TWI751401B - Pharmaceutical synergists for prevention and management of infectious diseases and related chronic diseases 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)(Cu²⁺, SeO₃ ^2-, Ag⁺, Mn²⁺, VO₄ ²⁺, Zn²⁺ and Sr²⁺) 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

Drug synergist for preventing and treating infectious diseases and related chronic diseases and methods

The present invention provides a series of pharmaceutical compositions (with broad neuroprotective, antibacterial and anticancer effects, which can be applied to prevent and treat amnesia and infectious diseases, diabetes, obesity, metabolic syndrome and osteoporosis, especially oral periodontal disease) , tooth decay and oral cancer. The present invention especially refers to the use and operation method of broad-effect antibacterial, anticancer, prevention and treatment of osteoporosis, metabolic syndrome and neuroprotection.

Many chronic diseases such as ageing amnesia, obesity, diabetes, osteoporosis, and cancer are increasingly prevalent in the world, most of which do not currently have complete cures [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 granulocyte function, (4) infection, (5) ) immune dysfunction. The key is that the oral-intestinal microbiota 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 antibiotic-resistant infections are caused, and there is no cure. Therefore, , The research and development of new antibacterial agents is the most urgent problem in the medical field, which needs to be solved urgently.

More than 30 years of research in our laboratory have proved that polyphenols have multifunctional pharmacological properties, especially tea polyphenols (EGCG), curcumin (C) and other flavonoids (such as apigenin, quercetin), etc. They all have multifunctional pharmacological properties such as anti-inflammatory, antioxidant, anti-cancer, anti-diabetic, 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 oxides have been shown to have regulatory effects on cell membrane calcium ion permeability, ion channels, ATPases and granulosa glands, and therefore have a positive effect on nerve cells. The release of conductive substances has a great regulatory effect, and has a wide range of regulatory effects on cell function.

Among the drugs for the treatment of amnesia, Memantine is approved by the US FDA, but it has side effects such as fantasy and dizziness. We have published the use of tea polyphenols EGCG and Memantine, which has the effect of enhancing the efficacy of Memantine (including amnesia, etc.). therapy [23-25], and obtained related US patents (Pub. No.: US 2014/0094513).

Our response strategy is to develop medicines with pleiotropic effects for increasingly serious and incurable chronic diseases (ageing amnesia, diabetes, obesity, osteoporosis and cancer), especially infectious diseases with multidrug resistance Composition of new treatments.

The present invention provides methods for inhibiting pathogenic bacteria and/or preventing and/or treating infectious diseases, neurodegenerative diseases, dementia, diabetes, obesity, metabolic syndrome, periodontitis, dental caries, osteoporosis, cancer and/or a pharmaceutical composition (PTM) for chronic pain, which comprises 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, tannins, catechins, chlorogenic acids, isoflavones , anthocyanins, cocoa polyphenols, tartrazine, rutin, ligustrazine and resveratrol.

According to the above concept, the selective target clinical drug (T) comprises at least one drug selected from receptor agonists, receptor antagonists, membrane ion channel modulators, membrane ion transporters, mitochondrial function modulators and antibiotics formed group.

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

According to the above concept, the metal ion includes 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 ruthenium red (RuR).

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

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

According to the above concept, polyphenolic compounds, clinical drugs with selective targets and metal ions have synergistic (synergism) effects under the interaction.

In one aspect, the present invention provides an antimicrobial effect against pathogens and/or for the prevention and treatment of infectious diseases, neurodegenerative diseases, dementia, diabetes, obesity, metabolic syndrome, osteoporosis, dental A method for periarthritis, dental caries, cancer and/or chronic pain, comprising administering to an individual a therapeutically effective dose of a polyphenolic compound, a clinical drug of a selective target, and a metal ion, wherein the polyphenolic compound, the selective target It has a synergistic (synergistic) effect under the interaction 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, tannins, catechins, chlorogenic acid, isoflavones, cyanines The group consisting of vitamin C, cocoa polyphenols, limonin, rutin and resveratrol.

According to the above concept, the selective target clinical drug comprises at least one drug selected from the group consisting of receptor agonists, receptor antagonists, membrane ion channel modulators, membrane ion transporters and mitochondrial function modulators.

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

According to the above concept, the metal ion includes 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 ruthenium red.

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

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

The present invention will make the foregoing content, other characteristics and many advantages disclosed in this case more easily understood by those skilled in the art by the following examples and descriptions.

Figure 1 shows the new scheme (pharmaceutical composition) to enhance the growth of Lactobacillus reuteri.

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

Figure 3 shows that the new protocol (pharmaceutical composition) reduces the tartrate-resistant acid phosphatase (TRAP) activities of cultured osteoclast RAW cells.

Figure 4A shows the neuroprotective effect of the new protocol (pharmaceutical composition) on the cytotoxicity of H ₂ O _{2 in cultured neuroma blast cells, after adding H 2} O ₂ to the cultured cells for 10 minutes.

Figure 4B shows the neuroprotective effect of the new protocol (pharmaceutical composition) on the cytotoxicity of H ₂ O _{2 in cultured neuroma blast cells, after adding H 2} O ₂ to the cultured cells for 30 minutes.

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

Figure 5B shows the effects of the new protocol (pharmaceutical composition) on the motor behavior of mice after oral administration of drugs, in which the rest time data of mice.

The present invention discloses methods and compositions for providing a range of pharmaceutical compositions and uses thereof. With reference to the following embodiments and description, those skilled in the art will be able to practice the present invention.

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

Pathogen culture

Anaerobic bacteria Streptococcus (Sm, UA159) and Porphyromonas gingivalis (Pg) were cultured in BHI medium (BHI, Becton Dickinson, Sparks, MD) and Wilkins-Chalgren Anaerobe medium, respectively, in an anaerobic incubator. The temperature was 37±0.5°C and contained 10% H2, 5% CO2 and 85% N2 (Forma Scientific Inc., Marietta, OH, USA) [26].

Four other pathogenic bacteria including Escherichia coli ( E.coli ), Pseudomonas aeruginosa ( Pa ), Bacillus subtilis ( Bs ), Staphylococcus aureus ( Sa ) and probiotic Lactobacillus lordosis ( Lr ) were found at 37±0.5℃ oxygen culture.

The antibacterial effect of drugs on the proliferation of pathogenic bacteria

In one embodiment, the proliferation rate of the cultured pathogenic bacteria is read by an enzyme immunoassay reader, and the optical density is 600 nm (OD600). After 16 hours of incubation, the OD600 value of the cultured pathogenic bacteria was adjusted to about 0.55, at which time the bacterial concentration was about 1.7× ^{10 9} CFU/ml. ^{Then diluted 10 6} times with the culture medium to contain 1.7× ^{10 3} CFU/ml, add different concentrations of drugs (10 μl/well) to 90 μl/well of diluted pathogens in 96-well microplates, and evaluate by the change of OD600 value The effect of this drug on bacterial proliferation. The control group was treated with excipient saline, and the OD600 value of the drug-treated group was calculated as a percentage of the OD600 value of the control group [26].

This experiment was performed in triplicate. The bacteriostatic effect of the drug was quantified by an inhibitory concentration curve and the concentration at which 50% inhibition (IC ₅₀ ) was obtained for each drug was calculated.

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 cells), SG (gingival epithelial cells), RAW (pre-osteoclasts) and SHSY5Y (neuroblastoma) were cultured under CO ₂ (5%), 37±0.2°C . 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 (mmoles 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 .

Alkaline dephosphatase assay and alizarin red mineral content assay

Alkaline dephosphatase (ALP) activity of MC3T3-E1 cells by the reaction product of substrate 8 mM p-nitrophenyl phosphate (PNPP) and ALP in Na ₂ CO ₃ buffer (pH 10) nitrophenol , the change in OD405nm value was measured after 30 minutes at 37±0.5°C [27].

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

Tartrate-resistant acid dephosphatase (TRAP) assay

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

Determination of the neuroprotective effect _{of drugs on H 2} O ₂ oxidative cytotoxicity in cultured neuroblastoma cells (SHSY5Y)

Control H ₂ O ₂ in 0.5, and 3mM cytotoxicity of 37 ± 0.5 ℃ SHSY5Y cells for 24 hours, and the control in% and vehicle-treated cells to the test by MTT assay.

By applying 1mM H 10 or 30 minutes after drug add ₂ O _2, to detect the nerve protective effect of the drug, and only with the processing 1mM H ₂ O ₂ cell viability by MTT cell viability test measurements, Compare [29.30].

TruScan photobeam Tracking (animal exercise measurement device)

TruScan photobeam Tracking was used to record the behavior of mice (walking distance, number of jumps, rest time, and total walking time in the limbic and central regions) to calculate the mood changes we reported previously [31, 32]. Tracking activity in depressed mice showed limited central area walking distance; normal mice had evenly distributed walking distances in the limbic and central areas. In addition, jumping and standing counts revealed exploratory and curious behaviors in normal mice.

Preparation of drugs

Preparation of Tea Polyphenols (TP)

In some embodiments, tea polyphenols are separated [13, 15], 100 g of green tea or black tea (produced by the Taiwanese Taipei Named Tea Company) is suspended in 1 liter of distilled water at 75±0.5°C for 30 minutes, and the upper layer is collected solution, this step will be repeated three times. The supernatant was 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 the tea polyphenols. 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. The golden-red solid substances are called tea polyphenols.

In some embodiments, purified curcumin (C) was 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 in the United States.

Assess the interaction of drug combinations in bacteriostatic capacity

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

CI <1, synergism ; CI =1, addition ; CI >1, antagonism

statistics

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

Experimental results

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

In some embodiments, the experimental results as summarized in Table 1 to table synergistic antimicrobial effect, a combination of three drugs in FIG XVII IC ₅₀ of each component showed a. As estimated by the equation in the experimental procedure, Tables 1 to 7 show the 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 pleiotropic inhibitory effects on the proliferation of various cultured pathogens (Pg, UA159, Pa, Sa) effects). Metal ions such as IC ₅₀ (mM), a combination of metal ions and polyphenols gain synergistic inhibition of bacterial growth than 10-fold (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. Antibacterial effects of various drugs and natural compounds studied in this report:

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

3. Powerful antibacterial effect of drug combination containing old drug new use:

As shown in Table 2A, the antibacterial effects of thioridazine and chlorpromazine alone were effective against Pg, UA159, Sa (in descending order of effect). Metformin alone had little effect, but a significant 20- to 80-fold increase in the new regimen (drug combination) (Table 4). EGCG (E) appeared to be more effective than curcumin (C) and black tea polyphenols (T) in enhancing antibacterial power against the 4 pathogens studied. Among them, E-MF-Zn is the best, followed by E-TRZ-Zn and E-CPZ-Zn. Drug combinations containing ruthenium red (RuR) were also effective, especially for Sa (Table 4). Further studies on the TRZ and CPZ regimens containing six metal ions (Cu ²⁺ , Ag ⁺ , Mn ²⁺ , VO4 ²⁺ , Zn ²⁺ and Sr ²⁺ ) showed that they were also effective against bacteria, but the Some marked as X were less effective than used alone (Table 5).

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

As shown in Table 2A, membrane transporter blockers (verapamil, diltiazem, dithiothreitol, dibucaine and digitonin) used alone were inactive, but their drug combination showed potent antibacterial effects against Pg and Pa, and against UA159 and Sa were invalid (Table 6).

5. Antibacterial effect of the new regimen containing antibiotics and polypeptides:

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

The E-Q, E-F or E-R combination polypeptides or toxin polypeptides shown in Table 9 were very effective in inhibiting the proliferation of P.g, UA159 and P.a. But in addition to E-Q(F,R) for S.a. invalid. RF is very effective in suppressing S.a. On the other hand, the combination of polypeptide and E-metal ion was only about 1/10 as effective as the above regimens containing E-Q, E-F or E-R (Tables 9 and 10).

6. Antibacterial effect of the new regimen containing memantine, metformin and natural products:

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

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

As shown in Table 13, etidronate (Eti), glibenclamide (Gbc) and 3,4-diaminopyridine (3,4-DAP) in combination with polyphenol-metal ion compositions also showed significant antibacterial effects, especially C The protocol of -Eti-metal ion composition was 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 against P.g. approximately 2-fold (Table 13C).

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

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

9. Antibacterial effect of herbal extract mixture

A mixture of herbal extracts (GIM: extract mixture of amira, rose hip and yeast GSH; or OP: bilberry extract, cassia, calendula and sitosterone) and EGCG, The licorice and peppermint oil blends were found to be as potent as berberine and quercetin (Table 15).

10. The selectivity of the antibacterial effect of the new regimen:

We have demonstrated that in 282 kinds of effective antimicrobial solutions tested, 83% had no effect on the proliferation of Lactobacillus reuteri bacteria (Lactobacillus reuteri, Lr). This is the result of each program tested at a concentration greater than _50-fold concentration IC 3-10. Indeed, a particular embodiment comprises MnCl ₂ Lr significantly increased proliferation (FIG. 1).

11. Selective anticancer effect of the new regimen:

As shown in Table 16, ^{the new regimen containing VO4 2-} and RuR had a stronger inhibitory effect on cultured oral squamous cell carcinoma cells (OECM-1) than it did on gingival epithelial cell SG cells.

12. The new protocol promotes osteogenic differentiation:

As shown in Figure 2, the new regimen contains EGCG and targeted drugs 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 ) could increase alkaline dephosphatase (ALP) activity and ARS mineral content in cultured MC3T3-E1 cells.

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

13. The new protocol reduces osteoclast differentiation:

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

14. Neuroprotective effects of the new regimen:

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

15. New protocol tested for safety in mice and zebrafish:

As shown in Figure 5, the drug combination (C-TRZ(CPZ, MF)-Zn(RuR)) was orally administered to mice for 3 weeks showed safety, and the C-TRZ(MF)-RuR regimen slightly increased the motor activity of mice. Zebra Toxicity test of the fish regimen, showing zero mortality after 1-5 days of intramuscular injection.

The new scheme has applications:

1. The gut and oral flora are closely related to human health. Many studies have shown that periodontitis, dementia, neurodegenerative diseases, diabetes, obesity, metabolic syndrome, intestinal inflammation, osteoporosis and cancer and so on are related to intestinal and oral bacteria. The novel regimens are not only anti-pathogenic, but also enhance 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 inhibition of cultured pathogens. Recently, we collaborated with Drs.H.Y.Dou and T.L.Yang (Institute of Infectious Diseases and Vaccines, National Institutes of Health, Taiwan) to test the inhibitory effect of C-TRZ(CPZ,MF)-RuR against multidrug resistant (MDR) bacteria. Preliminary results show that these new regimens are effective against multidrug-resistant Mycobacterium tuberculosis (MDR-Mycobacterium tuberculosis), drug-resistant Staphylococcus aureus (MRSA), and drug-resistant Pseudomonas aeruginosa and multidrug-resistant Enterococcus faecalis (MDR-E). facalis) proliferation.

3. Application of prevention and treatment of neurodegenerative diseases:

Our previous study showed that the synergistic gain of EGCG and memantine attenuated the excite neurotoxicity in mice.

The new program of E(C,G)-Memantine-metal ions in the project can inhibit the proliferation of oral periodontal bacteria (reduce periodontitis), and also have neuroprotective and regulatory effects, therefore, help dementia, Parkinson's disease Syndrome 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 potential benefits in combating these neurodegenerative diseases.

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

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

5. For the prevention and treatment of osteoporosis:

A new regimen containing etidronate, Zn ²⁺ , Sr ²⁺ , memantine, glibenclamide (Gbc) and 3,4-diaminopyridine was shown to significantly increase alkaline dephosphatase (ALP) activity in preosteoblasts (MC3T3-E1) (FIG. 2), while E,Eti(Clo)VO ₄ and E,Clo,Zn(Sr) decreased the tartrate-resistant dephosphatase (TRAP) activity of pre-osteoclasts (RAW) (FIG. 3). These regimens may have prophylactic and therapeutic effects on osteoporosis.

6. Prevent and treat cancer:

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

7. For the prevention and treatment of chronic pain:

We have previously reported that the combination of tea polyphenols and memantine is not only effective in reducing orofacial pain, but also inhibits the development of morphine analgesic tolerance. Potential efficacy of E(C,G)-Mem(MF)-Metals (especially RuR) combination for effective prevention and treatment of chronic pain.

Comparison of the abbreviations of various drugs in Tables 1 to 17:

P.g.：牙齦卟啉單胞菌；UA159：變形鏈球菌；P.a.：綠膿桿菌；S.a.：金黃色葡萄球菌。

Pg: Porphyromonas gingivalis; UA159: Streptococcus mutans; Pa: Pseudomonas aeruginosa; Sa: Staphylococcus aureus.

IC _50: 50% inhibitory concentration of bacteria proliferation.

When the pharmaceutical compositions of the present concentration listed in Table 3 to 10 times higher than the IC _50, the proliferation of cultured Lactobacillus reuteri (Lactobacillus reuteri) is not inhibited.

P.g.：牙齦卟啉單胞菌；UA159：變形鏈球菌；P.a.：綠膿桿菌；S.a.：金黃色葡萄球菌。

Pg: Porphyromonas gingivalis; UA159: Streptococcus mutans; Pa: Pseudomonas aeruginosa; Sa: Staphylococcus aureus.

IC _50: 50% inhibitory concentration of bacteria proliferation.

When the pharmaceutical compositions of the present concentration listed in Table 3 to 10 times higher than the IC _50, the proliferation of cultured Lactobacillus reuteri (Lactobacillus reuteri) is not inhibited.

P.g.：牙齦卟啉單胞菌；UA159：變形鏈球菌；P.a.：綠膿桿菌；S.a.：金黃色葡萄球菌。

Pg: Porphyromonas gingivalis; UA159: Streptococcus mutans; Pa: Pseudomonas aeruginosa; Sa: Staphylococcus aureus.

IC _50: 50% inhibitory concentration of bacteria proliferation.

P.g.：牙齦卟啉單胞菌；UA159：變形鏈球菌；P.a.：綠膿桿菌；S.a.：金黃色葡萄球菌。

Pg: Porphyromonas gingivalis; UA159: Streptococcus mutans; Pa: Pseudomonas aeruginosa; Sa: Staphylococcus aureus.

IC _50: 50% inhibitory concentration of bacteria proliferation.

When the pharmaceutical compositions of the present concentration listed in Table 3 to 10 times higher than the IC _50, the proliferation of cultured Lactobacillus reuteri (Lactobacillus reuteri) is not inhibited.

P.g.：牙齦卟啉單胞菌；UA159：變形鏈球菌；P.a.：綠膿桿菌；S.a.：金黃色葡萄球菌。

Pg: Porphyromonas gingivalis; UA159: Streptococcus mutans; Pa: Pseudomonas aeruginosa; Sa: Staphylococcus aureus.

IC _50: 50% inhibitory concentration of bacteria proliferation.

When the pharmaceutical compositions of the present concentration listed in Table 3 to 10 times higher than the IC _50, the proliferation of cultured Lactobacillus reuteri (Lactobacillus reuteri) is not inhibited.

P.g.：牙齦卟啉單胞菌；UA159：變形鏈球菌；P.a.：綠膿桿菌；S.a.：金黃色葡萄球菌。

Pg: Porphyromonas gingivalis; UA159: Streptococcus mutans; Pa: Pseudomonas aeruginosa; Sa: Staphylococcus aureus.

IC _50: 50% inhibitory concentration of bacteria proliferation.

The concentration of metal ions is expressed in mM.

P.g.：牙齦卟啉單胞菌；UA159：變形鏈球菌；P.a.：綠膿桿菌；S.a.：金黃色葡萄球菌。

Pg: Porphyromonas gingivalis; UA159: Streptococcus mutans; Pa: Pseudomonas aeruginosa; Sa: Staphylococcus aureus.

IC _50: 50% inhibitory concentration of bacteria proliferation.

P.g.：牙齦卟啉單胞菌；UA159：變形鏈球菌；P.a.：綠膿桿菌；S.a.：金黃色葡萄球菌。

Pg: Porphyromonas gingivalis; UA159: Streptococcus mutans; Pa: Pseudomonas aeruginosa; Sa: Staphylococcus aureus.

IC _50: 50% inhibitory concentration of bacteria proliferation.

P.g.：牙齦卟啉單胞菌；UA159：變形鏈球菌；P.a.：綠膿桿菌；S.a.：金黃色葡萄球菌。

Pg: Porphyromonas gingivalis; UA159: Streptococcus mutans; Pa: Pseudomonas aeruginosa; Sa: Staphylococcus aureus.

IC _50: 50% inhibitory concentration of bacteria proliferation.

P.g.：牙齦卟啉單胞菌；UA159：變形鏈球菌；P.a.：綠膿桿菌；S.a.：金黃色葡萄球菌。

Pg: Porphyromonas gingivalis; UA159: Streptococcus mutans; Pa: Pseudomonas aeruginosa; Sa: Staphylococcus aureus.

IC _50: 50% inhibitory concentration of bacteria proliferation.

P.g.：牙齦卟啉單胞菌；UA159：變形鏈球菌；P.a.：綠膿桿菌；S.a.：金黃色葡萄球菌。

Pg: Porphyromonas gingivalis; UA159: Streptococcus mutans; Pa: Pseudomonas aeruginosa; Sa: Staphylococcus aureus.

IC _50: 50% inhibitory concentration of bacteria proliferation.

When the pharmaceutical compositions of the present concentration listed in Table 3 to 10 times higher than the IC _50, the proliferation of cultured Lactobacillus reuteri (Lactobacillus reuteri) is not inhibited.

P.g.：牙齦卟啉單胞菌；UA159：變形鏈球菌；P.a.：綠膿桿菌；S.a.：金黃色葡萄球菌。

Pg: Porphyromonas gingivalis; UA159: Streptococcus mutans; Pa: Pseudomonas aeruginosa; Sa: Staphylococcus aureus.

IC _50: 50% inhibitory concentration of bacteria proliferation.

P.g.：牙齦卟啉單胞菌；UA159：變形鏈球菌；P.a.：綠膿桿菌；S.a.：金黃色葡萄球菌。

Pg: Porphyromonas gingivalis; UA159: Streptococcus mutans; Pa: Pseudomonas aeruginosa; Sa: Staphylococcus aureus.

IC _50: 50% inhibitory concentration of bacteria proliferation.

When the pharmaceutical compositions of the present concentration listed in Table 3 to 10 times higher than the IC _50, the proliferation of cultured Lactobacillus reuteri (Lactobacillus reuteri) is not inhibited.

P.g.：牙齦卟啉單胞菌；UA159：變形鏈球菌；P.a.：綠膿桿菌；S.a.：金黃色葡萄球菌。

Pg: Porphyromonas gingivalis; UA159: Streptococcus mutans; Pa: Pseudomonas aeruginosa; Sa: Staphylococcus aureus.

IC _50: 50% inhibitory concentration of bacteria proliferation.

IC₅₀：抑制50%細菌增殖的濃度。

IC _50: 50% inhibitory concentration of bacteria proliferation.

P.g.：牙齦卟啉單胞菌；UA159：變形鏈球菌；P.a.：綠膿桿菌；S.a.：金黃色葡萄球菌。

Pg: Porphyromonas gingivalis; UA159: Streptococcus mutans; Pa: Pseudomonas aeruginosa; Sa: Staphylococcus aureus.

IC _50: 50% inhibitory concentration of bacteria proliferation.

OECM-1：口腔鱗癌細胞；SG：正常牙齦上皮細胞。

OECM-1: oral squamous cell carcinoma cells; SG: normal gingival epithelial cells.

IC _50: 50% inhibitory concentration of bacteria 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, tannins , catechins, chlorogenic acid, isoflavones, anthocyanins, cocoa polyphenols, tartrazine, rutin, ligustrazine (TMP), guaiac (NDGA) and resveratrol.

In one embodiment, as shown in Tables 1 to 17, the selective target clinical drug is selected from the group consisting of receptor agonists, receptor antagonists, membrane ion channel modulators, membrane ion transporters and mitochondria One of the group of body function modulators.

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

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

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

In another embodiment, as shown in Table 17, the oral epidermal cancer cells are 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 selective target clinical drug is 1:0.1-3.

In another embodiment, as shown in Tables 1 to 17, the polyphenolic compound, the selective target clinical drug and the metal ion interact with each other to have a synergistic (synergistic) effect.

In another embodiment, as shown in Tables 16 and 17, various pharmaceutical compositions containing ruthenium red (RuR) not only have extensive and strong antibacterial effects, but also have strong inhibition of cancer cell growth, and can It is expected to be used in the prevention and treatment of infectious diseases and cancer.

In one example, a new protocol for enhancing the growth of Lactobacillus reuteri was tested and the results are shown in Figure 1. The final concentrations of drug combinations (1X: mg/ml˙mg/ml˙mM) were as follows: NaF: 1 mg/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 example, the new protocol was tested to increase alkaline dephosphatase (ALP) and ARS mineral content in cultured pre-osteoblasts MC3T3-E1, and the results are shown in Figure 2. The final concentrations at 1x (1X, mg/ml˙mg/ml˙mM) of each drug combination were 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˙0.0075mg/ml; EQMem: 0.1˙0.0003˙0.1mg/ml; ERMem: 0.1˙0.005˙0.1mg/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 0.1˙0.00066˙0.033; EGbcZnMem: 0.075˙0.0005˙0.075˙0.075mg / ml; EGbcGeMem: 0.075˙0.0005˙0.025˙0.075mg / ml; EGbcSrMem: 0.075˙0.0005˙0.225˙0.075mg / 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 example, the new protocol was tested to reduce the tartrate-resistant acid dephosphatase activity of cultured pre-osteoclasts (RAW), and the results are shown in Figure 3 . The final concentrations of each drug combination at 1x (1X, mg/ml˙mg/ml˙mM) were 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 example, the neuroprotective effect of the new protocol against H 2} O ₂ cytotoxicity in cultured neuroma blast cells was tested, and the results are shown in FIG. 4 . Was added to cultured cells at 10 minutes (figure IV A) and 30 minutes (Figure IV B), the H ₂ O _2, Protective effects of drugs nerves. The final concentration for cytotoxicity assays, the concentration of H ₂ O ₂ were 0.5, 1 and 3mM, each pharmaceutical composition was 1 times (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 effects of the new protocol on the motor behavior of mice after oral administration of drugs are tested, and the results are shown in Figure 5. Figure 5A shows the total movement of the mice, and Figure 5B shows the total rest time of the mice. The final concentrations at 1x (1X, mg/ml˙mg/ml˙mM) of each drug combination were as follows: CTRZZn, CCPZZn: 0.1˙0.01˙0.03; CTRZRuR, CCPZRuR: 0.1˙0.01˙0.035; CMFZn: 0.1˙0.1˙ 0.1˙0.03; CMFRuR: 0.1˙0.1˙0.035

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Claims (4)

A bacteriostatic agent, comprising: a polyphenolic compound; a metal ion or selenium ion; and a clinical drug, wherein the polyphenolic compound is selected from catechins, black tea polyphenols, green tea polyphenols and cinnamon polyphenols The group consisting of, the metal ion is selected from the group consisting of copper ion, manganese ion, zinc ion, vanadium ion, strontium ion, silver ion and ruthenium ion, and the clinical drug is selected from the group consisting of fluoride, memetin, metformin, methyl methacrylate Thiorazine, phenoxetine, tobramycin, rifampicin, streptomycin, isonicotinamide, verapamil, diltiazem, dithiothreitol, dibucaine, cisplatin, dibuprofen Quinammonium chloride, 4-hexylresorcinol, ursodeoxycholic acid, hydroxyethylidene diphosphate, ligustrazine, nordihydroguaiaretic acid, 3,4-diaminopyridine, berberine, cardiotoxin, Rehmannia glutinosa, glibenclamide, lysozyme, nystatin, polymyxin B, protamine, alpha -bungarotoxin, beta -bungarotoxin, tiger snake toxin, polylysine 37, poly The group consisting of lysine 84, phospholipase A2, polyarginine and short-chain peptides. The bacteriostatic agent as described in item 1 of the claimed scope, wherein the concentration ratio of the polyphenolic compound to the clinical drug is 1:0.1-3. A use of a pharmaceutical composition for preparing a medicine for inhibiting uniform pathogens, wherein the pharmaceutical composition comprises: an effective dose of the bacteriostatic agent as described in item 1 of the scope of the patent application, The pathogenic bacteria are selected from the group consisting of Porphyromonas gingivalis, Streptococcus, Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, Staphylococcus aureus, multidrug-resistant Staphylococcus aureus and Mycobacterium tuberculosis . The use as described in item 3 of the claimed scope, wherein the concentration ratio of the polyphenolic compound and the clinical drug is 1:0.1-3.

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