Prophylactic and / or therapeutic agent for internal carotid artery stenosis

Abstract

To provide a therapeutic agent capable of effectively inhibiting progression of internal carotid artery stenosis.SOLUTION: This prophylactic and / or therapeutic agent for internal carotid artery stenosis includes an inhibitor of the P2X4 receptor as an active ingredient. The inhibitor of the P2X4 receptor is an antagonist against the P2X4 receptor. Examples of the antagonist against the P2X4 receptor include paroxetine, suramin, fluvoxamine, NP-1815-PX, NC-2600, NCP-916, BAY 2328065, 5-BDBD, BX430, and the like. The antagonist is preferably paroxetine.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to a drug for preventing and / or treating internal carotid artery stenosis. [Background technology]

[0002] Internal carotid artery stenosis is a disease caused mostly by atherosclerotic lesions, in which the blood vessel narrows due to the accumulation of plaque (cholesterol mass) at the origin of the internal carotid artery. The arterial intima thickens, narrowing the arterial lumen, and if this progresses to severe stenosis or occlusion, it can lead to cerebral infarction (Non-Patent Documents 1 to 4).

[0003] In a cohort study of the general population aged 50 to 79, the prevalence of internal carotid artery stenosis was 7.9% in men and 1.3% in women with stenosis exceeding 50% as measured by the ECST method, and it was more common in men and tended to increase with age (Non-Patent Document 5).

[0004] Internal carotid artery stenosis is treated medically by treating underlying diseases such as diabetes, hypertension, and hyperlipidemia and administering antiplatelet drugs, or surgically by carotid endarterectomy (CEA), carotid artery stenting (CAS), and extracranial-intracranial artery bypass surgery (Non-Patent Documents 6 and 7).

[0005] However, no drugs are known that can effectively prevent and / or treat internal carotid artery stenosis. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Amarenco P, Bogousslavsky J, Callahan A 3rd, et al: Highdose atorvastatin after stroke or transient ischemic attack. N Engl J Med 355: 549-559, 2006 [Non-Patent Document 2] Sabatine MS, Wiviott SD, Im K, et al: Efficacy and safety of further lowering of low-density lipoprotein cholesterol in patients starting with very low levels. JAMA Cardiol 3: 823-828, 2018 [Non-Patent Document 3] Mihaylova B, Emberson J, Blackwell L, et al: The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 380: 581-590, 2012 [Non-Patent Document 4] Hirt LS: Progression rate and ipsilateral neurological events in asymptomatic carotid stenosis. Stroke 45: 702-706, 2014 [Non-Patent Document 5] Mannami T, Konishi M, Baba S, et al: Prevalence of asymptomatic carotid atherosclerotic lesions detected by high-resolution ultrasonography and its relation to cardiovascular risk factors in the general population of a Japanese city: the Suita study. Stroke 28: 518-525, 1997

Non-Patent Document 6

Non-Patent Document 7

Summary of the Invention

[0007] The present invention has been made in view of the above problems, and has as its object to provide an effective drug for preventing and / or treating internal carotid artery stenosis. [Means for solving the problem]

[0008] The preventive and / or therapeutic agent for internal carotid artery stenosis according to the present invention is characterized by comprising a P2X4 receptor inhibitor as an active ingredient. [Effects of the Invention]

[0009] According to the present invention, internal carotid artery stenosis can be effectively prevented and / or treated. [Brief explanation of the drawings]

[0010] [Figure 1] FIG. 1 is a diagram illustrating the definition of the stenosis rate according to the NASCET method. DETAILED DESCRIPTION OF THE INVENTION

[0011] Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings. However, these embodiments are intended to facilitate understanding of the principles of the present invention, and the scope of the present invention is not limited to the following embodiments. Other embodiments in which a person skilled in the art appropriately replaces the configuration of the following embodiments are also included in the scope of the present invention.

[0012] The preventive and / or therapeutic agent for internal carotid artery stenosis according to the present invention contains a P2X4 receptor inhibitor as an active ingredient.

[0013] P2X receptors are nonselective cation channels, and their structure is formed by the assembly of two-pass transmembrane subunits (approximately 400-600 amino acid residues) to form an ion channel. P2X4 receptors have higher calcium permeability than other P2X receptors. In humans, P2X4 receptors are expressed in a wide range of organs, including the brain, spinal cord, heart, lungs, liver, and kidneys. Their intracellular distribution is characterized by their localization in lysosomes, but multiple sugar chains on the lysosomal lumen side of the P2X4 receptor prevent proteolysis. P2X4 receptors expressed in vascular endothelial cells are involved in vasodilatory responses and vascular remodeling induced by changes in blood flow.

[0014] The P2X4 receptor inhibitor is an antagonist to the P2X4 receptor. Examples of the antagonist to the P2X4 receptor include paroxetine, suramin, fluvoxamine, NP-1815-PX, NC-2600, NCP-916, BAY 2328065, 5-BDBD, BX430, etc., and paroxetine is preferred.

[0015] Paroxetine has been used as an antidepressant under the trade name Paxil due to its other pharmacological action, namely, its serotonin reuptake inhibitory activity. Since it has been shown to have no significant side effects, it is expected to be clinically applicable as a drug for the prevention and / or treatment of internal carotid artery stenosis.

[0016] The degree of stenosis in cases of internal carotid artery stenosis, which is a target of the therapeutic agent of the present invention, is not particularly limited, but can be, for example, 50% or more by the NASCET method. As shown in Figure 1, the NASCET method is a method for determining the stenosis rate by using the normal blood vessel diameter as the denominator and the patent blood vessel diameter from the normal blood vessel diameter as the numerator. A high stenosis rate means that the patent blood vessel lumen is narrow. The internal carotid artery is one of the arteries that branch off from the left and right common carotid arteries, which branch off from the ascending aorta, a cardiac blood vessel, and is one of the major blood vessels in the head and neck.

[0017] The present invention relates to the prevention and / or treatment of internal carotid artery stenosis. As used herein, "treatment" includes halting the progression of stenosis in internal carotid artery stenosis and slowing the rate of progression of stenosis in internal carotid artery stenosis. On the other hand, "prevention" includes suppressing the onset of internal carotid artery stenosis and delaying its onset.

[0018] The prophylactic and / or therapeutic agent for internal carotid artery stenosis according to the present invention may contain additives generally used in pharmaceuticals in addition to the P2X4 receptor inhibitor as an active ingredient.

[0019] Examples of additives include excipients, binders, lubricants, disintegrants, colorants, flavorings, emulsifiers, surfactants, solubilizers, suspending agents, isotonicity agents, buffers, preservatives, antioxidants, stabilizers, and absorption enhancers, and these can also be used in appropriate combinations as desired.

[0020] Specific examples of the excipient include lactose, sucrose, glucose, corn starch, mannitol, sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, light anhydrous silicic acid, aluminum silicate, calcium silicate, magnesium aluminometasilicate, and calcium hydrogen phosphate. Examples of the binder include polyvinyl alcohol, methylcellulose, ethylcellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, and macrogol. Examples of the lubricant include magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, polyethylene glycol, and colloidal silica. Examples of the disintegrant include crystalline cellulose, agar, gelatin, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, low-substituted hydroxypropylcellulose, carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, carboxymethylstarch, and sodium carboxymethylstarch. Examples of the coloring agents include those permitted for use in pharmaceuticals, such as iron sesquioxide, yellow iron sesquioxide, carmine, caramel, β-carotene, titanium oxide, talc, riboflavin sodium phosphate, and yellow aluminum lake. Examples of the flavoring agents include cocoa powder, peppermint, aromatic powder, peppermint oil, menthol, borneol, and cinnamon powder. Examples of the emulsifiers or surfactants include stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, glycerin monostearate, sucrose fatty acid esters, and glycerin fatty acid esters. Examples of the solubilizers include polyethylene glycol, propylene glycol, benzyl benzoate, ethanol, cholesterol, triethanolamine, sodium carbonate, sodium citrate, polysorbate 80, and nicotinamide.Examples of the suspending agent include, in addition to the surfactants, hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose. Examples of the isotonic agent include glucose, sodium chloride, mannitol, and sorbitol. Examples of the buffer include buffer solutions such as phosphate, acetate, carbonate, and citrate. Examples of the preservative include methylparaben, propylparaben, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid. Examples of the antioxidant include sulfite, ascorbic acid, and α-tocopherol. Examples of the stabilizer include ascorbic acid, sodium edetate, erythorbic acid, and tocopherol. Examples of the absorption enhancer include isopropyl myristate, tocopherol, and calciferol.

[0021] The dosage of the preventive and / or therapeutic agent for internal carotid artery stenosis according to the present invention can be appropriately set within a range in which the P2X4 receptor inhibitor as an active ingredient is not toxic to the recipient. For example, the optimal amount can be appropriately determined depending on the physique, age, sex, etc. of the recipient, as well as the degree of stenosis. The same applies to the interval and number of administrations. Although not particularly limited, the dosage can be, for example, 0.01 to 1,000 mg per adult per day. Specifically, the dosage can be 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250, or 500 mg. Preferably, the dosage is 10 to 40 mg per day.

[0022] The prophylactic and / or therapeutic drug for internal carotid artery stenosis according to the present invention can be administered in combination with an antiplatelet drug. In internal carotid artery stenosis, microthrombi generated by plaque rupture or erosion formation are likely to become emboli and cause embolism at distal sites, so the platelet aggregation inhibitory effect of the antiplatelet drug is effective.

[0023] Furthermore, the preventive and / or therapeutic agent for internal carotid artery stenosis according to the present invention can be administered in combination with an HMG-CoA reductase inhibitor. HMG-CoA reductase inhibitors contribute to plaque stabilization, thereby suppressing local acute occlusion due to thrombus formation following plaque rupture and occlusion due to thrombus / plaque embolism from the rupture site. HMG-CoA reductase inhibitors are not particularly limited, and examples include mevastatin, atorvastatin, pravastatin, rosuvastatin, fluvastatin, and lovastatin. [Example]

[0024] (1) Verification that P2X4 receptor inhibitors are effective We placed a carotid artery constriction coil in the left carotid artery of 7-week-old P2X4 gene-deficient mice and control mice fed a high-cholesterol diet, and then excised the carotid arteries 4 weeks later to compare the carotid artery occlusion rates. The P2X4 gene-deficient mice were generated according to the method of Yamamoto et al. (Flow-dependent impaired regulation and remodeling of vascular tone in P2X4-deficient mice, Nature Medicine volume 12, pages 133-137 (2006)).

[0025] As shown in Table 1 below, 9 out of 13 control mice were occluded, whereas 5 out of 16 P2X4 gene-deficient mice were occluded, showing a significantly lower carotid artery occlusion rate (p = 0.039).

[0026] [Table 1]

[0027] This example showed that P2X4 gene-deficient mice could suppress the progression of carotid artery stenosis compared with control mice, revealing that stimulation of P2X4 receptors is related to the progression of carotid artery stenosis and that P2X4 receptor inhibitors can suppress the progression of carotid artery stenosis.

[0028] Since P2X4 gene-deficient mice are identical to control mice in other genes, the effects of P2X4 deficiency can be observed. Therefore, the fact that the progression of carotid artery stenosis was suppressed in P2X4 gene-deficient mice compared to control mice indicates that this effect was achieved by P2X4 inhibition. This indicates that all P2X4 inhibitors, including paroxetine, are effective in suppressing the progression of carotid artery stenosis.

[0029] (2) Confirmation that administration of paroxetine, a type of P2X4 receptor inhibitor, is effective To confirm the results of experiments using P2X4 gene-deficient mice in a different experimental system, we also performed experiments using a P2X4 receptor inhibitor. Paroxetine has a potent P2X4 antagonist activity. Therefore, we performed carotid artery constriction coil placement in 7-week-old mice fed a high-cholesterol diet and simultaneously implanted a capsule delivering 0.025 mg / kg paroxetine per hour subcutaneously in the abdominal cavity (paroxetine-treated mice group). Four weeks after capsule placement, we excised the carotid artery and observed the rate of carotid artery occlusion. Meanwhile, we performed carotid artery constriction coil placement in 7-week-old mice fed a high-cholesterol diet but did not administer paroxetine (control mice group). Four weeks after placement, we excised the carotid artery and observed the rate of carotid artery occlusion. In the paroxetine-treated group, all four of four mice had patent carotid arteries, whereas in the control group, only four of 13 mice had patent carotid arteries and nine of 13 mice had occluded carotid arteries (Fischer's exact test, p=0.0294).

[0030] This confirmed that paroxetine, an example of a P2X4 receptor inhibitor, has the effect of suppressing the progression of carotid artery stenosis. Combined with the results of experiments using P2X4 gene-deficient mice, it can be concluded that inhibition of P2X4 has the effect of suppressing the progression of carotid artery stenosis. Therefore, it is clear that all P2X4 receptor antagonists, including suramin, fluvoxamine, NP-1815-PX, NC-2600, NCP-916, BAY 2328065, 5-BDBD, BX430, etc., also have the effect of suppressing the progression of carotid artery stenosis.

[0031] (3) Verification of factors related to internal carotid artery stenosis Multiple inflammatory factors are associated with inflammatory diseases, but the expression patterns of inflammatory factors vary depending on the disease. Multiple inflammatory factors are also associated with internal carotid artery stenosis, and carotid artery stenosis has a unique expression pattern. As shown in Table 2 below, Western blotting analysis revealed that the expression levels of COX-2 and MCP-1 were significantly lower in the carotid arteries of P2X4 gene-deficient mice compared to those of control mice. In particular, in internal carotid artery stenosis, the difference in COX-2 expression was greater than the difference in MCP-1 expression between control mice and P2X4 gene-deficient mice. In cerebral aneurysms, the difference in MCP-1 expression was greater than the difference in COX-2 expression between control mice and P2X4 gene-deficient mice, contrary to carotid artery stenosis.

[0032] [Table 2]

[0033] Since the expression of inflammatory factors differs depending on the disease, the fact that P2X4 receptor inhibitors are effective in other inflammatory diseases does not necessarily mean that they will be effective in internal carotid artery stenosis. As shown in this example, the effectiveness of P2X4 receptor inhibitors in internal carotid artery stenosis can only be determined by comparing the carotid artery occlusion rate between P2X4 gene-deficient mice with a carotid artery constriction coil placed and a high-cholesterol diet fed control mice. [Industrial Applicability]

[0034] It can be used as a treatment for internal carotid artery stenosis.

Claims

1. A preventive and / or therapeutic drug for internal carotid artery stenosis, characterized by comprising a P2X4 receptor inhibitor as an active ingredient.

2. 2. The preventive and / or therapeutic drug for internal carotid artery stenosis according to claim 1, wherein the P2X4 receptor inhibitor is paroxetine.

3. 2. The preventive and / or therapeutic drug for internal carotid artery stenosis according to claim 1, wherein the degree of stenosis of the internal carotid artery is 50% or more as determined by the NASCET method.

4. The preventive and / or therapeutic drug for internal carotid artery stenosis according to claim 1, further comprising an antiplatelet drug for administration in combination.

5. 2. The drug for preventing and / or treating internal carotid artery stenosis according to claim 1, further comprising an HMG-CoA reductase inhibitor for administration.

6. 6. The drug for preventing and / or treating internal carotid artery stenosis according to claim 5, wherein the HMG-CoA reductase inhibitor is a drug selected from the group consisting of mevastatin, atorvastatin, pravastatin, rosuvastatin, fluvastatin and lovastatin.

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