CN114767685B - Use of tetrahydrofolate for inhibiting bacteria or preventing or treating eye diseases - Google Patents
Use of tetrahydrofolate for inhibiting bacteria or preventing or treating eye diseases Download PDFInfo
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- CN114767685B CN114767685B CN202210442474.6A CN202210442474A CN114767685B CN 114767685 B CN114767685 B CN 114767685B CN 202210442474 A CN202210442474 A CN 202210442474A CN 114767685 B CN114767685 B CN 114767685B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/02—Local antiseptics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
Abstract
The application provides an application of tetrahydrofolate in bacteriostasis or prevention or treatment of eye diseases. The application discovers that the tetrahydrofolic acid has good inhibition effect on fusarium, especially in a culture medium similar to an eye environment, so that the tetrahydrofolic acid can effectively inhibit the growth of fusarium under the condition of local administration of eyes, and further prevent and treat eye diseases, especially cornea fungal infection.
Description
Technical Field
The application relates to the field of medicines, in particular to application of tetrahydrofolate in bacteriostasis or prevention or treatment of eye diseases.
Background
Keratomycosis (Keratomycosis) is one of the infectious diseases in the cornea caused by fungi (mold), also called fungal keratitis (Mycotic keratitis); the cornea is severely blinded by fungal infection, one of the most damaging infections of the eye. The occurrence of fungal infections of the cornea is generally causative, the most important of which is corneal trauma. In addition, ocular disorders, particularly abnormalities in tear fluid, contact lens wear, and the long-term use of antibiotics and glucocorticoids are also common causative factors. Among fungal keratitis, fusarium is the most common pathogenic bacterium.
The current treatment effect of fungal infectious keratitis is very unsatisfactory. Different fungi have different morphological structures, growth and reproduction, variation and resistance, pathogenicity and growth and infiltration modes in tissues, and have different sensibility to antifungal drugs. Because of the similarity of fungi and mammals in biological and biochemical levels and the weak penetrability of drugs to the parts of the cornea, the local application efficiency of the eye is low, the systemic application toxicity is high, the available sites of the drugs are limited, the types of the drugs are few, and the drug-resistant bacteria are more and more visible. This presents great difficulty in both early control of infection and prevention of recurrence of fungal infection after surgery in fungal keratitis. At present, common medicines for clinically treating the fungal keratitis are polyene medicines or imidazole medicines, but the medicines are easy to cause adverse reactions, increase fungal drug resistance and cause secondary injury to patients. Therefore, there is a need to find a better drug that can effectively prevent and treat corneal fungal infection.
Folic acid, also known as pteroylglutamic acid, belongs to one of the B vitamins essential to people. In recent years, with the development of molecular biology and pharmacology, the action of folic acid has been attracting attention. The reduced product of folic acid hydrogenation, 5,6,7, 8-Tetrahydrofolate (THFA), is an active form of folic acid, and has the following molecular structure:
tetrahydrofolic acid is a coenzyme for transferring one-carbon group enzyme systems, and is a carrier of methyl, methylene, formyl and methine groups, so that various derivatives of tetrahydrofolic acid can be formed. N-5 and N-10 are reaction sites for transferring a carbon group. The transfer of one carbon unit plays an important role in amino participation in acid metabolism, purine and pyrimidine synthesis.
The application discovers that the tetrahydrofolate has a strong inhibition effect on fungi, especially fusarium, so that the tetrahydrofolate can be applied to the treatment of eye diseases, especially fungal keratitis.
Disclosure of Invention
The application aims to solve the problems of the prior art and provide a method for inhibiting fusarium and preventing or treating eye diseases such as fungal keratitis.
In previous studies by the inventors, it was found that nitrogen metabolism of fusarium has an important role in its growth and pathogenicity. Without a nitrogen source, fungi can hardly grow; but without a carbon source, the fungus can still grow. Whereas the cornea is an amino acid-rich tissue, proline is an important constituent thereof. Previous studies found that the proline component in the cornea was in a decreasing trend after infection of the cornea with fusarium, suggesting that proline is likely to be an important source of nitrogen nutrition after infection of the cornea with fusarium. In further studies, fusarium isolated from the ocular surface of keratitis patients was found to have significant expression of the P5C dehydrogenase (one of the proline metabolizing enzymes) gene, and in recurrent cases more of these enzymes were expressed. This suggests that proline metabolism plays an important role in the pathogenic process of fusarium. As shown in FIG. 1, the standard strain expressed TPM 0, while the clinical isolates expressed significantly activated, and the recurrent infectious strain expressed higher, suggesting that P5C dehydrogenase was involved in and likely associated with the pathogenicity of Fusarium infection of the cornea. Thus, it can be inferred that the growth and pathogenicity of fusarium in the cornea is related to proline. The inventors found that the growth of fusarium is significantly inhibited by culturing fusarium in a medium comprising proline as nitrogen source and adding tetrahydrofolate in different concentrations, and that the extent of inhibition has a correlation with the tetrahydrofolate concentration.
Accordingly, the present application provides the use of tetrahydrofolate or a salt thereof for inhibiting bacteria or for preventing or treating ocular diseases.
An aspect of the present application is to provide an application of tetrahydrofolic acid or a salt thereof in preparing antibacterial drugs.
In a preferred embodiment of the application, the bacteriostatic agent is for inhibiting fungi.
In a preferred embodiment of the application, the bacteriostatic drug is applied to the eye to inhibit fungi.
Another aspect of the present application is to provide a use of tetrahydrofolate or a salt thereof for the manufacture of a medicament for the prevention or treatment of an ocular disease.
In a preferred embodiment of the application, the ocular disease comprises an ocular fungal infection, for example the following ocular fungal infections: eyelid, conjunctiva, cornea, sclera, uvea (including iris, ciliary body, choroid), retina, vitreous, orbit, etc.
In a preferred embodiment of the application, the ocular diseases include blepharitis, conjunctivitis, keratitis, scleritis, uveitis (including iridocyclitis, choroiditis), retinitis, vitreoitis, orbital inflammatory diseases and the like, in particular the above-mentioned inflammation caused by fungi, such as fungal blepharitis, fungal conjunctivitis, fungal keratitis, fungal scleritis, fungal uveitis (including fungal iridocyclitis, fungal choroiditis), fungal retinitis, fungal vitreoitis, fungal orbital inflammatory diseases and the like.
Preferably, the fungi of the application include fusarium, aspergillus, candida, and podophyllum. More preferably, the fungus of the application is selected from Fusarium.
Another aspect of the present application is to provide a pharmaceutical composition for inhibiting bacteria or preventing or treating an ocular disease, the composition comprising tetrahydrofolate or a salt thereof.
The tetrahydrofolate or a salt thereof according to the application may be administered alone or in a pharmaceutical composition. Accordingly, the antibacterial agent, the agent for preventing or treating an ocular disease, and the pharmaceutical composition of the present application may further comprise one or more pharmaceutically acceptable carriers, diluents or excipients in addition to the tetrahydrofolate or a salt thereof. The carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The pharmaceutical composition of the application can also comprise isotonic regulator, pH regulator, preservative, thickener, eye ointment matrix and the like, and can be adjusted by a conventional method by selecting related varieties carried by pharmacopoeia, textbooks and documents.
The medicine/medicine composition provided by the application can be in the forms of cream, emulsion, solution and the like. Specifically, the medicine/medicine composition provided by the application can be liquid or semisolid ophthalmic preparations such as eye drops, eye washes, ophthalmic gels, ophthalmic creams, intraocular injection and the like.
In the uses and compositions of the application, tetrahydrofolate or a salt thereof may also be used in combination with other therapeutic agents for ocular diseases. When combination therapy is employed, the therapeutic agents may be administered together or separately. More than one therapeutic agent in a combination therapy may be administered in the same or different modes of administration. When the therapeutic agents are administered separately, they may be administered simultaneously or in any order.
Accordingly, another aspect of the present application is to provide a combination drug comprising tetrahydrofolate or a salt thereof, and other drugs useful for the treatment of ocular diseases.
Preferably, the other medicament is used for the treatment of blepharitis, conjunctivitis, keratitis, scleritis, uveitis (including iridocyclitis, choroiditis), retinitis, vitritis, orbital inflammatory diseases and the like, in particular the above-mentioned inflammation caused by fungi.
In the present application, the salts of tetrahydrofolate refer to pharmaceutically acceptable salts thereof, including acid addition salts of free compounds thereof with conventional acids, including inorganic and organic acids such as: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, carbonic acid, phosphoric acid, maleic acid, fumaric acid, malonic acid, succinic acid, tartaric acid, formic acid, acetic acid, caproic acid, caprylic acid, capric acid, stearic acid, amino acid, alginic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+) -camphoric acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, glycolic acid, hippuric acid, (+) -L-lactic acid, (+ -) -DL-lactic acid, lactobionic acid, (-) -L-malic acid, (+ -) -DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1, 5-disulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, L-glutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, p-toluenesulfonic acid, undecylenic acid, and the like. In the present application, the salt of tetrahydrofolate may also include alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; and salts with suitable organic ligands, such as quaternary ammonium salts.
In the present application, the term "preventing or treating" and other similar synonyms include alleviating, alleviating or ameliorating symptoms of a disease or disorder, preventing other symptoms, ameliorating or preventing underlying metabolic causes that lead to symptoms, inhibiting the disease or disorder, e.g., arresting the development of a disease or disorder, alleviating a disease or disorder, ameliorating a disease or disorder, alleviating symptoms that result from a disease or disorder, or halting symptoms of a disease or disorder, and furthermore, the term encompasses prophylactic purposes. The term also includes obtaining a therapeutic effect and/or a prophylactic effect. The therapeutic effect refers to curing or ameliorating the underlying disease being treated. In addition, the cure or amelioration of one or more physiological symptoms associated with the underlying disease is also a therapeutic effect, e.g., an improvement in patient condition is observed, although the patient may still be affected by the underlying disease. In terms of prophylactic effect, the composition may be administered to a patient at risk of developing a particular disease, or even if a disease diagnosis has not been made, to a patient exhibiting one or more physiological symptoms of the disease.
In the present application, the term "pharmaceutically acceptable" refers to a substance (e.g., carrier or adjuvant) that does not affect the biological activity or properties of the compounds of the present application, and is relatively non-toxic, i.e., the substance can be administered to an individual without causing an adverse biological reaction or interacting in an adverse manner with any of the components contained in the composition.
In the application, each preparation unit of the medicine/medicine composition contains 1-3000mg of tetrahydrofolate or salt thereof; the unit of the preparation is as follows: each, bottles, etc. The precise dosage and dosing regimen of the drug/pharmaceutical composition of the application will depend upon the biological activity itself, the age, weight and sex of the patient, the needs, pain or degree of need of the individual receiving the drug administration, and the judgment of the practitioner.
Advantageous effects
The application provides an application of tetrahydrofolate or a salt thereof in bacteriostasis or prevention or treatment of eye diseases. The application discovers that the tetrahydrofolate has better inhibition effect on fungi, particularly the most common pathogenic bacteria fusarium of fungal keratitis, and especially can effectively inhibit the growth of fusarium by adding a small amount of tetrahydrofolate into a culture medium similar to an eye environment. Therefore, the tetrahydrofolate can effectively inhibit the growth of fusarium under the condition of local ocular administration, thereby preventing and treating ocular diseases, in particular corneal fungal infection, namely fungal keratitis.
Drawings
Fig. 1: expression of different fusarium strains P5C dehydrogenase genes;
fig. 2: comparing the antibacterial effects of THFA with different concentrations under Pro-medium conditions;
fig. 3A-3D: the distribution of amino acids of cornea of different sources;
fig. 4: comparing the antibacterial effects of THFA under the condition of different amino acid nitrogen source culture mediums;
fig. 5: effect of THFA on fusarium growth in different amino acid nitrogen source media.
Detailed Description
The following description will clearly and fully describe the technical solutions of the embodiments of the present application, and it is apparent that the described embodiments are only some embodiments of the present application, not all embodiments. All other embodiments, which can be made by a person skilled in the art without making any inventive effort, are intended to fall within the scope of the present application.
Example 1: bacteriostatic effect of proline as sole nitrogen source in culture medium
A culture medium (pro-culture medium for short) with proline as the sole nitrogen source is prepared according to the following formula:
table 1:
1 filtration and disinfection
Wherein the formula of the microelement solution is that
Table 2:
fusarium (commercial source: china general microbiological culture collection center; number: CGMCC 3.5840) was cultured in solid pro-medium, 30mL of solid medium was placed in each dish, and 5. Mu.L of the solid medium was concentrated at 2X 10 6 Fusarium spore suspension/mL was inoculated into the medium, THFA (commercially available pure product, purity: 95%) was added at 0mM, 1.25mM, 2.5mM, 5mM, 10mM, 20mM, respectively, and the culture was carried out at 29℃for 72 hours, and colony observation was carried out at different time points to record colony morphology, diameter, etc. The THFA with different concentrations is added to intervene in the proline metabolic process of fusarium, so that the lowest concentration for realizing a good inhibition effect is found out. As a result, as shown in FIG. 2, the growth of Fusarium was significantly inhibited after the addition of THFA, and the extent of inhibition was correlated with the THFA concentration. As can be seen from FIG. 2, the colony diameters after 5mM THFA treatment were significantly smaller than in the 2.5mM, 1.25mM and 0mM groups, and both the 10mM and 20mM groups were significantly smaller than in the 5mM group.
Example 2: antibacterial effect under simulated cornea amino acid mixed environment
1. The cornea proline proportion (human, rat, pig, rabbit) of multiple species is analyzed, the nitrogen source species which can be utilized after infection of cornea by fusarium are found out, and the species which are close to the human cornea proline proportion are screened.
The results are shown in FIGS. 3A-3D: proline in the human cornea was about 1.08% and proline was not the highest amino acid in the human cornea, with taurine being the highest, followed by phenylalanine, lysine, and then glutamine and tyrosine (fig. 3A). The proportion of proline in the rat cornea was 2.59%, and taurine and glutamine were the first few more in each case (fig. 3B). The proportion of proline in the porcine cornea was 2.97%, the first amino acids occupying a relatively large number were taurine, glutamine, respectively (fig. 3C). The proportion of proline in the rabbit cornea was 4.04% and the first amino acids in the relatively large number were taurine, glutamine, respectively (fig. 3D).
The results show that the proportion of amino acids in the cornea of common experimental animals such as rats, pigs, rabbits and the like is not completely coincident with that of human cornea, and the cornea of the rats, pigs and the human cornea are closest to that of the human cornea aiming at proline, but the proportion of glutamine is higher than that of the human cornea, so that the method has great influence on the selection of dominant nitrogen sources of fungi.
2. According to the amino acid types obtained in the previous step, preparing culture mediums with different combination amino acids as nitrogen sources, preliminarily simulating the environment of cornea amino acid mixing, culturing fusarium, and observing the growth condition of fusarium. The preparation method comprises the steps of selecting 4 kinds of amino acids which occupy more in cornea, namely taurine (abbreviated as cattle), glutamine (abbreviated as Gln), glycine (abbreviated as glycerol) and proline (abbreviated as pro), and preparing a fusarium culture medium with mixed amino acids as nitrogen sources according to a formula shown in a table 3, wherein the microelement solution is the same as that of example 1:
table 3:
1 filtration and disinfection
After 10mM THFA was added to the solid medium, the culture was performed in the same manner as in example 1, and the results are shown in FIG. 4. Addition of 10mM THFA to various amino acids mixed together inhibited Fusarium growth and significantly attenuated its pigment (FIGS. 4B-D). Wherein, the culture dish mixed by taurine and proline has no obvious growth change compared with the culture dish with single proline; after 1.5 days, the culture dishes added with glutamine and glycine are all enhanced compared with colony pigments of single proline, which shows that different amino acids have different effects on the growth and pathogenicity of fusarium. And THFA can obviously inhibit the growth of fusarium under the condition of different mixed amino acid nitrogen sources, which shows that THFA has excellent inhibition effect on fusarium.
In additionAdding liquid culture medium, such as solid culture medium, into 96-well plate with concentration of 2×10 at 150 μl/well 6 50. Mu.L of Fusarium spore suspension/mL was incubated at 29℃for 72 hours, absorbance values (OD values) were read at various time points and growth curves were generated, and the results are shown in FIG. 5. The results of the growth curves of fig. 5 suggest that fusarium grows best in the four amino acid mixed medium, proline and glutamine mixed secondarily and quite close to the four amino acid mixed group, glycine and proline mixed culture dish is better than single proline, whereas taurine and proline mixed culture group has lower growth level instead than single proline group. Fusarium growth was significantly reduced by addition of 10mM THFA to each group (FIGS. 5B-F).
The results show that in the culture medium of proline and the mixture of proline and other amino acids, THFA has good inhibition effect on the growth of fusarium, so that the growth of fusarium can be effectively inhibited under the condition of local ocular administration, and the infection caused by fusarium and other fungi can be prevented and treated.
It should be understood that only some specific embodiments of the claimed application are illustrated herein, wherein one or more technical features described in one or more technical solutions may be combined with any one or more technical solutions, and the combined technical solutions are also within the scope of the present application, as the combined technical solutions are already specifically described in the present disclosure.
Claims (8)
1. Use of tetrahydrofolate or a salt thereof for the preparation of a bacteriostatic medicament for inhibiting fungi, which are fusarium.
2. Use of tetrahydrofolate or a salt thereof for the manufacture of a medicament for the prevention or treatment of an ocular disease, including an ocular fungal infection, said fungus being fusarium.
3. The use according to claim 2, wherein the ocular disease comprises a fungal infection of the eye: eyelid, conjunctiva, cornea, sclera, uvea, retina, vitreous body, orbit.
4. The use according to claim 2, wherein the ocular disease comprises a fungal infection of the eye: iris, ciliary body, choroid.
5. The use according to claim 2, wherein the ocular disease comprises fungal blepharitis, fungal conjunctivitis, fungal keratitis, fungal scleritis, fungal uveitis, fungal retinitis, fungal vitreoitis, fungal orbital inflammatory disease caused by fusarium.
6. The use according to claim 2, wherein the ocular disease comprises fungal iridocyclitis, fungal choroiditis caused by fusarium.
7. The use according to any one of claims 1 to 6, wherein the salt of tetrahydrofolate is a pharmaceutically acceptable salt thereof, including acid addition salts of free compounds thereof with conventional acids, including inorganic and organic acids; the salts of tetrahydrofolic acid also include alkali metal salts, alkaline earth metal salts and quaternary ammonium salts of tetrahydrofolic acid.
8. The use according to claim 7, wherein the regular acid comprises: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, carbonic acid, phosphoric acid, maleic acid, fumaric acid, malonic acid, succinic acid, tartaric acid, formic acid, acetic acid, caproic acid, caprylic acid, capric acid, stearic acid, amino acid, alginic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+) -camphoric acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, glycolic acid, hippuric acid, (+) -L-lactic acid, (±) -DL-lactic acid, lactobionic acid, (-) -L-malic acid, (±) -DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1, 5-disulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, L-glutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, p-toluenesulfonic acid, and undecylenic acid; the alkali metal salt of tetrahydrofolate includes sodium salt or potassium salt; the alkaline earth metal salts of tetrahydrofolate include calcium or magnesium salts.
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