Preventive or therapeutic agent for chronic sinusitis, and use of statins for producing the same

Abstract

To provide a novel agent for preventing or treating chronic sinusitis, and use of statin for producing the same.SOLUTION: An agent for preventing or treating chronic sinusitis contains statin as an active ingredient.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a preventive or therapeutic agent for chronic sinusitis, and the use of a statin for producing the same. [Background technology]

[0002] Chronic sinusitis is a disease in which chronic inflammation occurs in one or more of the maxillary, ethmoid, frontal, and sphenoid sinuses due to infection with a virus or bacteria, resulting in the accumulation of mucus and / or pus. Eosinophilic sinusitis, a type of chronic sinusitis, is recognized as a designated intractable disease in Japan, and is considered to be a disease for which intensive research into treatment is required. In addition, the number of patients with eosinophilic sinusitis has been increasing in East Asia in recent years, and for this reason, it is considered to be a disease for which intensive research into treatment is required (Non-Patent Document 1).

[0003] Chronic sinusitis, such as eosinophilic sinusitis, is a disease accompanied by the development of nasal polyps. Nasal polyps are fibrin clots formed by deposited fibrin (Non-Patent Document 2). In the treatment of chronic sinusitis, treatment is generally focused on removing nasal polyps. Examples of the treatment method for chronic sinusitis include oral administration of steroids to patients and surgical removal of nasal polyps. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] A. Tokunaga et al., “Novel scoring system and algorithm for classifying chronic rhinosinusitis: the JESREC Study” Allergy, 70(2015), 995-1003 [Non-Patent Document 2] T. Takabayashi et al., “Excessive Fibrin Deposition in Nasal Polyps Caused by Fibrinolytic Impairment through Reduction of Tissue Plasminogen Activator Expression” AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol.187, 2013, 49-57 [Non-Patent Document 3] Blood, “Tissue-type plasminogen activator(t-PA)is stored in Weibel-Palade bodies in human endothelial cells both in vitro and in vivo”2002, May 15;99(10):3637-45 [Non-Patent Document 4] J Thromb Haemost. “Retinoids and activation of PKC induce tissue-type plasminogen activator expression and storage in human astrocytes”2008 6(10):1796-803. Summary of the Invention [Problem to be solved by the invention]

[0005] However, oral administration of steroids to patients requires administration of steroids for a long period of time, which has the problem of side effects. On the other hand, surgical removal of nasal polyps has the problem that even if nasal polyps are removed, they tend to recur. For this reason, the development of a new method of treating chronic sinusitis is desired.

[0006] The present invention has been made in consideration of the above-mentioned conventional problems, and an object of the present invention is to provide a novel agent for preventing or treating chronic sinusitis, and use of a statin for producing the same. [Means for solving the problem]

[0007] Tissue plasminogen activator (t-PA) is known to promote the degradation of fibrin clots. The mechanisms controlling the expression of tissue plasminogen activator are known to vary depending on the type of cells expressing tissue plasminogen activator, but the mechanisms controlling the expression of tissue plasminogen activator in airway epithelial cells involved in the formation of nasal polyps have not been fully understood.

[0008] As a result of intensive research conducted by the present inventors to achieve the above object, they discovered that statins have the effect of increasing the expression level of t-PA in airway epithelial cells, and thus completed the present invention. That is, the present invention has the following configurations.

[0009] <1> A preventive or therapeutic agent for chronic sinusitis, which contains a statin as an active ingredient.

[0010] <2> The statin is one or more substances selected from the group consisting of fluvastatin, simvastatin, atorvastatin, pitavastatin, rosuvastatin, pravastatin, cerivastatin and lovastatin, or a derivative or salt of said substance; <1> A preventive or therapeutic agent for chronic sinusitis described in the above.

[0011] <3> The chronic sinusitis is eosinophilic sinusitis, nasal polyps associated with aspirin asthma, choanal polyps, or cystic fibrosis. <1> or <2> A preventive or therapeutic agent for chronic sinusitis described in the above.

[0012] <4> Use of a statin for the manufacture of a preventive or therapeutic agent for chronic sinusitis. Effect of the Invention

[0013] According to one aspect of the present invention, there is provided an agent for preventing or treating chronic sinusitis, and use of a statin for producing the same.

[0014] Statins are substances used to treat diseases other than chronic sinusitis, and therefore, according to one embodiment of the present invention, a safe preventive or therapeutic agent for chronic sinusitis can be provided.

[0015] Statins are substances that can be produced inexpensively, and therefore, according to one embodiment of the present invention, an inexpensive preventive or therapeutic agent for chronic sinusitis can be provided. [Brief description of the drawings]

[0016] [Figure 1] 1 is a graph showing the expression level of t-PA mRNA in human airway epithelial cells in the presence of different concentrations of fluvastatin. [Diagram 2] 1 is a graph showing the amount of t-PA mRNA expression in human airway epithelial cells in the presence of different concentrations of simvastatin. [Diagram 3] 1 is a graph showing the rate of change in nasal polyp weight in the presence of different concentrations of fluvastatin. [Figure 4] 1 is a graph showing the amount of t-PA in nasal polyp supernatants in the presence of different concentrations of fluvastatin. [Diagram 5] 1 is a graph showing the amount of t-PA in nasal polyp tissues in the presence of different concentrations of fluvastatin. [Figure 6] 1 is a graph showing ddimers in nasal polyp tissue in the presence of different concentrations of fluvastatin. [Figure 7] 1 is a graph showing the amount of t-PA mRNA expression in human airway epithelial cells in the presence of multiple types of statins. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] 1. Definitions of Terms [1-1.Chronic sinusitis] As used herein, the term "chronic sinusitis" refers to a disease in which chronic inflammation occurs for 12 weeks or more in one or more of the paranasal sinuses, namely the maxillary sinus, the ethmoid sinus, the frontal sinus, and the sphenoid sinus, and nasal polyps are formed.

[0018] Specific examples of chronic sinusitis include eosinophilic sinusitis, nasal polyps associated with aspirin asthma, choanal polyps, and cystic fibrosis. The prophylactic or therapeutic agent for chronic sinusitis according to one embodiment of the present invention is preferably used for the purpose of preventing or treating eosinophilic sinusitis.

[0019] [1-2. Preventive agents] As used herein, the term "prophylactic agent" refers to a drug that provides a prophylactic effect. The prophylactic effect includes, but is not limited to, the effects exemplified below.

[0020] (1) Preventing or reducing the risk of developing one or more symptoms of a disease (e.g., nasal polyps) compared to when the prophylactic agent is not administered.

[0021] (2) preventing or reducing the risk of recurrence of one or more symptoms associated with a disease (e.g., nasal polyps) compared to not administering the prophylactic agent;

[0022] (3) preventing or reducing the risk of developing one or more symptoms of a disease (e.g., nasal polyps) compared to when the prophylactic agent is not administered;

[0023] [1-3. Therapeutic Agents] As used herein, the term "therapeutic agent" refers to a drug that provides a therapeutic effect. The above therapeutic effect refers to, but is not limited to, the effects exemplified below.

[0024] (1) reducing the severity of one or more symptoms associated with the disease (e.g., nasal polyps) compared to when the therapeutic agent is not administered;

[0025] (2) preventing an increase in severity or progression of one or more symptoms of the disease (e.g., nasal polyps) compared to when the therapeutic agent is not administered;

[0026] (3) reducing the rate at which one or more symptoms associated with the disease (e.g., nasal polyps) increase in severity or progress compared to when the therapeutic agent is not administered;

[0027] 2. Statins One embodiment of the present invention contains a statin as an active ingredient. As used herein, the term "statin" refers to a substance that inhibits the activity of HMG-CoA reductase, a rate-limiting enzyme in the cholesterol biosynthesis pathway.

[0028] The inventors have found that the statin has the effect of increasing the expression level of t-PA in airway epithelial cells involved in the formation of nasal polyps. Nasal polyps in chronic sinusitis are fibrin clots formed by the deposition of fibrin. It is believed that plasmin, an active protease, is formed from plasminogen by the action of t-PA, and the plasmin decomposes fibrin, thereby shrinking the nasal polyps. When fibrin is decomposed by the action of t-PA, ddimer, a fibrin degradation product, is generated. Therefore, whether or not the fibrin that constitutes nasal polyps has actually been decomposed can be confirmed by examining the concentration of ddimer after administration of a statin.

[0029] Direct administration of t-PA by intravenous injection is used to treat acute myocardial infarction, acute cerebral infarction, pulmonary embolism, acute peripheral arterial thrombosis, etc. However, t-PA is not suitable for long-term administration because of its neurotoxicity under ischemic conditions. On the other hand, statins stimulate t-PA production in nasal mucosa epithelial cells, which results in the production of t-PA, and as a result, the above-mentioned side effects do not occur.

[0030] Statins are also known as drugs for treating hyperlipidemia that lower cholesterol levels in the blood, and do not cause side effects even when taken on a daily basis. Therefore, the prophylactic or therapeutic agent for chronic sinusitis according to one embodiment of the present invention can be taken for a long period of time without causing side effects.

[0031] The prophylactic or therapeutic agent for chronic sinusitis according to one embodiment of the present invention can reduce nasal polyps and prevent recurrence after surgery to remove nasal polyps.

[0032] In the present specification, the term "prevent" may mean an effect of stabilizing symptoms during a period in which the symptoms of chronic sinusitis are alleviated, such as after surgery to remove nasal polyps, and / or an effect of maintaining said period for a longer period. Therefore, the prophylactic agent for chronic sinusitis according to one embodiment of the present invention may be an agent for preventing recurrence of chronic sinusitis.

[0033] In one embodiment, the statin is fluvastatin, whose IUPAC name is (3R,5S,6E)-7-[3-(4-Fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3,5-dihydroxyhept-6-enoic acid and CAS number is 93957-54-1.

[0034] In one embodiment, the statin is simvastatin, whose IUPAC name is (1S,3R,7S,8S,8aR)-8-{2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl 2,2-dimethylbutanoate and CAS number is 79902-63-9.

[0035] In one embodiment, the statin is atorvastatin, whose IUPAC name is (3R,5R)-7-[2-(4-Fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid and CAS number is 134523-00-5.

[0036] In one embodiment, the statin is pitavastatin, whose IUPAC name is (3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxyhept-6-enoic acid and CAS number is 147511-69-1.

[0037] In one embodiment, the statin is rosuvastatin, whose IUPAC name is (3R,5S,6E)-7-[4-(4-Fluorophenyl)-2-(N-methylmethanesulfonamido)-6-(propan-2-yl)pyrimidin-5-yl]-3,5-dihydroxyhept-6-enoic acid and CAS number is 287714-41-4.

[0038] In one embodiment, the statin is pravastatin, whose IUPAC name is (3R,5R)-3,5-dihydroxy-7-((1R,2S,6S,8R,8aR)-6-hydroxy-2-methyl-8-{[(2S)-2-methylbutanoyl]oxy}-1,2,6,7,8,8a-hexahydronaphthalen-1-yl)-heptanoic acid and CAS number is 81093-37-0.

[0039] In one embodiment, the statin is cerivastatin, whose IUPAC name is (3R,5S,6E)-7-[4-(4-Fluorophenyl)-5-(methoxymethyl)-2,6-bis(propan-2-yl)pyridin-3-yl]-3,5-dihydroxyhept-6-enoic acid and CAS number is 145599-86-6.

[0040] In one embodiment, the statin is lovastatin, whose IUPAC name is (1S,3R,7S,8S,8aR)-8-{2-[(2R,4R)-4-Hydroxy-6-oxooxan-2-yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl (2S)-2-methylbutanoate and CAS number is 75330-75-5.

[0041] In one embodiment, the statin may be a derivative or salt of the above-mentioned substances.

[0042] As used herein, the term "derivative" refers to a group of compounds that are produced by replacing a portion of a molecule of a specific compound with another functional group or another atom.

[0043] Examples of the other functional groups include an alkyl group, an alkoxy group, an alkylthio group, an aryl group, an aryloxy group, an arylthio group, an arylalkyl group, an arylalkoxy group, an arylalkylthio group, an arylalkenyl group, an arylalkynyl group, an allyl group, an amino group, a substituted amino group, a silyl group, a substituted silyl group, a silyloxy group, a substituted silyloxy group, an arylsulfonyloxy group, an alkylsulfonyloxy group, a nitro group, etc. Examples of the other atoms include a carbon atom, a hydrogen atom, an oxygen atom, a nitrogen atom, a sulfur atom, a phosphorus atom, a halogen atom, etc.

[0044] In this specification, the term "salt" is not limited as long as it is a physiologically acceptable salt to be administered to a subject as a pharmaceutical. Examples of salts include alkali metal salts (potassium salt, etc.), alkaline earth metal salts (calcium salt, magnesium salt, etc.), ammonium salts, organic base salts (trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.), organic acid salts (acetate salt, maleate salt, tartrate salt, methanesulfonate salt, benzenesulfonate salt, formate salt, toluenesulfonate salt, trifluoroacetate salt, etc.), and inorganic acid salts (hydrochloride salt, hydrobromide salt, sulfate salt, phosphate salt, etc.).

[0045] The derivatives or salts of the above-mentioned substances can be produced by known methods. Of course, commercially available derivatives or salts can also be used.

[0046] 3. Preventive or therapeutic agent for chronic sinusitis [3-1. Dosage form and dosage form] The subject of administration of the prophylactic or therapeutic agent for chronic sinusitis according to one embodiment of the present invention is not limited. In one embodiment, the subject of administration is a human. In another embodiment, the subject of administration is an animal other than a human. Examples of the animal other than a human include mammals other than a human (such as cows, pigs, sheep, goats, horses, dogs, cats, rabbits, mice, and rats).

[0047] The prophylactic or therapeutic agent for chronic sinusitis according to one embodiment of the present invention can be administered to a subject by any administration route. Examples of the administration route include oral administration, parenteral administration, transdermal administration, transmucosal administration, and intravenous administration. Therefore, the dosage form of the prophylactic or therapeutic agent for chronic sinusitis can be an oral drug, an external drug, an injection, etc.

[0048] Among the above-mentioned administration routes, oral administration and transmucosal administration are preferred, and transmucosal administration is more preferred. Examples of transmucosal administration include nasal sprays, nasal drops, nasal irrigation, and direct injection into the nasal cavity. With this configuration, administration is simple and the therapeutic effect can be sufficiently obtained.

[0049] The prophylactic or therapeutic agent for chronic sinusitis according to one embodiment of the present invention may be administered by a method of indwelling the agent in a living body, etc. Specifically, the method may be (i) a method of encapsulating the prophylactic or therapeutic agent inside a substrate (e.g., a biodegradable polymer) and indwelling the substrate in a living body, (ii) a method of covering the surface of a substrate (e.g., a biodegradable polymer) with the prophylactic or therapeutic agent and indwelling the substrate in a living body, or (iii) a method of solidifying the prophylactic or therapeutic agent and indwelling the prophylactic or therapeutic agent in a living body.

[0050] The prophylactic or therapeutic agent for chronic sinusitis according to one embodiment of the present invention may be in the form of a liquid, powder, gel, or tablet. From the viewpoint of easy administration, the prophylactic or therapeutic agent for chronic sinusitis is preferably in the form of a tablet. On the other hand, from the viewpoint of excellent absorption efficiency, the prophylactic or therapeutic agent for chronic sinusitis is preferably in the form of a liquid or powder.

[0051] [3-2. Ingredients] The prophylactic or therapeutic agent for chronic sinusitis according to one embodiment of the present invention contains a statin as an active ingredient. In this specification, the term "active ingredient" refers to a substance that can provide a prophylactic or therapeutic effect against one or more symptoms (e.g., nasal polyps).

[0052] The concentration of the statin contained in the prophylactic or therapeutic agent for chronic sinusitis according to one embodiment of the present invention is not particularly limited. The concentration of the statin contained in the prophylactic or therapeutic agent for chronic sinusitis according to one embodiment of the present invention may be set according to the type of the statin, the selected administration route, dosage form, etc. In one example, the amount of an active ingredient in a preventive or therapeutic agent for chronic sinusitis according to one embodiment of the present invention is not particularly limited, and may be, for example, 0.001% by weight to 100% by weight, 0.01% by weight to 100% by weight, 0.1% by weight to 100% by weight, 0.1% by weight to 95% by weight, 0.1% by weight to 90% by weight, 0.1% by weight to 80% by weight, 0.1% by weight to 70% by weight, 0.1% by weight to 60% by weight, 0.1% by weight to 50% by weight, 0.1% by weight to 40% by weight, 0.1% by weight to 30% by weight, 0.1% by weight to 20% by weight, or 0.1% by weight to 10% by weight, relative to the total weight of the drug.

[0053] In one embodiment, the lower limit of the concentration of fluvastatin in the prophylactic or therapeutic agent is 1 nM or more, preferably 10 nM or more, more preferably 100 nM or more, even more preferably 1 μM or more, and most preferably 10 μM or more. The upper limit is not particularly limited, and may be, for example, 10 mM or less, 1 mM or less, or 100 μM or less.

[0054] In one embodiment, the concentration of simvastatin in the prophylactic or therapeutic agent is 1 nM to 100 μM, preferably 10 nM to 10 μM, more preferably 10 nM to 1 μM, and most preferably 10 nM to 100 nM.

[0055] The prophylactic or therapeutic agent for chronic sinusitis according to one embodiment of the present invention may contain an ingredient other than a statin.

[0056] The amount of components other than statins in the preventive or therapeutic agent for chronic sinusitis according to one embodiment of the present invention is not particularly limited, and may be, for example, 0% by weight to 99.999% by weight, 0% by weight to 99.99% by weight, 0% by weight to 99.99% by weight, 5% by weight to 99.9% by weight, 10% by weight to 99.9% by weight, 20% by weight to 99.9% by weight, 30% by weight to 99.9% by weight, 40% by weight to 99.9% by weight, 50% by weight to 99.9% by weight, 60% by weight to 99.9% by weight, 70% by weight to 99.9% by weight, 80% by weight to 99.9% by weight, or 90% by weight to 99.9% by weight, relative to the total weight of the drug.

[0057] The component other than the statin may be a component for treating symptoms associated with chronic sinusitis (such as symptoms of chronic sinusitis, symptoms of complications of chronic sinusitis, etc.) or may be a component for treating symptoms not associated with chronic sinusitis.

[0058] Examples of components other than statins include buffers, pH adjusters, isotonicity agents, preservatives, antioxidants, high molecular weight polymers, excipients, carriers, diluents, solvents, solubilizers, stabilizers, fillers, binders, surfactants, and stabilizers.

[0059] Examples of the buffering agent include phosphoric acid or a phosphate salt, boric acid or a borate salt, citric acid or a citrate salt, acetic acid or a acetate salt, carbonic acid or a carbonate salt, tartaric acid or a tartrate salt, ε-aminocaproic acid, trometamol, etc. Examples of the phosphate salt include sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, etc. Examples of the borate salt include borax, sodium borate, potassium borate, etc. Examples of the citrate salt include sodium citrate, disodium citrate, trisodium citrate, etc. Examples of the acetate salt include sodium acetate, potassium acetate, etc. Examples of the carbonate salt include sodium carbonate, sodium bicarbonate, etc. Examples of the tartrate salt include sodium tartrate, potassium tartrate, etc.

[0060] Examples of the pH adjuster include hydrochloric acid, phosphoric acid, citric acid, acetic acid, sodium hydroxide, and potassium hydroxide.

[0061] Examples of the isotonicity agent include ionic isotonicity agents (sodium chloride, potassium chloride, calcium chloride, magnesium chloride, etc.) and non-ionic isotonicity agents (glycerin, propylene glycol, sorbitol, mannitol, etc.).

[0062] Examples of the preservatives include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, sorbic acid, potassium sorbate, methyl parahydroxybenzoate, propyl parahydroxybenzoate, and chlorobutanol.

[0063] Examples of the antioxidant include ascorbic acid, tocopherol, dibutylhydroxytoluene, butylhydroxyanisole, sodium erythorbate, propyl gallate, and sodium sulfite.

[0064] Examples of the high molecular weight polymer include methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, carboxymethyl ethyl cellulose, cellulose acetate phthalate, polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, polyethylene glycol, and atelocollagen.

[0065] The prophylactic or therapeutic agent for chronic sinusitis according to one embodiment of the present invention may contain pharma- ceutically acceptable ingredients other than those exemplified above.

[0066] [3-3. Preparations and formulations] A preventive or therapeutic agent for chronic sinusitis according to one embodiment of the present invention can be prepared by a known method using a statin and the above-exemplified components other than the statin as raw materials. For example, a preventive or therapeutic agent for chronic sinusitis according to one embodiment of the present invention can be prepared by mixing a statin and the above-exemplified components other than the statin.

[0067] When administering a prophylactic or therapeutic agent for chronic sinusitis according to one embodiment of the present invention, there is no limitation on the dosage as long as the desired effect is obtained.

[0068] When administering the chronic sinusitis preventive or therapeutic agent according to one embodiment of the present invention, there is no restriction on the administration interval, as long as it can obtain the desired effect.The administration interval is, for example, once every hour to 6 months, preferably once every hour, once every 2 hours, once every 3 hours, once every 6 hours, once every 12 hours, once every day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every week, once every 2 weeks, once every 3 weeks, once every month, once every 2 months, once every 3 months, once every 4 months, once every 5 months, once every 6 months, more preferably once every day, at least once every 2 days, at least once every 3 days, at least once every 4 days, at least once every 5 days, at least once every 6 days, at least once every week.

[0069] The prophylactic or therapeutic agent for chronic sinusitis according to one embodiment of the present invention may be administered in combination with a drug for preventing or treating chronic sinusitis and / or other diseases, such as steroids, anti-leukotriene receptor antagonists, and antibody preparations (anti-IgE antibodies, anti-IL-4 receptor α antibodies, anti-IL-5 antibodies, and anti-IL-5 receptor α antibodies).

[0070] The present invention is not limited to the above-described embodiments, and various modifications are possible within the scope of the claims. Embodiments obtained by appropriately combining the technical means disclosed in different embodiments are also included in the technical scope of the present invention.

[0071] [4. Other] An embodiment of the present invention can also be configured as follows. <1> A method for preventing or treating chronic sinusitis, comprising the step of administering a preventive or therapeutic agent for chronic sinusitis containing a statin as an active ingredient to a subject (a human or a non-human mammal (such as a cow, pig, sheep, goat, horse, dog, cat, rabbit, mouse, rat, etc.)). <2> The statin is one or more substances selected from the group consisting of fluvastatin, simvastatin, atorvastatin, pitavastatin, rosuvastatin, pravastatin, cerivastatin and lovastatin, or a derivative or salt of said substance; <1> A method for preventing or treating chronic sinusitis as described in the above. <3> The dosage form of the prophylactic or therapeutic agent is a tablet. <1> or <2> A method for preventing or treating chronic sinusitis as described in the above. <4> The chronic sinusitis is eosinophilic sinusitis, nasal polyps associated with aspirin asthma, choanal polyps, or cystic fibrosis. <1> from <3> 2. A method for preventing or treating chronic sinusitis described in any one of the above. EXAMPLES

[0072] The effect of statins on promoting t-PA production was investigated using normal human airway epithelial cells.

[0073] Example 1 Five petri dishes were prepared in which human normal airway epithelial cells (NHBE) were cultured in BEGM medium. Fluvastatin was added to the medium at concentrations of 0 nM (control), 10 nM, 100 nM, 1 μM, and 10 μM, respectively, and cultured at 37° C. for 24 hours. Thereafter, the human normal airway epithelial cells were removed, and the mRNA expression level of t-PA in the human normal airway epithelial cells was measured by real-time PCR. The real-time PCR was performed according to a known method.

[0074] The above experiment was repeated 3 to 6 times, and the average value of the t-PA mRNA expression level was calculated. The t-PA mRNA expression level in the control was set as "1", and the t-PA mRNA expression level in each sample was calculated. The results are shown in Figure 1.

[0075] Example 2 The same experiment as in Example 1 was carried out, except that fluvastatin was replaced with simvastatin. The results are shown in FIG.

[0076] 〔result〕 1 and 2, it was revealed that both fluvastatin and simvastatin increased the expression level of t-PA mRNA in a concentration-dependent manner. When comparing fluvastatin and simvastatin, fluvastatin had a greater effect of increasing the expression level of t-PA mRNA.

[0077] Example 3 Human nasal polyps were harvested by surgery. The harvested nasal polyps were cut, and the weights of the resulting pieces were measured. One nasal polyp piece was placed in each well of a 24-well plate, and the nasal polyp piece was immersed in 500 μL of BEGM culture medium (prepared according to Lonza, Walkersville, MD), and fluvastatin was added to the culture medium at 0 nM (control), 0.1 μM, and 1 μM, respectively. The nasal polyp pieces were cultured in a constant temperature shaking incubator at 37° C. for 24 hours. The weights of the nasal polyp pieces after 24 hours were measured. The results are shown in FIG. 3.

[0078] 3, it was revealed that the weight of nasal polyps was significantly reduced depending on the concentration of fluvastatin, thus demonstrating that fluvastatin has an effect of reducing the weight of nasal polyps.

[0079] Example 4 In Example 3, the nasal polyp pieces whose weight was measured after culture were frozen and then crushed, and a protein-containing extract was obtained using a total protein extractor T-PER (Thermo, Waltham, MA). Then, the t-PA contained in each of the protein-containing extract and the supernatant obtained by culturing the nasal polyp pieces was measured using a tPA ELISA kit (Assaypro, St. Charles, MO). Furthermore, the ddimer contained in the protein-containing extract was measured using a ddimer ELISA kit (Diagnostica Stago, Asnieres-Sur-Seine, France). The amount of t-PA in the supernatant, the amount of t-PA in the protein-containing extract, and the amount of ddimer in the protein-containing extract are shown in FIG. 4, FIG. 5, and FIG. 6, respectively.

[0080] Figure 4 shows that the t-PA in the supernatant tends to increase depending on the concentration of fluvastatin, but the difference is not significant. Figure 5 shows that there is no significant difference in the t-PA in the nasal polyp tissue. On the other hand, Figure 6 shows that the ddimer in the nasal polyp tissue is significantly increased. t-PA is consumed in fibrin degradation. The reason why there was no significant difference in the amount of t-PA in the supernatant and tissue is thought to be because t-PA was consumed in fibrin degradation. It was shown that the increase in the production of t-PA m-RNA by fluvastatin shown in Figure 1 promotes the decomposition of nasal polyps, which are fibrin clots shown in Figure 3.

[0081] Example 5 An experiment was carried out in the same manner as in Example 1, except that BEGM medium supplemented with atorvastatin, rosuvastatin, pravastatin, or lovastatin was used instead of fluvastatin. The results are shown in FIG.

[0082] As shown in Figure 7, it was revealed that the expression of t-PA mRNA in human normal airway epithelial cells to which any statin had been added was increased compared to the control cells. In particular, rosuvastatin, lovastatin, and pravastatin increased the expression of t-PA mRNA in human normal airway epithelial cells at 1 μM more than fluvastatin. Therefore, it was shown that statins other than fluvastatin also have a similar degrading activity against nasal polyps. [Industrial Applicability]

[0083] The present invention can be used as a preventive or therapeutic agent for chronic sinusitis.

Claims

1. A therapeutic agent for nasal polyps caused by chronic sinusitis, comprising a statin as an active ingredient, the statin being one or more substances selected from the group consisting of fluvastatin, simvastatin, atorvastatin, pitavastatin, rosuvastatin, pravastatin, cerivastatin and lovastatin, or a salt of said substance.

2. The therapeutic agent for nasal polyps associated with chronic sinusitis according to claim 1, wherein the nasal polyps associated with chronic sinusitis are nasal polyps associated with eosinophilic sinusitis, nasal polyps associated with aspirin asthma, choanal polyps, or nasal polyps associated with cystic fibrosis.

3. Use of a statin for the manufacture of a medicament for treating nasal polyps in chronic sinusitis, wherein the statin is one or more substances selected from the group consisting of fluvastatin, simvastatin, atorvastatin, pitavastatin, rosuvastatin, pravastatin, cerivastatin and lovastatin, or a salt of said substance.

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