Use of CYP450 inhibitors in controlling or killing mites and treating xerophthalmia

Abstract

The present invention relates to the use of CYP450 inhibitors in the inhibition or killing of mites and the treatment of xerophthalmia. The inventors have conducted extensive experiments and found that CYP450 inhibitors can be used to inhibit and kill mites, effectively shorten the survival time of mites, and can be used in products for the inhibition and killing of mites (such as medicines, cosmetics, daily necessities, etc.). The inventors have also found that CYP450 inhibitors can be used to treat xerophthalmia, effectively alleviating and improving the symptoms of xerophthalmia.

Description

[Technical field]

[0001] The present invention relates to the field of medicine, specifically to the use of CYP450 inhibitors in controlling or killing mites and treating xerophthalmia. [Background technology]

[0002] Mites are microscopic animals belonging to the Arthropoda phylum, Arachnida class, Platypus subclass, and generally have a body size of about 0.5 mm, some as small as 0.1 mm, and most are less than 1 mm. Mites have been found to be closely related to the health of humans and animals (pets such as dogs and cats). Mites such as Gamasid mites, Chigger mites, Sarcoptes scabiei, Demodex mites, Acarid mites, House mites, and House lice mites suck blood, invade the skin, and cause "rosacea-like dermatitis" or demodicosis, allergies, urinary tract mitosis, pulmonary mitosis, intestinal mitosis, and scabies, thus posing a significant risk to the health of humans and animals.

[0003] Demodex mites (Arachnid, Acarina) are microscopic ectoparasites that usually infect the pilosebaceous unit of the skin. Among the wide range of reported species, at least Demodex follicularis and Demodex sebacea have been found on the human body surface, where they mainly infest hair follicles, sebaceous glands, and meibomian glands. Demodex mites can phagocytose hair follicle epithelial cells, causing hair follicle dilation and hair loss, and clinical symptoms include blepharitis, blepharokeratoconjunctivitis, eyelash loss, abnormal eyelash alignment, conjunctivitis and blepharoconjunctivitis, pterygium, keratitis, and eyelid basal cell carcinoma. Demodex mites can also phagocytose lipids and cause meibomian gland dysfunction, inducing xerophthalmia. In addition, Demodex mites can also cause blockage of the meibomian gland drainage ducts by mechanical obstruction, leading to difficulty in lipid excretion and retention of excess secretions, leading to the formation of chalazions.Clinical symptoms of eye disease related to Demodex infection mainly include recurrent redness and itching around the eyes, dry eyes, burning eyes, foreign body sensation in the eye, photophobia, increased secretions, which may be accompanied by recurrent eyelash loss, and in severe cases involving the cornea, blurred vision and decreased vision.In addition to the eye diseases mentioned above, many studies have recently reported that Demodex folliculorum infection is associated with many common skin diseases, including seborrheic dermatitis, acne, rosacea-like dermatitis, pityriasis follicularis, perioral dermatitis, demodicosis, and basal cell carcinoma (e.g., Luo, X., Li, J., Chen, C., Tseng, S. & Liang, L. Ocular Demodicosis as a Potential Cause of Ocular Surface Inflammation. Cornea 36 Suppl 1, S9-s14;Karincaoglu, Y., Tepe, B., Kalayci, B., Atambay, M. &Seyhan, M. Is Demodex folliculorum an aetiological factor in seborrhoeic dermatitis Clinical and experimental dermatology 34, e516-520;Chen, W. &Plewig, G. Human demodicosis: revisit and a proposed classification. The British journal of dermatology (see 170, 1219-1225).

[0004] Mite-related diseases (e.g., eye and skin diseases) have not yet received much clinical attention and are often misdiagnosed as bacterial diseases, and conventional antibiotic treatments are often ineffective. Summary of the Invention

[0005] To overcome the deficiencies of the prior art, the present invention provides the use of a CYP450 inhibitor in the manufacture of a product for controlling and / or killing mites.

[0006] Specifically, the CYP450 is one or more selected from CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2C6, CYP2C8, CYP2C9, CYP2C10, CYP2C19, CYP2D6, CYP2E1, CYP3A3, CYP3A4, CYP3A5, CYP3A7, and Pan CYP, and in particular, one or more selected from CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6, and Pan CYP.

[0007] Specifically, the CYP450 inhibitors can be used as the sole active ingredient or in combination with other, same or different, active ingredients to control or kill mites.

[0008] In particular, the acaricidal products according to the invention may be used for therapeutic and / or preventive purposes, but also for non-therapeutic and / or preventive purposes.

[0009] Specifically, the mites according to the invention may be one or more of Demodex, House dust mite, Sarcoptes scabiei, etc. In one embodiment of the invention, the mites according to the invention are Demodex, such as Demodex folliculorum and Demodex sebaceus.

[0010] In one embodiment of the invention, the mite controlling and / or killing product according to the invention is a pharmaceutical composition.

[0011] Specifically, the pharmaceutical composition further comprises a pharma- ceutically acceptable excipient.

[0012] In particular, the pharmaceutical compositions according to the present invention can be used for the prevention and / or treatment of diseases caused by tick infection.

[0013] In one embodiment of the invention, the use is the use of a CYP450 inhibitor in the manufacture of a medicament for the prevention and / or treatment of a disease caused by a tick infestation.

[0014] Specifically, the disease may be an eye disease, a skin disease, an allergic disease, or the like.

[0015] Specifically, the eye disease may be one or more of blepharitis, blepharokeratoconjunctivitis, meibomian gland dysfunction, eyelash loss, abnormal eyelash arrangement, conjunctivitis and blepharoconjunctivitis, pterygium, keratitis, eyelid basal cell carcinoma, xerophthalmia, chalazion, etc., and may have one or more symptoms selected from redness and itching of the eye, dry eye, burning sensation in the eye, foreign body sensation, photophobia, increased eye discharge, eyelash loss, blurred vision, decreased vision, etc.

[0016] Specifically, the skin disease may be one or more of seborrheic dermatitis, acne, rosacea-like dermatitis, pityriasis follicularis, perioral dermatitis, demodex, scabies mites, basal cell carcinoma, and the like.

[0017] Specifically, the allergic disease may be one or more of allergic asthma, allergic rhinitis, allergic dermatitis, allergic conjunctivitis, and the like.

[0018] Specifically, the pharmaceutical composition may be in any dosage form suitable for administration, such as a topical preparation, in particular an ophthalmic preparation, a skin topical preparation, and the like.

[0019] Specifically, the ophthalmic preparation may be eye drops, eye ointments, eye gels, eye emulsions, eye suspensions, eye films, eye washes, intraocular injections, and the like.

[0020] Specifically, the topical skin preparation may be an aerosol, a powder, a detergent, a tincture, a liniment, a coating, an ointment, a gel, a paste, an emulsion, or the like.

[0021] Specifically, various dosage forms of the pharmaceutical composition according to the present invention can be prepared according to conventional methods in the pharmaceutical field.

[0022] Specifically, the pharmaceutical compositions according to the present invention may contain 0.01-99.5% by weight of the active ingredient (specifically, for example, 0.01%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, 99.5%).

[0023] Specifically, the pharmaceutical composition can be used for humans, and can also be used as an animal drug for non-human animals, such as non-human mammals, for example, pet animals (e.g., dogs, cats, rabbits, mice, etc.), livestock animals (e.g., horses, cows, sheep, pigs, etc.), etc.

[0024] In another embodiment of the invention, the acaricidal product according to the invention is a cosmetic product.

[0025] In particular, the cosmetic product further comprises additives acceptable in the cosmetic field.

[0026] Specifically, the cosmetic product according to the present invention may be a cosmetic product used on the face, such as a facial cleanser, soap, smoothing toner, cleansing lotion, skin care lotion, gel, face cream, sunscreen, essence, face mask, gel, liquid foundation, scrub cream, etc.

[0027] Specifically, the cosmetic product according to the present invention may be a cosmetic product to be used on parts of the body other than the face, such as neck cream, shampoo, body soap, soap, conditioner, body lotion, scrub cream, etc.

[0028] Specifically, the cosmetic product according to the present invention may be a cosmetic product used on or around the eyes, such as an eye cream, mascara, eyeliner powder, eyeliner cream, eyeliner pencil, eyeshadow powder, eyeshadow cream, eyebrow pencil, eyebrow powder, etc.

[0029] Specifically, the various forms of the cosmetic product according to the present invention can be produced according to conventional methods in the cosmetic field.

[0030] Specifically, the cosmetic product according to the present invention may contain 0.01-99.5% by weight of the active ingredient (specifically, for example, 0.01%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, 99.5%).

[0031] In another embodiment of the present invention, the acaricidal product according to the present invention is a miticide and can be used to kill and suppress mites that can infest items in the living environment (e.g., pillowcases, pillow inserts, sheets, futons, mattresses, clothing, carpets, cushions, sofas, mats, stuffed toys, air conditioners, etc.).

[0032] Specifically, the miticide may contain any suitable additive capable of achieving the required performance.

[0033] Specifically, the miticide may be in the form of a spray, a detergent, a patch, a small packet, or the like.

[0034] Specifically, the various forms of the acaricide according to the present invention can be prepared according to conventional methods in the field of daily care products.

[0035] Specifically, the miticide according to the present invention may contain 0.01-99.5% by weight of active ingredient (specifically, for example, 0.01%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, 99.5%).

[0036] The present invention further provides a method for preventing and / or treating a disease caused by a tick infestation comprising the step of administering to a subject in need thereof a CYP450 inhibitor or a pharmaceutical composition according to the present invention.

[0037] Specifically, in said method, the disease, the CYP450 inhibitor, the pharmaceutical composition have the corresponding definitions as defined above in the present invention.

[0038] In particular, the subject may be any animal, in particular a mammalian animal, such as a human, cat, dog, rabbit, rat, horse, cow, sheep, pig, etc. In one embodiment of the invention, the subject is a human. In another embodiment of the invention, the subject is a non-human animal.

[0039] Specifically, the dosage of the CYP450 inhibitor or pharmaceutical composition may vary depending on factors such as the administration route, the age and weight of the subject, and the type and severity of the disease being treated.

[0040] The present invention further provides a cosmetic method comprising the step of administering a CYP450 inhibitor to a subject in need thereof to improve skin problems, such as rough skin, increased scale, and itching, caused by mites in the subject.

[0041] Specifically, in said method, the subject is a human.

[0042] Specifically, CYP450 inhibitors have the corresponding definitions set forth above in the present invention.

[0043] The present invention further provides the use of a CYP450 inhibitor in the manufacture of a medicament for preventing and / or treating xerophthalmia.

[0044] Specifically, the CYP450 is one or more selected from CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2C6, CYP2C8, CYP2C9, CYP2C10, CYP2C19, CYP2D6, CYP2E1, CYP3A3, CYP3A4, CYP3A5, CYP3A7, and Pan CYP, and in particular, one or more selected from CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6, and Pan CYP.

[0045] In particular, said CYP450 inhibitors can be used as the sole active ingredient or in combination with other identical or different active ingredients for the prevention and / or treatment of xerophthalmia.

[0046] Specifically, the dry eye syndrome has one or more symptoms selected from itchy eyes, foreign body sensation, burning sensation, photophobia, blurred vision, fluctuation in vision, dry eyes, tired eyes, viscous secretions, sensitivity to external stimuli, red and swollen eyes, congestion, keratinization, damage to the corneal epithelium and adhesion of thread-like substances, etc.

[0047] In one embodiment of the invention, said xerophthalmia is xerophthalmia caused by or associated with a mite infestation.

[0048] Specifically, the drug can be used in humans, and can also be used as a veterinary medicine in non-human animals, such as non-human mammals, including pet animals (e.g., dogs, cats, rabbits, mice, etc.), livestock animals (e.g., horses, cows, sheep, pigs, etc.), etc.

[0049] In particular, the drug may further comprise suitable pharma- ceutically acceptable excipients.

[0050] In particular, the drug may be in any suitable dosage form for administration, such as a topical formulation, in particular an ophthalmic formulation.

[0051] Specifically, the ophthalmic preparation may be eye drops, eye ointments, eye gels, eye emulsions, eye suspensions, eye films, eye washes, intraocular injections, and the like.

[0052] The present invention further provides a method for preventing and / or treating xerophthalmia comprising the step of administering to a subject in need thereof a CYP450 inhibitor or a medicament according to the present invention.

[0053] Specifically, in said method, the xerophthalmia, CYP450 inhibitor, drug have the corresponding definitions as set forth above in the present invention.

[0054] In particular, the subject may be any animal, in particular a mammalian animal, such as a human, cat, dog, rabbit, rat, horse, cow, sheep, pig, etc. In one embodiment of the invention, the subject is a human. In another embodiment of the invention, the subject is a non-human animal.

[0055] Specifically, the dosage of the CYP450 inhibitor or drug may vary depending on factors such as the administration route, the age and weight of the subject, and the type and severity of the disease being treated.

[0056] Through extensive experiments, the present inventors have found that CYP450 inhibitors can be used to inhibit and kill mites, effectively shorten the survival time of Demodex mites, and can be used in mite killing and inhibiting products (such as medicines, cosmetics, daily necessities, etc.).The present inventors have also found that CYP450 inhibitors can be used to treat xerophthalmia, and can effectively alleviate and improve the symptoms of xerophthalmia. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0057] Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0058] The terms "cytochrome P450", "cytochrome P450 isozyme", "cytochrome P450 enzyme", and "CYP450" may be used interchangeably herein and are b-family cytochrome proteins with iron protoporphyrin as a prosthetic group. CYP450 mainly includes the I-III family. The CYP450I family has three subtypes: CYP1A1, CYP1A2, and CYP1B1. The CYP450II family is the largest family in the CYP450 enzyme system and includes many families such as CYP2A, CYP2B, CYP2C, CYP2D, CYP2E, and CYP2F. For example, CYP2A6, CYP2B6, CYP2C6, CYP2C8, CYP2C9, CYP2C10, CYP2C19, CYP2D6, CYP2E1, CYP450III family mainly includes CYP3A3, CYP3A4, CYP3A5, CYP3A7. CYP450 can be derived from animals, plants, microorganisms, and particularly from mammals, e.g., humans.

[0059] The term "CYP450 inhibitor" refers to a substance that can inhibit the activity of at least one CYP450 enzyme (as described above) and reduce the activity of the enzyme by at least 1%, 5%, 10%, 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or even 99.5%, 99.9%, or 100%.

[0060] CYP450 inhibitors may be derived from natural products (e.g., active monomers extracted from natural products, antibiotics obtained by fermentation, semisynthetic herbal medicines or semisynthetic antibiotics obtained by chemical semisynthesis or biosynthesis using natural active substances or antibiotics as raw materials), synthetic products (low molecular weight compounds obtained by chemical synthesis), or biopharmaceuticals (therapeutic agents produced by recombinant DNA technology or other innovative biotechnologies, e.g., recombinant protein or recombinant peptide drugs, recombinant DNA drugs, etc.).

[0061] In one embodiment of the present invention, the CYP450 inhibitor comprises a substance capable of inhibiting at least CYP1A1 ("CYP1A1 inhibitor"), including, but not limited to, dihydroanthraquinone, emodin, 1,4-naphthoquinone, resveratrol, methoxypsoralen, diosmetin, pharma- ceutically acceptable salts, esters, stereoisomers, derivatives, prodrugs, and solvates thereof.

[0062] In one embodiment of the present invention, the CYP450 inhibitor includes at least one CYP1A2 inhibitor that can inhibit CYP1A2 ("CYP1A2 inhibitor"), and includes Acyclovir, Amiodarone, Atazanavir, Caffeine, Cimetidine, Ciprofloxacin, Enoxacin, Famotidine, Flutamide, Fluvoxamine, Lidocaine, Lomefloxacin, and the like. Examples of antihistamines include, but are not limited to, efloxacin, mexiletine, moclobemide, norfloxacin, ofloxacin, perphenazine, propafenone, ropinirole, tacrine, ticlopidine, tocainide, verapamil, and pharma- ceutically acceptable salts, esters, stereoisomers, derivatives, prodrugs, and solvates thereof.

[0063] In one embodiment of the present invention, the CYP450 inhibitor comprises a substance capable of inhibiting at least CYP1B1 ("CYP1B1 inhibitor"), and is selected from the group consisting of 1,2-phenylenebis(methylene)selenocyanate, 1,3-phenylenebis(methylene)selenocyanate, 1,4-phenylenebis(methylene)selenocyanate, and the like. lene selenocyanate), α-naphthoflavone, acetylenes, 2-ethynylpyrene, hesperetin, homoeriodictyol, acacetin, diosmetin, resveratrol, Oltipraz, 2,4,3′,5′-tetramethoxystilbene (2,4,3′,5′-Tetramethoxystilbene (TMS), hydroxystilbenes, Flutamide, Paclitaxel, Mitoxantrone, Docetaxel, Tamoxifen, Doxorubicin, Daunorubicin, trans-stilbene analogues, Imperatorin, Isopimpinellin, Purpurin, Alizarin, Polycyclic aromatic hydrocarbons hydrocarbons), apigenin, kaempferol, quercetin, amethoflavone, quercitrin, rutin, trans-resveratrol methyl ethers, 3',4'-dimethoxyflavone, 5,7,4'-trimethoxyflavone, curcumin, 7,4'-dimethoxyflavone, 7,3'-dimethoxyflavone, thiomethylstilbenes, 2,2',4,6'-tetramethylstilbenes, 4,4'-tetramethylstilbenes, 5,7,4'-trimethoxyflavone ... 2,2′,4,6′-Tetramethoxystilbene, methoxyflavonoids, melatonin, 2,3,4-trimethoxy-4′-methylthio-stilbene, propargyloxyflavones, 4′-methoxy-5,7-dihydroxyflavone7-dihydroxyflavone, 3'-fluoro-6,7,10-trimethoxy-α-naphthoflavone, coumarin, pharma- ceutically acceptable salts, esters, stereoisomers, derivatives, prodrugs, and solvates thereof.

[0064] In one embodiment of the present invention, the CYP450 inhibitor comprises a substance capable of inhibiting at least CYP2A6 ("CYP2A6 inhibitor"), and examples thereof include Letrozole, Clotrimazole, Tranylcypromine, Pilocarpine, Miconazole, Amiodarone, Ketoconazole, Memantine, Amphetamine, Fenofibrate, Methoxsalen, Metyrapone, and the like. These include, but are not limited to, benzodiazepine, benzodiazepine, benzocaine, benzodiazepine, benzocaine, benzodiazepine, benzocaine, benzoyl pertazolidine ...

[0065] In one embodiment of the present invention, the CYP450 inhibitor comprises a substance capable of inhibiting at least CYP2B6 ("CYP2B6 inhibitor"), and includes, for example, ticlopidine, orphenadrine, clotrimazole, itraconazole, raloxifene, thiamazole, rilpivirine, memantine, clopidogrel, thiotepa, curcumin, sorafenib, tamoxifen, ketoconazole, crisaborole, manidipine, cyclospor ... ne), Piperaquine, Lopinavir, Amprenavir, Simvastatin, Nelfinavir, Selegiline, Amlodipine, Desipramine, Doxorubicin, Phencyclidine, Azelastine, Colchicine, Ethanol, Isoflurane, Miconazole, Quinidine, Roxithromycin, Sulfaphenazole, Nitric OxideOxide, Cisplatin, Regorafenib, Enzalutamide, Quazepam, Crizotinib, Enasidenib, Voriconazole, Safinamide, Lenvatinib, Rifamycin, Triclabendazole, Paroxetine, Pexidartinib, Fluvoxamine, Modafinil, Curcumin Sulfate These include, but are not limited to, acetaminophen sulfate, Abemaciclib, Elexacaftor, Cenobamate, Sertraline, Lopinavir, Ritonavir, Methylene blue, 5,5'-Dimethyl-2,2-bipyridine (Abametapir), Cedrol, and pharmaceutically acceptable salts, esters, stereoisomers, derivatives, prodrugs, and solvates thereof.

[0066] In one embodiment of the present invention, the CYP450 inhibitor comprises at least a substance capable of inhibiting CYP2C8 ("CYP2C8 inhibitor"), and is selected from the group consisting of gemfibrozil, clopidogrel, felodipine, mometasone furoate, zafirlukast, sorafenib, erlotinib, dabrafenib, candesartan cilexetil, salmeterol, trametinib, fluticasone, fluticasone furoate, fluticasone propionate, and the like.propionate, Ritonavir, Clotrimazole, Ketoconazole, Rucaparib, Pazopanib, Cabozantinib, Atazanavir, Terbinafine, Rofecoxib, Quinidine, Fenofibrate fibrate, Bezafibrate, Cimetidine, Ketoprofen, Pyrimethamine, Ticlopidine, Idelalisib, Belinostat, Candesartan, Opicapone, Tegaserod, Abiraterone rone, Ubrogepant, Amoxicillin, Rosiglitazone, Trimethoprim, Tamoxifen, Irbesartan, Quinine, Efavirenz, Rabeprazole, Crisaborole, Nabilone ), Bexarotene, Nicardipine, Loratadine, Eltrombopag, Diltiazem, Enzalutamide, Fluvastatin, Levothyroxine, Oxybutynin, Medroxyprogesterone acetateacetate), Spironolactone, Amlodipine, Saquinavir, Genistein, Lenvatinib, Pioglitazone, Nilotinib, Teriflunomide, Topiroxostat, Lovastatin, Troglitazone, Amitriptyline, Cerivastatin, Warfarin Arfarin, Lapatinib, Raloxifene, Quercetin, Ethinylestradiol, Colchicine, Isoniazid, Metronidazole, Nilutamide, Phenelzine, Piroxicam, Sulfaphenazole, Terfenadine, Triazolam, Valproic Acidacid, Diethylstilbestrol, Vismodegib, Regorafenib, Lumacaftor, Midostaurin, Enasidenib, Letermovir, Bosutinib, Deferasirox, Rifampicin, Verapamil, Simvastatin, Sulfinpyrazone, Montelukast, Nilvadipine, Liotrix, Mometasone, Mifepristone, Vemurafe Vemurafenib, Licofelone, Rutin, Ponatinib, Isavuconazole, Rifamycin, Triclabendazole, Alpelisib, Balaglitazone, Ciglitazone, Lobeglitazone, Netoglitazone, Rivoglitazone, Tolbutamide, Nifedipine, Cholecalciferol, Atorvastatin, Losartan, Mefenamic Acid acid, Troleandomycin, Ezetimibe, Anastrozole, Abemaciclib, Elexacaftor, Favipiravir, Methylene Blueblue), Selpercatinib, Ripretinib, Clofazimine, Miconazole, pharmaceutically acceptable salts, esters, stereoisomers, derivatives, prodrugs, and solvates thereof.

[0067] In one embodiment of the present invention, the CYP450 inhibitor comprises at least a substance capable of inhibiting CYP2C19 ("CYP2C19 inhibitor"), and includes Fluvoxamine, Ticlopidine, Chloramphenicol, Delavirdine, Gemfibrozil, Stiripentol, Fluoxetine, Imipramine, and the like. ipramine, Clomipramine, Lansoprazole, Isoniazid, Zafirlukast, Tioconazole, Miconazole, Sertraline, Efavirenz, Armodafinil, Eslicarbazepine acetate acetate), Abiraterone, Zucapsaicin, Cisapride, Manidipine, Artenimol, Lopinavir, Omeprazole, Voriconazole, Esomeprazole, Pantoprazole, Rucaparib, Dovitinib, Oritavancin, Zotero Zonisamide, Luliconazole, Bortezomib, Nilutamide, Sitaxentan, Clozapine, Ethanol, Nilvadipine, Olanzapine, Tipranavir, Naloxegol, Midostaurin, Etoricoxib, Sildenafil,Citalopram, Memantine, Dexlansoprazole, Clinafloxacin, Fenofibrate, Loratadine, Aprepitant, Ubrogepant, Amiodarone, Osilodrostat, Moclobemide, Nicardipine, Indomethacin, Progesterone, Felbamate, Rabeprazole, Troglitazone ne), Amitriptyline, Ritonavir, Mephenytoin, Tranylcypromine, Oxcarbazepine, Ketoconazole, Thalidomide, Aminopyrine, Fluvastatin, Quinine, Warfarin, Diazepam, Cimetidine, Probenecid, Carbamazepine, Buprenorphine, Dimethyl Sulfoxide sulfoxide, Losartan, Phenelzine, Sulfanilamide, Telmisartan, Methimazole, Valproic acid, Sorafenib, Bicalutamide, Clevidipine, Vismodegib, Idelalisib, Topiroxostat, Lobeglitazone,Dosulepin, Benzbromarone, Enasidenib, Piperaquine Phosphate, Isavuconazole, Safinamide, Lenvatinib, Methsuximide, Etravirine, Modafinil, Azelastine, Amprenavir, Geficitinib, Gefitinib, Seproxetine, Rifamycin, Fluconazole, Triclabendazole, Alpelisib, Lynestrenol, Ethinylestradiol, Gestodene, Paroxetine, Avasimibe, Curcumin Sulfate These include, but are not limited to, acetaminophen sulfate, eslicarbazepine, elexacaftor, topiramate, cenobamate, atorvastatin, cyclosporine, letrozole, methylene blue, and pharma- ceutically acceptable salts, esters, stereoisomers, derivatives, prodrugs, and solvates thereof.

[0068] In one embodiment of the present invention, the CYP450 inhibitor comprises at least a substance capable of inhibiting CYP2D6 ("CYP2D6 inhibitor"), and examples thereof include Thioridazine, Paroxetine, Cinacalcet, Bupropion, Methotrimeprazine, Fluoxetine, Midostaurin, Propafenone, Glycerol Phenylbutyrate, and the like. phenylbutyrate, halofantrine, cisapride, dacomitinib, orphenadrine, quinidine, fluvoxamine, venlafaxine, duloxetine, chlorpromazine, darifenacin, clozapine, celecoxib, cimetidine, tranylcypromine, chloroquine, bromoquinone, bromoquinone, bromoquinone, bromoquinone Chloroquine, Lumefantrine, Nilotinib, Cholecalciferol, Abiraterone, Clobazam, Rolapitant, Panobinostat, Rucaparib, Manidipine, Pitolisant, Curcumin, Delavirdine, Tipranavir, Vilazodone, Phenylbutyric Acid acid, Sulconazole, Rhein, Asunaprevir, Ritanserin, Fusidic acid, Lercanidipine,Perhexiline, Metoprolol, Desipramine, Clotrimazole, Imipramine, Quinine, Ketoconazole, Dosulepin, Terfenadine, Cyclosporine, Sulfaphenazole, Tegaserod, Ritonavir, Terbinafine, Primaquine, Nicardipine, Lorcaserin, Mirabegron, Drone Dronedarone, Risperidone, Pindolol, Loratadine, Propranolol, Imatinib, Lansoprazole, Mefloquine, Omeprazole, Selegiline, Methimazole, Verapamil, Vinblastine, Vinorelbine, Temsirolimus, Rabeprazole, Deramciclane, Peginterferon α-2b alfa-2b), Entacapone, Ospemifene, Buprenorphine, Amlodipine, Cobicistat, Ziprasidone, Amitriptyline, Vemurafenib, Reboxetine, Nevirapine, Fluphenazine, Proguanil, Nefazodone,Dexfenfluramine, Etoricoxib, Epinastine, Lovastatin, Saquinavir, Trospium, Gefitinib, Lomustine, St. John's Wort Wort, Lisdexamfetamine, Desvenlafaxine, Amiodarone, Clinafloxacin, Isoniazid, Escitalopram, Pazopanib, Asenapine, Sertraline, Ubrogepant, Ranolazine, Osilodrostat, Oritavancin, Lidocaine, Hydroxyzine, Fenfluramine, Dextropropoxyphene, Tamoxifen, Perfena Perphenazine, Promethazine, Chlorpheniramine, Acebutolol, Moclobemide, Miconazole, Rotigotine, Atorvastatin, Cerivastatin, Tripelennamine, Sparteine, Mibefradil, Pipotiazine, Biperiden, Hydroxyurea, Hydroxychloroquine, Labetalol, Mifepristone, Oxprenolol,Rosiglitazone, Sulfanilamide, Sorafenib, Bicalutamide, Dexmedetomidine, Indisulam, Tapentadol, Naloxegol, Oxymetholone, Stiripentol, Levosalbutamol, Vernakalant, Enasidenib, Artenimol, Melperone, Isavuconazole, Black Cohosh cohosh, phenelzine, safinamide, iproniazid, lenvatinib, rilpivirine, diacerein, rifamycin, dapoxetine, triclabendazole, citalopram, clemastine, clomipramine, cocaine, diphenhydramine, Diphenhydramine, Doxepin, Doxorubicin, Dexchlorpheniramine, Mizolastine, Trazodone, Methadone, Metoclopramide, Ranitidine, Haloperidol, Amoxapine, Dexchlorpheniramine maleate, Ticlopidine, Thiothixene, Nifedipine, Indinavir, Oxybutynin,Pimozide, Azelastine, Olanzapine, Felodipine, Mepyramine, Dimethyl sulfoxide, Nicotinamide, Nicotinic acid, Efavirenz, Nelfinavir, Amodiaquine, Oxamniquine, Bepridil, 1-(2-Phenylethyl)-4-phenyl-4-acetoxypiperidine, Cannabidiol, Medical Cannabis, Nabiximols, Curcumin sulfate sulfate, Eliglustat, Everolimus, Flecainide, Abemaciclib, Lasmiditan, Elexacaftor, Nortriptyline, Darunavir, Fedratinib, Methylene blue, Clofazimine, pharmaceutically acceptable salts, esters, stereoisomers, derivatives, prodrugs and solvates thereof.

[0069] In one embodiment of the present invention, the CYP450 inhibitor comprises an agent capable of inhibiting at least CYP2E1 ("CYP2E1 inhibitor"), including, but not limited to, clomethiazole, disulfiram, diethyl dithiocarbamate, isothiocyanic acid, S-adenosylmethionine, insulin, pharma- ceutically acceptable salts, esters, stereoisomers, derivatives, prodrugs, and solvates thereof.

[0070] In one embodiment of the present invention, the CYP450 inhibitor comprises a substance capable of inhibiting at least CYP3A4 ("CYP3A4 inhibitor"), and includes, for example, telithromycin, clarithromycin, itraconazole, ketoconazole, indinavir, ritonavir, saquinavir, nefazodone, diltiazem, erythromycin, fluconazole, verapamil, and the like. Examples of anti-inflammatory drugs include, but are not limited to, rapamil, Cimetidine, Amiodarone, Amprenavir, Aprepitant, Ciprofloxacin, Doxycycline, Enoxacin, Fluvoxamine, Imatinib, Miconazole, Voriconazole, Cedrol, and pharmaceutically acceptable salts, esters, stereoisomers, derivatives, prodrugs, and solvates thereof.

[0071] In one embodiment of the present invention, the CYP450 inhibitor includes a substance capable of inhibiting at least Pan-CYP450 ("Pan-CYP450 inhibitor"), and includes atipamezole, 1-aminobenzotriazole (1-ABT), Prodifen (SKF-525A), acetylshikonin, ketoconazole, chlorophyllin, cimetidine, satraplatin (JM216), metyrapone, miconazole, 17-octadecynoic acid ... acid), stripentol, amiodarone, pharmaceutically acceptable salts, esters, stereoisomers, derivatives, prodrugs, and solvates thereof.

[0072] In one embodiment of the invention, the CYP450 inhibitors further include β-cedrene, alpha-bisabolol, Chamazulene, Pogostone.

[0073] Specifically, the CYP450 inhibitor of the present invention is quinidine, montelukast, quercetin, sulfaphenazole, methoxsalen, ketoconazole, itraconazole, tranylcypromine (2-PCPA), alpha-naphthoflavone, atipamezole, sertraline, cimetidine, curcumin, thiotepa, permethrin, clotrimazole, miconazole, le, Paroxetine, Cisapride, Gemfibrozil, Clopidogrel, Zafirlukast, Sorafenib, Ritonavir, Voriconazole, Triclabendazole, Orphenadrine, Felodipine, Memantine, Letrozole, Fluoxetine, Midostaurin, Metronidazole, and pharma- ceutically acceptable salts, esters, stereoisomers, derivatives, prodrugs, and solvates thereof.

[0074] Specifically, the CYP450 inhibitor of the present invention is selected from quinidine, montelukast, quercetin, tranylcypromine, sertraline, thiotepa, clotrimazole, paroxetine, orphenadrine, pharma- ceutically acceptable salts, esters, stereoisomers, derivatives, prodrugs, and solvates thereof.

[0075] Specifically, the CYP450 inhibitor of the present invention is selected from methoxsalen, clopidogrel, memantine, pharma- ceutically acceptable salts, esters, stereoisomers, derivatives, prodrugs, and solvates thereof.

[0076] Specifically, the CYP450 inhibitor of the present invention is selected from cimetidine, curcumin, midostaurin, metronidazole, pharma- ceutically acceptable salts, esters, stereoisomers, derivatives, prodrugs, and solvates thereof.

[0077] In some embodiments of the present invention, the CYP450 inhibitor is selected from the group consisting of Quinidine sulfate, Montelukast Sodium, Quercetin, Sulfaphenazole, Methoxsalen, Ketoconazole, Itraconazole, Tranylcypromine (2-PCPA) HCl, alpha-Naphthoflavone, Atipamezole, Sertraline Hydrochloride, and the like. HCl), Cimetidine, Curcumin, Thiotepa, Permethrin, Clotrimazole, Miconazole, Paroxetine, Cisapride, Gemfibrozil, Clopidogrel Bisulfate, Zafirlukast, Sorafenib, Ritonavir, Voriconazole, Triclabendazole, Orphenadrine Citrate, Felodipine, Memantine Hydrochloride HCl), Letrozole, Fluoxetine, Midostaurin, Metronidazole, Cedrol, β-cedrene, alpha-bisabolol, Chamazulene, and Pogostone.

[0078] In particular, the CYP450 inhibitor of the present invention is selected from quinidine sulfate, montelukast sodium, quercetin, tranylcypromine hydrochloride, sertraline hydrochloride, thiotepa, clotrimazole, paroxetine, orphenadine citrate, methoxsalen, clopidogrel sulfate, memantine hydrochloride, cimetidine, curcumin, midostaurin, metronidazole, cedrol, β-cedrene, α-bisabolol, chamazulene, pogostone.More particularly, the CYP450 inhibitor of the present invention is selected from quinidine sulfate, montelukast sodium, quercetin, tranylcypromine hydrochloride, sertraline hydrochloride, thiotepa, clotrimazole, paroxetine, orphenadine citrate, cedrol, α-bisabolol, chamazulene, pogostone.

[0079] "Dry eye syndrome" refers to an eye disease caused by many factors, characterized by dry eyes as the main symptom, and is always accompanied by phenomena such as itching in both eyes, foreign body sensation, burning sensation or photophobia, blurred vision, and fluctuations in vision. Common symptoms include dry eyes, eye fatigue, itchy eyes, foreign body sensation, painful burning sensation, viscous secretion, phobia, photophobia, and sensitivity to external stimuli. Eyes may become too dry and tear production may be insufficient, stimulating tear secretion and causing frequent tearing. In severe cases, the eyes may become red and swollen, bloodshot, keratinized, and the corneal epithelium may be damaged and thread-like material may adhere to the eye. Over time, this damage may cause keratoconjunctivitis and affect vision. The dry eye syndrome of the present invention includes keratoconjunctivitis sicca (KCS), and further includes either one of dry eye syndrome with reduced tear secretion and dry eye syndrome with increased tear evaporation.

[0080] Dry eye syndrome with reduced tear secretion is divided into dry eye syndrome with Sjögren's syndrome and dry eye syndrome without Sjögren's syndrome. Dry eye syndrome with Sjögren's syndrome includes cases with lacrimal gland disease such as congenital alacrimal gland disease, sarcoidosis, and graft-versus-host disease (GVHD) due to bone marrow transplantation, cases with lacrimal obstruction due to ocular pemphigoid, Stevens-Johnson syndrome, and trachoma, and cases with reduced reflex secretion due to diabetes and corneal refractive surgery (LASIK: Laser (assisted) in situ keratomileusis).

[0081] In addition, xerophthalmia with increased tear evaporation may include cases accompanied by a decrease in the oil layer due to meibomian gland dysfunction, blepharitis, etc.; cases accompanied by insufficient blinking or eyelid closure due to exophthalmos, lagophthalmos, etc.; cases accompanied by decreased tear stability due to contact lens wear; cases accompanied by decreased mucin secretion from free goblet cells; and cases accompanied by VDT work.

[0082] The terms "prevention" or "treatment" include therapeutic or prophylactic treatments or measures aimed at preventing or delaying the targeted pathological condition or disease state. A subject is shown to have been successfully "prevented" or "treated" by the methods of the invention if, after receiving a therapeutically effective amount of a CYP450 inhibitor, pharmaceutical composition or drug described in the invention, one or more observable and / or measurable signs and symptoms of a particular disease are reduced or eliminated in the subject.

[0083] In the present invention, the term "animal" generally refers to vertebrates, particularly mammals, including humans. The term "non-human animals" refers to any vertebrate other than humans, particularly mammals. In some embodiments of the present invention, the non-human animals described in the present invention are animals kept at home (i.e., animals kept and tamed by humans, whose reproduction can be controlled by humans, and used for functions such as food, labor, fur, pets, experiments, etc.), such as economic animals, pet animals, and laboratory animals. Economic animals (e.g., livestock) include, for example, pigs, cows, sheep, horses, donkeys, foxes, raccoon dogs, minks, and camels. Pet animals include, for example, dogs, cats, rabbits, and mice (e.g., guinea pigs, hamsters, gerbils, chinchillas, squirrels, etc.). Laboratory animals include, for example, monkeys, dogs, rabbits, cats, and mice (e.g., rats, mice).

[0084] Various publications, patents, and published patent specifications cited herein are hereby incorporated by reference in their entireties.

[0085] The following embodiments of the present invention will clearly and completely describe the technical solutions of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, and are not all of the embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative efforts are all included in the protection scope of the present invention. EXAMPLES

[0086] Example 1: Miticidal experiment 1. Experimental subjects This study was conducted in accordance with the ethical principles of the Declaration of Helsinki, "Ethical Guidelines for Life Science and Medical Research Involving Human Subjects." Demodex mites were collected from patients with a confirmed diagnosis of ophthalmic Demodex infection. Those who met the inclusion criteria were informed and agreed to participate in the study after signing a written informed consent.

[0087] 2. Demodex detection Demodex detection was performed by standard eyelash microscopy. Three eyelashes were plucked from each eyelid, for a total of 12 eyelashes. Three plucked eyelashes were immediately placed on a glass slide and observed under a standard light microscope. Demodex mites of all stages were counted and classified based on morphology (specific criteria: head-to-body ratio of 1:1 for sebaceous Demodex mites, and head-to-body ratio of 1:3-1:4 for follicular Demodex mites). Only adults fully exposed to the field of view were used as experimental subjects (larvae and eggs were not studied because they tend to die in the early stages of life).

[0088] 3. In Vitro Cultivation of Demodex mites Based on the Demodex detection, 50μl of different solutions were added to each slide, and the survival of the parasites was observed every hour. The movement of the parasites (body, limbs, etc.) was observed under a microscope to determine whether they died. During the experiment, two experienced Demodex-related experimenters observed and judged them separately, and if the judgment results differed, a third experienced experimenter judged them independently. In vitro culture was performed in an artificial climate chamber at a temperature of 20℃ and a humidity of 96%. The slides were transported in a humid chamber during observation, and a high humidity state was ensured by adding the solution appropriately before the solution evaporated and bubbles were generated.

[0089] 4. Screening of Anti-mite Compounds The test compounds are shown in Table 1. (1) Preparation of compound solutions: Each compound was taken and prepared in 0.9% NaCl solution. The final concentrations of the compounds are shown in Table 1. (2) 50 μl of each compound solution was dropped onto the mites, and a cover glass was placed over the mites. (3) To the control group, 50 μl of the solute of this compound, i.e., 0.9% NaCl solution, was dropped and a cover glass was placed on it. (4) The number of mites and the administration time were recorded, and the mites were then placed in an artificial incubation chamber and cultured. (5) The mites' ability to move was periodically observed under a microscope until they died. (6) The time of tick death was recorded. (7) The anti-mite activity of the compounds was statistically determined.

[0090] The experimental results are shown in Table 1.

[0091] [Table 1-1] [Table 1-2]

[0092] Example 2: Clinical study on the treatment of dry eye caused by mite infestation

[0093] (1) Inclusion and Exclusion Criteria 1.Case Selection Criteria (1) Patients who met the diagnostic criteria for dry eye based on their medical history (2) Age: 18-70 years (3) Regardless of gender (4) People who can cooperate with treatment 2.Case Exclusion Criteria (1) Patients with iridocyclitis diagnosed by slit lamp (2) Patients with high or low intraocular pressure (3) Patients with ulcerated wounds on the eyelid skin and corneal epithelial infiltration lesions on the corneal surface (4) Patients with systemic diseases, e.g., Sjögren's syndrome and liver / renal dysfunction, were excluded. (5) Those under 18 years of age or over 70 years of age (6) Individuals who are unable to cooperate with the evaluation due to their mental condition (7) Pregnant or breastfeeding women 3. Dropout and Exclusion Criteria (1) Those who are unable or do not wish to continue treatment due to the development of other diseases during the course of treatment (2) Patients who are unable to cooperate with the treatment process or whose symptoms have worsened and who do not wish to continue treatment. (3) Those who violate the study plan and use drugs not used in the study. (4) Those whose final data are incomplete and therefore the effectiveness of treatment cannot be determined

[0094] (2) End point indicator Patients were scored for ocular surface discomfort, had a general eye examination (visual acuity, intraocular pressure, slit lamp examination), had three dry eye tests (conjunctival hyperemia scoring, BUT test, Schirmer I test), had an ocular surface disease index score (OSDI), and had dry eye instrument and ocular Demodex folliculorum tests before and every week after treatment.

[0095] (3) Statistics 1. Estimation of sample content Considering that dry eye is a common clinical disease of the ocular surface and the positive rate of ocular Demodex mites is 23.8%-90.0%, the sample size calculation formula for quantitative data superiority test was used to calculate that the experimental and control groups had 30 patients each.

[0096] 2. Statistics and analysis of research data Statistical processing was performed using SPSS20.0 software and excel. Count data were analyzed using paired sample t-test for normal distribution data, quantitative data using chi-square test, and non-normal distribution data using non-parametric test. The results are shown as mean ± standard deviation x + s), and there is a statistically significant difference when P<0.05.

[0097] The above description is merely a preferred embodiment of the present invention, and does not limit the present invention. Any modifications, equivalent replacements, etc. made within the scope of the spirit and principle of the present invention should be included within the protection scope of the present invention.

[0098] The embodiments and methods described herein may be modified according to the capabilities, experience and preferences of those skilled in the art.

[0099] The method steps specified in a certain order in the present invention do not constitute any limitation on the order of the method steps.

Claims

1. A pharmaceutical composition for use in the prevention and / or treatment of diseases caused by acne mite infection for suppressing and / or killing acne mites in a subject, the pharmaceutical composition comprising a cytochrome CYP450 inhibitor.

2. The pharmaceutical composition according to claim 1, wherein the disease is selected from the group consisting of eye diseases, skin diseases, and allergic diseases.

3. The eye disease is selected from the group consisting of blepharitis, blepharokeratoconjunctivitis, meibomian gland dysfunction, eyelash loss, abnormal eyelash arrangement, conjunctivitis and eyelid conjunctivitis, pterygium, keratitis, eyelid basal cell carcinoma, dry eye, and chalazion, the skin disease is selected from the group consisting of seborrheic dermatitis, acne, rosacea-like dermatitis, follicular pityriasis, perioral dermatitis, acne mite disease, sarcoptic mange mite disease, and basal cell carcinoma, or the allergic disease is selected from the group consisting of allergic asthma, allergic rhinitis, allergic dermatitis, and allergic conjunctivitis, the pharmaceutical composition according to claim 2.

4. The pharmaceutical composition according to claim 1, wherein the disease is keratoconjunctivitis sicca.

5. The keratoconjunctivitis sicca has one or more symptoms selected from the symptoms of eye itching, foreign body sensation, burning sensation, photophobia, haziness, visual fluctuation, eye dryness, tired eyes, thickened secretions, sensitivity to external stimuli, red and swollen eyes, congestion, keratinization, and damage to the corneal epithelium with filaments adhering thereto, the pharmaceutical composition according to claim 1.

6. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is in the form of a topical preparation.

7. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is in the form of an ophthalmic preparation or a topical skin preparation.

8. The ophthalmic preparation is selected from the group consisting of eye drops, eye ointments, ophthalmic gels, ophthalmic emulsions, ophthalmic suspensions, ophthalmic film agents, eye washes, and intraocular injections, or the skin preparation is selected from the group consisting of aerosol agents, powders, detergents, tinctures, liniments, coating agents, ointments, gels, pastes, and emulsions, the pharmaceutical composition according to claim 7.

9. The cytochrome CYP450 inhibitor is selected from the group consisting of dihydroanthraquinone, emodin, 1,4-naphthoquinone, resveratrol, methoxysoralen, diosmetin, its pharmaceutically acceptable salts, esters, stereoisomers, derivatives, prodrugs and solvates. The pharmaceutical composition according to any one of claims 1 to 8.

10. The cytochrome CYP450 inhibitor is selected from the group consisting of acyclovir, amiodarone, atazanavir, caffeine, cimetidine, ciprofloxacin, enoxacin, famotidine, flutamide, fluvoxamine, lidocaine, lomefloxacin, mexiletine, moclobemide, norfloxacin, ofloxacin, perphenazine, propafenone, ropinirole, tacrine, ticlopidine, tocainide, verapamil, its pharmaceutically acceptable salts, esters, stereoisomers, derivatives, prodrugs and solvates. The pharmaceutical composition according to any one of claims 1 to 8.

11. The cytochrome CYP450 inhibitor is selected from the group consisting of 1,2-phenylenebis(methylene)selenocyanate, 1,3-phenylenebis(methylene)selenocyanate, 1,4-phenylenebis(methylene)selenocyanate, α-naphthoflavone, acetylene, 2-ethynylpyrene, hesperetin, homoeriodictyol, acacetin, diosmetin, resveratrol, ortipraz, 2,4,3',5'-tetramethoxystilbene, hydroxystilbenes, flutamide, paclitaxel, mitoxantrone, docetaxel, tamoxifen, doxorubicin, daunorubicin, trans-stilbene analogs, imperatorin, isopimpinellin, purpurin, alizarin, polycyclic aromatic hydrocarbons, apigenin, kaempferol, quercetin, amethoflavone, quercitrin, rutin, trans-resveratrol methyl ethers, 3',4'-dimethoxyflavone, 5,7,4'-trimethoxyflavone, curcumin, 7,4'-dimethoxyflavone, 7,3'-dimethoxyflavone, thiomethylstilbenes, 2,2',4,6'-tetramethoxystilbene, methoxyflavonoids, melatonin, 2,3,4-trimethoxy-4'-methylthiostilbene, propargyloxyflavones, 4'-methoxy-5,7-dihydroxyflavone, 3'-fluoro-6,7,10-trimethoxy-α-naphthoflavone, coumarin, its pharmaceutically acceptable salts, esters, stereoisomers, derivatives, prodrugs and solvates, and the pharmaceutical composition according to any one of claims 1 to 8.

12. The cytochrome CYP450 inhibitor is selected from the group consisting of letrozole, clotrimazole, tranylcypromine, pilocarpine, miconazole, amiodarone, ketoconazole, memantine, amphetamine, fenofibrate, methoxsalen, methyrapone, azelastine, clofibrate, homopiperizole, isoniazid, menadione, nilvadipine, rosiglitazone, seratrodast, azithromycin, nicotine, triclabendazole, selegiline, its pharmaceutically acceptable salts, esters, stereoisomers, derivatives, prodrugs and solvates, and the pharmaceutical composition according to any one of claims 1 to 8.

13. The cytochrome CYP450 inhibitor is selected from the group consisting of ticlopidine, orphenadrine, clotrimazole, itraconazole, raloxifene, thiamazole, rilpivirine, memantine, clopidogrel, thiotepa, curcumin, sorafenib, tamoxifen, ketoconazole, crisaborole, manidipine, piperazine, lopinavir, amprenavir, simvastatin, nelfinavir, selegiline, amlodipine, desipramine, doxorubicin, fenciclovir, azelastine, colchicine, ethanol, isoflurane, miconazole, quinidine, roxithromycin, sulfafenazole, nitric oxide, cisplatin, regorafenib, enzalutamide, quazepam, crizotinib, enasidenib, voriconazole, safinamide, lenvatinib, rifamycin, triclabendazole, paroxetine, pezidartinib, fluvoxamine, modafinil, curcumin sulfate, abemaciclib, elezacaftor, senobamate, sertraline, lopinavir, ritonavir, methylene blue, 5,5'-dimethyl-2,2'-bipyridine, cedrol, its pharmaceutically acceptable salts, esters, stereoisomers, derivatives, prodrugs and solvates, and the pharmaceutical composition according to any one of claims 1 to 8.

14. The cytochrome CYP450 inhibitor is gemfibrozil, clopidogrel, felodipine, mometasone furoate, zafirlukast, sorafenib, erlotinib, dabrafenib, candesartan cilexetil, salmeterol, trametinib, fluticasone, fluticasone furoate ester, fluticasone propionate ester, ritonavir, clotrimazole, ketoconazole, rucaparib, pazopanib, cabozantinib, atazanavir, terbinafine, rofecoxib, quinidine, fenofibrate, bezafibrate, cimetidine, ketoprofen, pyrimethamine, ticlopidine, idelalisib, belinostat, candesartan, opicapone, tegaserod, abiraterone, ubrogepant, amoxicillin, rosiglitazone, trimethoprim, tamoxifen, irbesartan, quinine, efavirenz, rabeprazole, crisaborole, navirone, bexarotene, nicardipine, loratadine, eltrombopag, diltiazem, enzalutamide, fluvastatin, levothyroxine, oxybutynin, medroxyprogesterone acetate, spironolactone, amlodipine, saquinavir, genistein, lenvatinib, pioglitazone, nilotinib, teriflunomide, topiroxostat, rosuvastatin, troglitazone, amitriptyline, cerivastatin, warfarin, lapatinib, raloxifene, quercetin, ethinyl estradiol, colchicine, isoniazid, metronidazole, nilutamide, phenelzine, piroxicam, sulfafenazole, terfenadine, triazolam, valproic acid, diethylstilbestrol, besimodegib, legolasfenib, lumacaftor, midostaurin, enasidenib, retelmovir, bosutinib, deferasirox, rifampicin, verapamil, simvastatin, sulfinpyrazone, montelukast, nilvadipine, riotrix, mometasone, mifepristone, bemrafenib, licoferon, rutin, ponatinib, isavuconazole, rifamycin, triclabendazole, alpelisib, balaglitazone, siglitazone, lobeglitazone, netoglitazone, riboglitazone, tolbutamide, nifedipine, cholecalciferol, atorvastatin, losartan, mefenamic acid, troleandomycin,The pharmaceutical composition according to any one of claims 1 to 8, which is selected from the group consisting of ezetimibe, anastrozole, abemaciclib, elecsacaftor, favipiravir, methylene blue, selpercatinib, repotrectinib, clofazimine, saquinavir, miconazole, its pharmaceutically acceptable salts, esters, stereoisomers, derivatives, prodrugs, and solvates.

15. The cytochrome CYP450 inhibitor is fluvoxamine, chloramphenicol, delavirdine, gemfibrozil, stilbene tol, fluoxetine, imipramine, clomipramine, lansoprazole, isoniazid, zafirlukast, tioconazole, miconazole, sertraline, efavirenz, modafinil, eslicarbazepine acetate, abiraterone, zucapsaicin, ticlopidine, cisapride, manidipine, altenimul, lopinavir, omeprazole, voriconazole, esomeprazole, pantoprazole, rucaparib, dovitinib, oritavancin, zonisamide, luliconazole, bortezomib, nilutamide, sitaxentan, clozapine, ethanol, nilvadipine, olanzapine, tipranavir, naloxegol, midostaurin, etoricoxib, sildenafil, citalopram, memantine, dexlansoprazole, clinofloxacin, fenofibrate, loratadine, ubrogepant, amiodarone, osilodrostat, moclobemide, nicardipine, indomethacin, progesterone, felbamate, rabeprazole, troglitazone, amitriptyline, ritonavir, mephenytoin, tranylcypromine, oxcarbazepine, ketoconazole, thalidomide, aminopyrine, fluvastatin, quinine, warfarin, diazepam, cimetidine, probenecid, carbamazepine, buprenorphine, dimethyl sulfoxide, losartan, phenelzine, sulfanilamide, telmisartan, thiamazole, valproic acid, sorafenib, bicalutamide, clevidipine, besmidegib, idelalisib, topiroxostat, lobeglitazone, dosulepin, benzobromarone, enasidenib, piperazine phosphate, isavuconazole, safinamide, lenvatinib, methsuximide, etravirine, modafinil, azelastine, amprenavir, gefitinib, seproxetine, rifamycin, fluconazole, triclabendazole, alpelisib, linestrenol, ethinyl estradiol, gestodene, paroxetine, aprepitant, avasimibe, curcumin sulfate, eslicarbazepine, elecacaftor, topiramate, cenobamate, atorvastatin, cyclosporine, letrozole, methylene blue,The pharmaceutical composition according to any one of claims 1 to 8, selected from the group consisting of pharmaceutically acceptable salts, esters, stereoisomers, derivatives, prodrugs and solvates.

16. The cytochrome CYP450 inhibitors include thioridazine, paroxetine, cinacalcet, bupropion, metotrimeprazine, fluoxetine, midostaurin, propafenone, phenylbutyrate glycerol, halofantrine, cisapride, dacomitinib, orphenadrine, quinidine, fluvoxamine, venlafaxine, duloxetine, chlorpromazine, darifenacin, clozapine, celecoxib, cimetidine, tranylcypromine, chloroquine, lumefantrine, nilotinib, colecalciferol, abiraterone, clobazam, loralpitant, panobinostat, rucaparib, manidipine, pinitol, curcumin, delavirdine, tipranavir, vilazodone, phenylbutyric acid, sulconazole, ray, asunaprevir, ritanserin, fusidic acid, lercanidipine, perhexiline, metoprolol, desipramine, clotrimazole, imipramine, quinine, ketoconazole, dosulepin, trifluoperazine, cyclosporine, sulfafenazole, tegaserod, ritonavir, terbinafine, primaquine, nicardipine, lorcaserin, mirabegron, dronedarone, risperidone, pindolol, loratadine, propranolol, imatinib, lansoprazole, mefloquine, omeprazole, selegiline, thiamazole, verapamil, vincristine, vinorelbine, temsirolimus, rabeprazole, delamycline, peginterferon α-2b, entacapone, ospemifene, buprenorphine, amlodipine, cobicistat, diprasidone, amitriptyline, bemrafenib, levoxetine, nevirapine, perphenazine, promethazine, chlorpheniramine, acebutolol, moclobemide, miconazole, rotigotine, atorvastatin,Celevastatin, tripelenamine, sparteine, mibefradil, pipothiazine, biperiden, hydroxycarbamide, hydroxychloroquine, labetalol, mifepristone, oxprenolol, rosiglitazone, sulfanilamide, sorafenib, bicalutamide, dexmedetomidine, indisulam, tapentadol, naloxegol, oximetron, stiripentol, levosalbutamol, bernacalant, enasidenib, altenimol, melperone, isavuconazole, black cohosh, phenergan, safinamide, iproniazid, lenvatinib, rilpivirine, diacerein, rifamycin, dapoxetine, triclabendazole, citalopram, clemastine, clomipramine, cocaine, diphenhydramine, doxepin, doxorubicin, dexchlorpheniramine, mizolastine, trazodone, methadone, metoclopramide, ranitidine, haloperidol, amoxapine, dexchlorpheniramine maleate, ticlopidine, thiothixene, nifedipine, indinavir, oxybutynin, pimozide, azelastine, olanzapine, felodipine, mepyramine, dimethyl sulfoxide, nicotinamide, nicotinic acid, efavirenz, nelfinavir, amodiaquine, oxamniquine, bepridil, 1-(2-phenylethyl)-4-phenyl-4-acetoxypiperidine, cannabidiol, medical cannabis, nabiximols, curcumin sulfate, eliglustat, everolimus, flecainide, abemaciclib, lasmiditan, elecsacaftor, nortriptyline, darunavir, fedratinib, methylene blue, clofazimine, its pharmaceutically acceptable salts, esters, stereoisomers, derivatives, prodrugs and solvates, the pharmaceutical composition according to any one of claims 1 to 8.

17. The cytochrome CYP450 inhibitor is selected from the group consisting of chlormethiazole, disulfiram, diethyl dithiocarbamate, isothiocyanic acid, S-adenosylmethionine, insulin, its pharmaceutically acceptable salts, esters, stereoisomers, derivatives, prodrugs and solvates, the pharmaceutical composition according to any one of claims 1 to 8.

18. The cytochrome CYP450 inhibitor is selected from the group consisting of telithromycin, clarithromycin, itraconazole, ketoconazole, indinavir, ritonavir, saquinavir, nefazodone, diltiazem, erythromycin, fluconazole, verapamil, cimetidine, amiodarone, amprenavir, aprepitant, ciprofloxacin, doxycycline, enoxacin, fluvoxamine, imatinib, miconazole, voriconazole, cedrol, its pharmaceutically acceptable salts, esters, stereoisomers, derivatives, prodrugs and solvates, the pharmaceutical composition according to any one of claims 1 to 8.

19. The cytochrome CYP450 inhibitor is selected from the group consisting of atipamezole, 1-aminobenzotriazole, prodifen, acetylcicinnine, ketoconazole, chlorophyllin, cimetidine, satraplatin, methylrapone, miconazole, 17-octadecenoic acid, stiripentol, amiodarone, its pharmaceutically acceptable salts, esters, stereoisomers, derivatives, prodrugs and solvates, the pharmaceutical composition according to any one of claims 1 to 8.

20. The cytochrome CYP450 inhibitor is selected from the group consisting of quinidine, montelukast, quercetin, sulfafenazole, methoxsalen, ketoconazole, itraconazole, tranylcypromine, α-naphthoflavone, atipamezole, sertraline, cimetidine, curcumin, thiotepa, permethrin, clotrimazole, miconazole, paroxetine, cisapride, gemfibrozil, clopidogrel, zafirlukast, sorafenib, ritonavir, voriconazole, triclabendazole, orphenadrine, felodipine, memantine, letrozole, fluoxetine, midostaurin, metronidazole, cedrol, β-cedrene, α-bisabolol, camazulene, patchouli alcohol, its pharmaceutically acceptable salts, esters, stereoisomers, derivatives, prodrugs and solvates, the pharmaceutical composition according to any one of claims 1 to 8.