterilized fetal bovine serum FBS (JRH Biosciences or Hyclone, Thermo Scientific) [19-20].

OECM-1 (oral squamous cell carcinoma), SG (gingival epithelial cells), RAW (pre-osteoclast) and SHSY5Y (neuroblastoma) in CO ₂ (5%), 37±0.2°C to cultivate. MC3T3-E1 (pre-osteoblast) cells were cultured in growth medium α-MEM (containing 10% FBS, 2 mM L-glutamine and 20 mM HEPES, 10 mM (milliol per liter) β-glycerophosphate and 50 mg/L (mg/L) ascorbic acid). All cells were cultured at 37 ± 0.2 ° C and 5% CO ₂ .

Determination of alkaline dephosphatase and detection of alizarin red ore

Alkaline dephosphatase (ALP) activity of MC3T3-E1 cells by nitrophenol in the reaction of 8 mM p-nitrophenyl phosphate (PNPP) with ALP in Na ₂ CO ₃ buffer (pH 10) After 30 minutes of measurement at 37 ± 0.5 ° C, the change in OD 405 nm value was measured [27].

The mineral content of MC3T3-E1 cells was measured by reaction with Alizarin Red (ARS) and quantified by OD562nm [27].

Determination of tartrate-resistant acid dephosphatase (TRAP)

The TRAP activity of RAW cells was measured by the production of p-nitrophenol in a matrix of 8 mM PNPP (p-nitrophenyl-phosphate) via 0.1 M sodium acetate containing 40 mM sodium tartrate (Na tartrate) ( Na acetate) (pH 5.7), the absorbance at 405 nm was measured after incubation at 37 ± 0.5 ° C for 30 minutes [28].

Neuroprotective effect of drugs on H ₂ O ₂ oxidative cytotoxicity by cultured neuroblastoma cells (SHSY5Y)

The cytotoxic effect of control H ₂ O ₂ at 37 ± 0.5 ° C SHSY5Y cells at 0.5, 1 and 3 mM for 24 hours was determined by MTT assay and in % and vehicle treated cell controls.

The neuroprotective effect of the drug was detected by adding the drug 10 minutes or 30 minutes after the application of 1 mM H ₂ O ₂ , and the cell viability measured by the MTT test was performed with the cell survival rate treated with only 1 mM H ₂ O ₂ . Compare [29.30].

TruScan photobeam Tracking

TruScan photobeam Tracking is used to record mouse behavior (walking distance in the marginal and central regions, number of jumps, rest time and total walking time) to calculate the emotional changes we reported previously [31 ^, 32]. The tracking activity of depressed mice showed a limited central walking distance; while normal mice were evenly spaced at the marginal and central regions. In addition, the counts of jumping and standing show the exploration and curiosity of normal mice.

Preparation of drugs

Preparation of tea polyphenols (TP)

In some embodiments, the tea polyphenol is separated [13, 15], and 100 g of green tea or black tea (produced by a registered tea company in Taipei, Taiwan) is suspended in 75 ± 0.5 ° C 1 liter of distilled water for 30 minutes, and then collected. For the supernatant, this step is repeated three times. The supernatant is filtered to remove chlorophyll and undissolved particles. The total aqueous layer was concentrated to 0.5 liter under reduced pressure using a rotary vacuum evaporator. The concentrated solution was extracted three times with an equal volume of chloroform (chloroform) to remove caffeine and pigment. The remaining aqueous layer was then extracted three times with an equal volume of ethyl acetate to extract tea polyphenol. The tea polyphenols were combined in ethyl acetate and evaporated in vacuo. The residue was dissolved in a small amount of distilled water and lyophilized. This gold-red solid material is called tea polyphenols.

In some embodiments, the purified curcumin (C) is purchased from Merck Co., Germany, memantine (Mem), metformin (MF), hydroxyethylidene diphosphate (etidronate, Eti) ), thioridazine (TRZ), chlorpromazine (CPZ), and ruthenium red (RuR) were purchased from Sigma Chemical Company, USA.

Assess the interaction of drug combinations in bacteriostatic capacity

In some embodiments, the combination index (CI) is used to compare the bacteriostatic ability of multiple drug combinations with drugs alone [33].

statistics

The results of each experiment are shown as mean ± SEM, after one-way independent variable factor analysis (One way ANOVA), the difference between the groups was assessed by post-hoc t test, the level of significance Significance) is defined as p < 0.05.

Experimental result

1. Antibacterial effect of polyphenols and metal ions alone or in combination

In some of the examples, as shown in the experimental results summarized in Tables 1 to 17, the IC ₅₀ of each of the three drug combinations showed synergistic bacteriostatic action. As shown by the equations in the experimental procedure, Tables 1 to 7 show the fold increase in the average potency of the antibacterial and anticancer effects of each drug combination.

As shown in Tables 1A and 1B, plant polyphenols (EGCG, green tea polyphenols and curcumin, excluding cinnamon) exhibited broad-spectrum inhibition of proliferation of various cultured pathogens (Pg, UA159, Pa, Sa) (pleiotropic inhibitory) Effects). As shown by the IC ₅₀ (mM) of the metal ion, the combination of polyphenols and metal ions synergistically enhanced the growth of the bacteria by more than 10 times (Table 1C). Cinnamon - metal ion composition had no effect on bacterial growth, cinnamon -RuR only in the case of the composition to reduce the IC ₅₀ calculated synergistic inhibition Pa and Pg, respectively 2.6 times and 1.3 times.

2. The antibacterial effects of various drugs and natural compounds studied in this report:

As shown in Table 2A, dequalinium, thioridazine and chlorpromazine have stronger antibacterial effects than other drugs (NaF, 4-hexyl-resorcinol, memantine, metformin, etidronate and quinine) in the study of new drugs. The natural products (berberine, lysozyme, quercetin, tetramethylpyrazine and nordihydroguaiaretic acid) are also weakly resistant (Table 2B). ). However, antibiotics (tobramycin, rifampicin and streptomycin) have strong antibacterial effects (Table 3A), but neither nystatin nor isoniazide alone has these effects. (Table 3A). Polypeptide (polyarginine, protamine, polylysine, Arg-Phe) and toxin peptide (notexin, cobra cardiotoxin, Cobra phospholipase a ₂ (cobra phospholipase a ₂₎ and α- antibacterial effect bungarotoxin (α-bungarotoxin)) is also weak, but some of these peptides Pg growth inhibition (table 3B).

3. Strong antibacterial effect of a combination of drugs with new drugs:

As shown in Table 2A, the antibacterial action of thioridazine and chlorpromazine alone was effective against Pg, UA159, Sa (effects were in descending order). The use of Metformin alone had little effect, but was significantly increased by 20 to 80 times in the new protocol (drug combination) (Table 4). EGCG(E) appears to be more effective than curcumin (C) and black tea polyphenols (T) in enhancing the antibacterial activity against the four pathogens studied. Among them, E-MF-Zn is the best, followed by E-TRZ-Zn and E-CPZ-Zn. Combinations of drugs containing eosin (RuR) are also effective, especially for Sa (Table 4). Further studies on TRZ and CPZ schemes containing six metal ions (Cu ²⁺ , Ag ⁺ , Mn ²⁺ , VO ^{4 2 +} , Zn ²⁺ and Sr ²⁺ ) have shown that their antibacterial effects are also effective, but Some of the effects marked X are not as good as used alone (Table 5).

4. Antibacterial effects of a new regimen containing membrane transporter blockers:

As shown in Table 2A, the membrane transporter blockers (verapamil, diltiazem, dithiothreitol, dibucaine and digitonin) used alone had no antibacterial effect, but their drug combinations showed an effective antibacterial effect on Pg and Pa, on UA159. And Sa is invalid (Table 6).

5. Antibacterial effects of new regimens containing antibiotics and multipeptides:

As shown in Table 3, the antibiotics (tobramycin, rifampicin and streptomycin) alone had very potent antibacterial effects, but still showed stronger potency in some new regimens (Tables 7 and 8). Protocols containing polymycin B (PM) also showed significant efficacy (Table 7). Although nystatin and isoniazid alone have little effect, they are a very effective antibacterial combination in the new regimen (Table 7).

The multi-peptide or toxin multi-peptide of the E-Q, E-F or E-R combination shown in Table 9 is very effective in inhibiting the proliferation of P.g, UA159 and P.a. However, it is not valid for S.a. except for E-Q (F, R). RF is very effective in suppressing S.a. On the other hand, the combination of the multi-peptide and the E-metal ion was compared with the effect of the above-mentioned scheme containing E-Q, E-F or E-R, and was only about 1/10 of the potency (Tables 9 and 10).

6. Antibacterial effects of new solutions containing memantine, metformin and natural products:

Although memantine and metformin alone were almost ineffective in antibacterial action (Table 2A), they exhibited synergistically synergistic gain with various polyphenol-metal ion compositions (Table 11). Similarly, the natural compounds (berberine, quercetin, tetramethylpirazine and nordihydroguaiaretic acid) were themselves very weak in terms of antimicrobial efficacy (Table 2B), but they exhibited synergistically synergistic effects with the combination of polyphenol-metal ion compositions (Table 12).

7. Antibacterial effect of a new regimen containing etidronate, glibenclamide (Gbc) and 3,4-diaminopyridine (3,4-DAP):

As shown in Table 13, the combination of etidronate (Eti), glibenclamide (Gbc) and 3,4-diaminopyridine (3,4-DAP) and polyphenol-metal ion compositions also showed significant antibacterial effects, especially C. The -Eti-metal ion composition protocol is very effective in inhibiting the proliferation of Sa (Table 13A). The addition of Memantine enhanced the antibacterial efficacy of the combination containing Gbc or 3,4-DAP to P.g. about 2 times (Table 13C).

8. Antibacterial effect of a new solution containing Ag, Ge132 and cisplatin (Pt):

As shown in Table 14, the new formulation containing Ag, Ge132 and cisplatin (Pt) has better antibacterial efficacy against P.a. and S.a.

9. Antibacterial effect of herbal extracts

A mixture of herbal extracts (GIM: a mixture of extracts of amilose, rose hip and yeast GSH; or OP: bilberry extract, cassia seed, marigold and gluten) and EGCG, licorice and peppermint oil were found to be It has the same antibacterial effect as berberine and quercetin (Table 15).

10. Selectivity of the antibacterial effect of the new regimen:

We have shown that 83% of the 282 effective antibacterial regimens tested have no effect on the proliferation of Lactobacillus reuteri (Lr). This result was tested at a concentration of 3-10 times higher than the IC ₅₀ concentration for each protocol. In fact, especially the regimen containing MnCl ₂ significantly increased Lr proliferation (Fig. 1).

11. Selective anticancer effects of the new regimen:

As shown in Table 16, the new regimen containing VO4 ^2- and RuR inhibited cultured oral squamous cell carcinoma cells (OECM-1) more strongly than gingival epithelial cells.

12. The new program promotes osteogenic differentiation:

As shown in Figure 2, the new regimen contains EGCG and the targeted drug Dequalinium (Q), NaF (F), 4-hexyl-resorcinal (R), Memantine (mem), Glibenclamide (Gbc) or 3,4-diaminopyridine (3). , 4-DAP), and metal ions (ZnCl ₂ , SrCl ₂ or Ge132) can increase the alkaline dephosphatase (ALP) activity and ARS mineral content of cultured MC3T3-E1 cells.

E-Mem-Sr, E-Q-Sr, E-R-Zn, E-Gbc-Zn (or Ge) and E-3,4-DAP-Sr have enhanced alkaline dephosphatase activity of cultured MC3T3-E1 cells. On the other hand, EQ-Mem, EF-Sr, E-Eti-Zn, E-Gbc-Zn (Sr) and E-3,4-DAP-Sr plus Mem significantly increased the ARS mineral of cultured MC3T3-E1 cells. Material content.

13. New regimen Reduces osteoclast differentiation:

As shown in Figure 3, E-Eti-SeO ₃ (VO ₄ ) and E-Clo-VO ₄ (Zn, Sr) reduced the anti-tartar acid dephosphatase activity of cultured pre-osteocytes (RAW cells) (tartrate) -resistant acid phosphatase activities of the cultured preosteoblast RAW cells).

14. Neuroprotective effects of the new programme:

As shown in Figures 4A and 4B, the cytotoxic effect of H ₂ O ₂ on cultured neuroblastoma SHSY5Y cells can be achieved by E-TRZ (CPZ, MF)-RuR, T-MF (Eti), respectively. The new schemes for RuR, E-(C) Mem-Zn and G-Mem-Zn are weakened.

15. New protocol for testing mouse and zebrafish safety:

As shown in Figure 5, the mice were orally administered for 3 weeks (C-TRZ(CPZ, MF)-Zn(RuR) showed safety, and the C-TRZ(MF)-RuR protocol slightly increased the motor activity of the mice. Zebra The toxicity test of the fish program showed zero mortality after 1-5 days of intramuscular injection.

The application of the new program:

1. Intestinal and oral fungi are closely related to human health. Many studies have shown periodontitis, dementia, neurodegenerative diseases, diabetes, obesity, metabolic syndrome, intestinal inflammation, osteoporosis and cancer. All are related to intestinal and oral bacteria. The new regimen not only has anti-pathogenic bacteria, but also enhances the growth of probiotics, suggesting that they have the potential to alter the dysbiosis in the human body, thereby reducing disease and enhancing health.

2. Application of prevention and treatment of infectious diseases:

Various new protocols have shown broad inhibitory effects on cultured pathogens. Recently, we cooperated with Drs. H. Y. Dou and T.L. Yang (Infectious Diseases and Vaccine Research Institute, National Institutes of Health, Taiwan) to test the inhibitory effect of C-TRZ (CPZ, MF)-RuR on multidrug-resistant (MDR) bacteria. Preliminary results indicate that these new regimens are effective in inhibiting multiple drug-resistant MDR-Mycobacterium tuberculosis, drug-resistant Staphylococcus aureus (MRSA), and drug-resistant Pseudomonas aeruginosa and multiple drug-resistant Enterococcus faecium (MDR-E) Proliferation of facalis).

3. Application of prevention and treatment of neurodegenerative diseases:

Our previous studies have shown that the synergistic effect of EGCG and memantine can alleviate the excite neurotoxicity of the central nervous system in mice.

The new scheme of E(C,G)-Memantine-metal ions in the program can inhibit the increase of periodontal bacteria (reducing periodontitis), and has neuroprotective and regulatory effects, thus contributing to dementia, Parkinson's disease. Prevention and treatment of schizophrenia and other neurodegenerative diseases. Similarly, E (T) -TRZ (CPZ , MF, Eti) -RuR compositions exhibit neuroprotective oxide cytotoxicity by inhibiting H ₂ O ₂ in. Therefore, they may have the potential benefit of preventing these neurodegenerative diseases.

4. Prevention and treatment of metabolic syndrome, diabetes and obesity:

The combination of drugs containing metformin (E(C, G)-MF-Zn (RuR)) is significantly more effective in preventing and treating these metabolic diseases and their associated bacteriological phase regulation and normalization than metformin alone.

5. For the prevention and treatment of osteoporosis:

A new regimen containing etidronate, Zn ²⁺ , Sr ²⁺ , memantine, glibenclamide (Gbc) and 3,4-diaminopyridine showed significant increase in alkaline dephosphatase (ALP) activity of pre-osteoblasts (MC3T3-E1) (Fig. 2), while E, Eti(Clo)VO ₄ and E, Clo, Zn(Sr) reduced the anti-tartaric acid dephosphatase (TRAP) activity of pre-osteoclasts (RAW) (Fig. 3). These regimens may have preventive and therapeutic effects on osteoporosis.

6. Prevention and treatment of cancer:

As shown in Table 17, the selective anticancer effect of the new regimen on cultured oral cancer cells (OECM-1) may have potential applications for the prevention and treatment of cancer.

7. Prevention and treatment of chronic pain:

We have previously reported that the combination of tea polyphenols and memantine not only effectively reduces oral facial pain, but also inhibits the development of morphine analgesic tolerance. E(C, G) – A new approach to the combination of Mem(MF)-Metals (especially RuR) that effectively prevents and treats the potential effects of chronic pain.

Tables 1 to 17 are the abbreviations of various drugs:

Table 1: Antibacterial effect 50% required concentration (IC ₅₀ ). Polyphenols, metal ions and polyphenols-metal ion composite salts Table A.






Table 1 B.














Table 1 C.























Pg: Porphyromonas gingivalis; UA159: Streptococcus mutans; Pa: Pseudomonas aeruginosa; Sa: Staphylococcus aureus.
IC ₅₀ : concentration that inhibits 50% of bacterial proliferation.
When the concentration of the drug combination listed in this table is 3 to 10 times higher than the IC ₅₀ , there is no inhibitory effect on the proliferation of the cultured Lactobacillus reuteri .

Table 2: The concentration (IC ₅₀ ) required for the 50% inhibition of the new drug (A) and the natural product (B).
Table II A.











Table II B.









Pg: Porphyromonas gingivalis; UA159: Streptococcus mutans; Pa: Pseudomonas aeruginosa; Sa: Staphylococcus aureus.
IC ₅₀ : concentration that inhibits 50% of bacterial proliferation.
When the concentration of the drug combination listed in this table is 3 to 10 times higher than the IC ₅₀ , there is no inhibitory effect on the proliferation of the cultured Lactobacillus reuteri .

Table 3: Concentrations (IC ₅₀ ) required for 50% inhibition of antibiotic (A) and multi-peptide (B)
Table III A.






Table III B.









Pg: Porphyromonas gingivalis; UA159: Streptococcus mutans; Pa: Pseudomonas aeruginosa; Sa: Staphylococcus aureus.
IC ₅₀ : concentration that inhibits 50% of bacterial proliferation.

Table 4: Antibacterial effect of new drug regimens for old drugs
Pg: Porphyromonas gingivalis; UA159: Streptococcus mutans; Pa: Pseudomonas aeruginosa; Sa: Staphylococcus aureus.
IC ₅₀ : concentration that inhibits 50% of bacterial proliferation.
When the concentration of the drug combination listed in this table is 3 to 10 times higher than the IC ₅₀ , there is no inhibitory effect on the proliferation of the cultured Lactobacillus reuteri .

Table 5: Antibacterial effects of thioridazine (TRZ) and chlorpromazine (CPZ) regimen

Pg: Porphyromonas gingivalis; UA159: Streptococcus mutans; Pa: Pseudomonas aeruginosa; Sa: Staphylococcus aureus.
IC ₅₀ : concentration that inhibits 50% of bacterial proliferation.
When the concentration of the drug combination listed in this table is 3 to 10 times higher than the IC ₅₀ , there is no inhibitory effect on the proliferation of the cultured Lactobacillus reuteri .

Table 6: Antibacterial effects of a new regimen containing membrane transporter blockers
Pg: Porphyromonas gingivalis; UA159: Streptococcus mutans; Pa: Pseudomonas aeruginosa; Sa: Staphylococcus aureus.
IC ₅₀ : concentration that inhibits 50% of bacterial proliferation.
The concentration of metal ions is expressed in mM.

Table 7: Antibacterial effects of new regimens containing antibiotics
Pg: Porphyromonas gingivalis; UA159: Streptococcus mutans; Pa: Pseudomonas aeruginosa; Sa: Staphylococcus aureus.
IC ₅₀ : concentration that inhibits 50% of bacterial proliferation.

Table 8: Antibacterial effects of a new regimen containing rifampin and streptomycin
Pg: Porphyromonas gingivalis; UA159: Streptococcus mutans; Pa: Pseudomonas aeruginosa; Sa: Staphylococcus aureus.
IC ₅₀ : concentration that inhibits 50% of bacterial proliferation.

Table 9: Antibacterial effect of a new regimen containing multi-peptide
Pg: Porphyromonas gingivalis; UA159: Streptococcus mutans; Pa: Pseudomonas aeruginosa; Sa: Staphylococcus aureus.
IC ₅₀ : concentration that inhibits 50% of bacterial proliferation.

Table 10: Antibacterial effect of a new regimen containing multi-peptide
Pg: Porphyromonas gingivalis; UA159: Streptococcus mutans; Pa: Pseudomonas aeruginosa; Sa: Staphylococcus aureus.
IC ₅₀ : concentration that inhibits 50% of bacterial proliferation.

Table 11: Antibacterial effects of Memantine (Mem) and Metformin (MF) protocols
Pg: Porphyromonas gingivalis; UA159: Streptococcus mutans; Pa: Pseudomonas aeruginosa; Sa: Staphylococcus aureus.
IC ₅₀ : concentration that inhibits 50% of bacterial proliferation.
When the concentration of the drug combination listed in this table is 3 to 10 times higher than the IC ₅₀ , there is no inhibitory effect on the proliferation of the cultured Lactobacillus reuteri .

Table 12: Antibacterial effects of new solutions containing natural products
Pg: Porphyromonas gingivalis; UA159: Streptococcus mutans; Pa: Pseudomonas aeruginosa; Sa: Staphylococcus aureus.
IC ₅₀ : concentration that inhibits 50% of bacterial proliferation.

Table 13: New protocols containing hydroxyethylidene diphosphate (Etidronate, Eti), glibenclamide (Gbc) or 3,4-diaminopysidine (3,4-DAP) Antibacterial effect Table 13 A.








Table 13B.

Table 13 C.

Pg: Porphyromonas gingivalis; UA159: Streptococcus mutans; Pa: Pseudomonas aeruginosa; Sa: Staphylococcus aureus.
IC ₅₀ : concentration that inhibits 50% of bacterial proliferation.
When the concentration of the drug combination listed in this table is 3 to 10 times higher than the IC ₅₀ , there is no inhibitory effect on the proliferation of the cultured Lactobacillus reuteri .

Table 14: Antibacterial effect of a new scheme containing AgCl, Ge and cisplatin (Pt) Table 14A.
Table XIV.B.
Table XIV.
Pg: Porphyromonas gingivalis; UA159: Streptococcus mutans; Pa: Pseudomonas aeruginosa; Sa: Staphylococcus aureus.
IC ₅₀ : concentration that inhibits 50% of bacterial proliferation.

Table 15: Antibacterial effects of herbal-metal ion compositions Table 15A.
Table 15 B.

IC ₅₀ : concentration that inhibits 50% of bacterial proliferation.

Table 16: The selective antibacterial effect of the new regimen does not inhibit neuroblastoma SHSY5Y cells
Pg: Porphyromonas gingivalis; UA159: Streptococcus mutans; Pa: Pseudomonas aeruginosa; Sa: Staphylococcus aureus.
IC ₅₀ : concentration that inhibits 50% of bacterial proliferation.

Table 17: Drug combination inhibits the proliferation of cancer cells more than it inhibits the growth of normal SG cells
OECM-1: oral squamous cell carcinoma; SG: normal gingival epithelial cells.
IC ₅₀ : concentration that inhibits 50% of bacterial proliferation.

In one embodiment, as shown in Tables 1 to 17, the polyphenolic compound is selected from the group consisting of at least one polyphenol selected from the group consisting of tea polyphenols, curcumin, theaflavins, apigenin, quercetin, and tannic acid. a group consisting of catechins, chlorogenic acids, isoflavones, anthocyanins, cocoa polyphenols, citrose, rutin, tetramethylpyrazine (TMP), guaiac (NDGA) and resveratrol.

In one embodiment, as shown in Tables 1 to 17, the clinical target of the selective target is selected from the group consisting of a receptor agonist, a receptor antagonist, a membrane ion channel modulator, a membrane ion transporter, and a granular line. One of the groups of body function regulators.

In another embodiment, as shown in Tables 1 to 17, the clinical target of the selective target is selected from the group consisting of an antibiotic, memantine (Mem), metformin (MF), and methotridazine (Thioridazine). , TRZ), chlorpromazine (CPZ), tobramycin (tobramycin), rifampin, streptomycin, isoniazid indigo (isoniazide), verapamil ( Verapamil), diltiazem, dithiothreitol, dibucaine, cisplatin, dequalinium, 4-hexylresorcinol ), one of the groups of ursodeoxycholic acid and etidronate (Eti).

In another embodiment, as shown in Tables 1 to 17, the metal ion is selected from the group consisting of copper ions, manganese ions, zinc ions, vanadium ions, strontium ions, selenium oxide, silver ions, and blush. .

In one embodiment, as shown in Tables 1 to 17, the pathogenic bacteria comprise Porphyromonas gingivalis , Streptococcus mutans , E. coli , Pseudomonas aeruginosa. ( Pseudomonas aeruginosa ), Bacillus subtilis or Staphylococcus aureus .

In another embodiment, as shown in Table 17, the oral epithelial cancer cell is an oral squamous cell carcinoma cell line (OECM-1).

In one embodiment, as shown in Tables 1 to 17, the concentration ratio of the polyphenolic compound to the clinical drug of the selective target is 1:0.1-3.

In another embodiment, as shown in Tables 1 to 17, the polyphenolic compound, the clinical drug of the selective target, and the synergistic (potentiating) effect of the metal ion interaction.

In another embodiment, as shown in Table 16 and Table 17, various pharmaceutical compositions containing eosin (RuR) not only have broad and extremely strong antibacterial effects, but also inhibit cancer cell growth. It is expected to be used in the prevention and treatment of infectious diseases and cancer.

In one embodiment, a new protocol for enhancing the growth of L. reuteri is tested and the results are shown in FIG. The final concentration of the drug combination (1X: mg / ml • mg / ml • mM) is as follows:
NaF: 1mg / ml
EQCu: 0.1•0.0003•0.03
EQMn: 0.1•0.0003•0.03
EFCu: 0.1•0.03•0.03
EFMn: 0.1•0.03•0.03
EFSr: 0.1•0.03•0.1

In one embodiment, the new protocol is tested to increase the alkaline dephosphatase (ALP) and ARS mineral content of the cultured pre-osteoblast MC3T3-E1, as shown in Figure 2. The final concentrations for each combination of drugs (1X, mg / ml • mg / ml • mM) are as follows:
EMemZn, EEtiZn: 0.1•0.1•0.1;
EMemSr, EEtiSr: 0.1•0.1•0.3;
EQ: 0.15•0.0005;
ER: 0.15•0.0075 mg/ml;
EQMem: 0.1•0.0003•0.1mg/ml;
ERMem: 0.1•0.005•0.1 mg/ml;
EQZn: 0.03•0.0001•0.01;
EQSr: 0.03•0.0001•0.03;
EFZn: 0.03•0.01•0.01;
EFSr: 0.03•0.01•0.03;
ERZn: 0.1•0.005•0.03;
EGbcZn: 0.1•0.00066•0.1;
EGbcSr: 0.1•0.00066•0.3;
EGbcGe: 0.1•0.00066•0.033;
EGbcZnMem: 0.075•0.0005•0.075•0.075 mg/ml;
EGbcGeMem: 0.075 • 0.0005 • 0.025 • 0.075 mg/ml;
EGbcSrMem: 0.075•0.0005•0.225•0.075 mg/ml;
E34DAPZn: 0.1•0.03•0.1;
E34DAPSr: 0.1•0.03•0.3;
E34DAPGe: 0.1•0.03•0.03;
E34DAPZnMem: 0.075•0.025•0.075•0.075mg/ml;
E34DAPSrMem: 0.075•0.025 • 0.225•0.075mg/ml;
E34DAPGeMem: 0.075•0.025•0.025•0.075mg/ml.

In one embodiment, a new protocol is tested to reduce the anti-tartaric acid dephosphatase activity of cultured pre-osteoclasts (RAW), the results of which are shown in FIG. The final concentrations for each combination of drugs (1X, mg / ml • mg / ml • mM) are as follows:
EEtiCu: 0.1•0.1•0.1;
EEtiSe (Mn, VO4, Zn): 0.1•0.1•0.1;
EEtiSr: 0.1•0.1•0.3;
ECloCu: 0.1•0.3•0.1;
ECloSe (Mn, VO4, Zn): 0.1•0.3•0.1;
ECloSr: 0.1•0.3•0.3.

In one embodiment, the novel regimen is tested to inhibit the neuroprotective effects of H ₂ O ₂ cytotoxicity in cultured neuroblastoma cells, and the results are shown in FIG. The neuroprotective effects of the drug were studied after adding H ₂ O _{2 for} 10 minutes (Fig. 4A) and 30 minutes (Fig. 4B) to the cultured cells. For cytotoxicity tests, the concentrations of H ₂ O ₂ were 0.5, 1 and 3 mM, respectively, and the final concentrations for each drug combination was 1 (1X, mg / ml • mg / ml • mM) as follows:
ETRZRuR, ECPZRuR: 0.3•0.03•0.035;
EEtiRuR: 0.3•0.3•0.035;
TMFRuR: 0.1•0.1•0.035;
TEtiRuR: 0.1•0.3•0.035;
ECZn, EMemZn, GMemZn: 0.1•0.03•0.03;
EMFRuR: 0.3•0.1•0.035.

In one embodiment, the effect of the new regimen on the motor behavior of the mice after oral administration is tested. The results are shown in Figure 5. Figure 5A shows the total movement of the mice, and Figure 5B shows the total resting time of the mice. The final concentrations for each combination of drugs (1X, mg / ml • mg / ml • mM) are as follows:
CTRZZn, CCPZZn: 0.1•0.01•0.03;
CTRZRuR, CCPZRuR: 0.1•0.01•0.035;
CMFZn: 0.1•0.1•0.03;
CMFRuR: 0.1•0.1•0.035

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no

Figure 1 is a new protocol (pharmaceutical composition) to enhance the growth of L. reuteri.

Figure 2 shows the new protocol (pharmaceutical composition) increasing the alkaline phosphatase (ALP) and ARS mineral content of cultured pre-osteoblast MC3T3-E1.

Figure 3 is a new protocol (pharmaceutical composition) to reduce the tartrate-resistant acid phosphatase (TRAP) activities of cultured osteoclast RAW cells.

Figure 4A shows the neuroprotective effect of a new regimen (pharmaceutical composition) on the H ₂ O ₂ cytotoxicity of cultured neuroblastoma cells, after adding 10 minutes of H ₂ O ₂ to the cultured cells.

Figure 4B shows the neuroprotective effect of a novel regimen (pharmaceutical composition) on H ₂ O ₂ cytotoxicity of cultured neuroblastoma cells, after adding 30 minutes of H ₂ O ₂ to the cultured cells.

Figure 5A shows the effect of a new regimen (pharmaceutical composition) on the motor behavior of mice after oral administration, with total mouse movement data.

Figure 5B is the effect of a new regimen (pharmaceutical composition) on the motor behavior of mice after oral administration, with mouse rest time data.

Claims (18)

A pharmaceutical composition for inhibiting at least one pathogen and/or preventing and/or treating at least one indication comprising: a polyphenolic compound; a selective target clinical drug; a metal ion. The pharmaceutical composition according to claim 1, wherein the indication comprises an infectious disease, a neurodegenerative disease, dementia, diabetes, obesity, metabolic syndrome, periodontal disease, dental caries, osteoporosis, Cancer or chronic pain. The pharmaceutical composition according to claim 1, wherein the polyphenolic compound comprises at least one polyphenol selected from the group consisting of tea polyphenols, curcumin, theaflavins, apigenin, quercetin, tannic acid, and the like. A group consisting of tea, chlorogenic acid, isoflavones, anthocyanins, cocoa polyphenols, tartrins, rutin, resveratrol, ligustrazine and dihydroguaiaretic acid. The pharmaceutical composition according to claim 1, wherein the selective target clinical drug comprises at least one drug selected from the group consisting of an antibiotic, a receptor agonist, a receptor antagonist, a membrane ion channel modulator, and a membrane ion. A group of transporter and mitochondrial function regulators. The pharmaceutical composition according to claim 1, wherein the selective target clinical drug comprises at least one drug selected from the group consisting of fluoride, melamine, metformin, methylthiodazine, phenolic acid, tobramycin , rifampicin, streptomycin, isoniazid ingot, verapamil, diltiazem, dithiothreitol, dibucaine, cisplatin, deqinyl chloride, 4-hexyl resorcinol, A group consisting of ursodeoxycholic acid and hydroxyethylidene diphosphate. The pharmaceutical composition according to claim 1, wherein the metal ion comprises at least one metal ion selected from the group consisting of copper ion, manganese ion, zinc ion, vanadium ion, strontium ion, selenium oxide, silver ion and blush. Group. The pharmaceutical composition according to claim 1, wherein the pathogenic bacteria comprises at least one pathogen selected from the group consisting of Porphyromonas gingivalis, Streptococcus, Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, Staphylococcus aureus , a multi-drug resistant Staphylococcus aureus and a group consisting of Mycobacterium tuberculosis. The pharmaceutical composition according to claim 1, wherein the concentration ratio of the polyphenolic compound to the clinical target drug of the selective target is 1:0.1 to 3. The pharmaceutical composition according to claim 1, wherein the polyphenolic compound, the clinical drug of the selective target, and the metal ion have a synergistic interaction. A pharmaceutical composition for the manufacture of a medicament for inhibiting at least a uniform pathogen and/or preventing and/or treating at least one indication, wherein the pharmaceutical composition comprises a therapeutically effective dose: a polyphenolic compound; a selective target clinical drug; a metal ion. The use of claim 10, wherein the indication comprises an infectious disease, a neurodegenerative disease, dementia, diabetes, obesity, metabolic syndrome, periodontal disease, dental caries, osteoporosis, cancer or Chronic pain. The use according to claim 10, wherein the polyphenolic compound comprises at least one polyphenol selected from the group consisting of tea polyphenols, curcumin, theaflavins, apigenin, quercetin, tannic acid, catechins. a group consisting of chlorogenic acid, isoflavones, anthocyanins, cocoa polyphenols, tartrins, rutin, resveratrol, ligustrazine and dihydroguaiaretic acid. The use according to claim 10, wherein the selective target clinical drug comprises at least one drug selected from the group consisting of an antibiotic, a receptor agonist, a receptor antagonist, a membrane ion channel modulator, and a membrane ion transporter. And a group consisting of mitochondrial function regulators. The use according to claim 10, wherein the selective target clinical drug comprises at least one drug selected from the group consisting of fluoride, melamine, metformin, methylthiodazine, phenolic acid, tobramycin, and Fuping, streptomycin, isoniazid ingot, verapamil, diltiazem, dithiothreitol, dibucaine, cisplatin, dequinoxalam, 4-hexyl resorcinol, bear go A group consisting of oxycholic acid and hydroxyethylidene diphosphate. The use of claim 10, wherein the metal ion comprises at least one metal ion selected from the group consisting of copper ions, manganese ions, zinc ions, vanadium ions, strontium ions, selenium oxide, silver ions, and blush. . The use according to claim 10, wherein the pathogen comprises at least one pathogen selected from the group consisting of Porphyromonas gingivalis, Streptococcus, Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, Staphylococcus aureus, multiple A group consisting of drug resistant Staphylococcus aureus and Mycobacterium tuberculosis. The use according to claim 10, wherein the concentration ratio of the polyphenolic compound to the clinical target drug of the selective target is 1:0.1-3. The use of claim 10, wherein the polyphenolic compound, the clinical drug of the selective target, and the metal ion have a synergistic interaction.