JP6688009B2 - Oxidatively modified LDL complex inhibitor - Google Patents

Description

  The present invention relates to a novel oxidatively modified LDL complex inhibitor.

  Chronic obstructive pulmonary disease (COPD) is a lifestyle-related disease of the lung mainly caused by smoking habit and is one of independent risk factors for ischemic heart disease. However, the mechanism that links COPD to ischemic heart disease has not been clarified.

  COPD is an inflammatory disease accompanied by damage to the alveolar septum, and inflammatory mediators such as CRP, IL-6, IL-1β, and TNFα increase in lung lung. It has been suggested that these may spread to the systemic circulation and cause systemic inflammation to cause co-morbidities such as cardiovascular disease, and in recent years, it has been noted that COPD has an aspect as a systemic disease. It was

  However, drug therapy for COPD is mainly symptomatic therapy to prevent symptom reduction and exacerbation by bronchodilators, and there is no effective drug for lung and airway inflammation in COPD patients and development of obstructive disorder accompanying it. is the current situation.

On the other hand, oxidized LDL plays an important role in the onset and progression of arteriosclerosis, and recently, serum amyloid A / LDL complex (SAA-LDL) and α ₁ -antitrypsin-LDL complex (AT-LDL) are among them. It was identified and these two markers were found to be important for the onset and progression of arteriosclerosis (Non-Patent Documents 1 and 2).

J. Atheroscler. Thromb., 19: 47-58.2012 Anti-Aging Medicine 9: 51-60.2012

  An object of the present invention is to provide means for suppressing the onset of ischemic heart disease in COPD patients.

  The present inventors have found that smoking causes a significant increase in one of oxidatively modified LDLs (SAA-LDL) and (AT-LDL) in serum, and these complexes are associated with the pathophysiology of COPD. I thought Therefore, when a substance that suppresses the blood level of these complexes was searched for, surprisingly, by ingesting curcumin orally, the blood level of SAA-LDL and AT-LDL was decreased, and lung function was also increased. The inventors have found that they should be improved and have completed the present invention.

  That is, the present invention provides the following [1] to [3].

[1] An inhibitor of serum amyloid A / LDL complex and / or α ₁ -antitrypsin-LDL complex, which contains one or more selected from curcumin and its analogs as an active ingredient.
[2] The serum amyloid A / LDL complex and / or α according to [1], which is an inhibitor of serum amyloid A / LDL complex and / or α ₁ -antitrypsin-LDL complex in patients with chronic obstructive pulmonary disease. Inhibitor of ₁ -antitrypsin-LDL complex.
[3] A pulmonary function improving agent containing, as an active ingredient, one or more kinds selected from curcumin and its analogs.

  ADVANTAGE OF THE INVENTION According to this invention, the inhibitor of SAA-LDL and / or AT-LDL, especially the inhibitor of SAA-LDL and / or AT-LDL in COPD patients can be provided, and the onset inhibitor of ischemic heart disease of COPD patients can be provided. Can be provided. In addition, a pulmonary function improving agent can be provided.

  The active ingredient of the SAA-LDL and / or AT-LDL inhibitor and the lung function improving agent of the present invention is at least one selected from curcumin and its analogs.

  Curcumin is a main component of curcuminoid contained in the turmeric pigment, and is a compound represented by the following structural formula (1).

The curcumin used in the present invention may be a chemically-synthesized curcumin, or may be a curcumin that is commercially available as a turmeric pigment. As the turmeric pigment, a turmeric powder obtained by powdering a dried product of a rhizome of the curcuma turmeric ( Curcuma longa LINNE), and using a suitable solvent (for example, ethanol, oil and fat, propylene glycol, hexane, acetone, etc.) for the turmeric powder Examples include crude curcumin or oleoresin (turmeric oleoresin) obtained by extraction, and purified curcumin.
It should be noted that curcumin includes both keto-type and enol-type tautomers.

  Examples of curcumin analogs include desmethoxycurcumin, bisdesmethoxycurcumin, tetrahydrocurcumin, dihydroxytetrahydrocurcumin and the like. The turmeric pigment contains curcumin, desmethoxycurcumin and bisdesmethoxycurcumin. The curcumin analog is preferably one or more selected from desmethoxycurcumin, bisdesmethoxycurcumin and tetrahydrocurcumin.

  As one or more selected from curcumin and its analogs, it is preferable to use a turmeric extract, and it is more preferable to use a turmeric pigment containing at least one selected from curcumin and its analogs. Commercially available turmeric pigment containing at least one selected from curcumin and its analogs is not particularly limited as long as it contains at least one selected from curcumin and its analogs, but absorbability into the body Is preferred, and Ceracrumin (manufactured by CeraValues) is particularly preferred.

As shown in Examples described later, curcumin or its analog significantly suppressed the increase in blood SAA-LDL and AT-LDL in COPD patients by oral administration, and significantly reduced lung function, especially the 1 second rate. Improve.
Here, SAA-LDL means that serum amyloid A (SAA), which is an acute phase-reactive protein that is present in association with HDL, is oxidized by active oxygen derived from activated inflammatory cells at the site of intravascular inflammation and is low in level. It refers to a complex bound to specific gravity lipoprotein (LDL). AT-LDL refers to a complex of oxidized α ₁ antitrypsin (AT) and low-density lipoprotein (LDL). Both SAA-LDL and AT-LDL have an action of promoting arteriosclerosis, and are considered to cause the onset of severe ischemic heart disease such as myocardial infarction. Therefore, curcumin or its analog significantly suppresses the increase of SAA-LDL and AT-LDL in COPD patients, and suppresses the onset of arteriosclerosis and the onset of ischemic heart disease.
The one-second rate is an important factor in lung function tests using a spirometer, and 70% or more is a reference value, and improving it to 70% or more significantly improves lung function.

  The inhibitor of SAA-LDL and / or AT-LDL and the agent for improving lung function of the present invention are preferably orally administered, and preferably an oral administration preparation.

  Examples of orally-administered preparations include tablets, coated tablets, powders, granules, capsules, solutions and the like. To produce an orally-administered preparation, a pharmaceutically acceptable carrier such as an excipient, a binder, a disintegrating agent, a lubricant, a diluent, a stabilizer, a coloring agent, a flavoring agent, a flavoring agent, etc. is added. can do.

  Examples of the excipient include lactose, sucrose, sodium chloride, glucose, maltose, mannitol, erythritol, xylitol, maltitol, inositol, dextran, sorbitol, albumin, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silica. Acids, methyl cellulose, glycerin, sodium alginate, gum arabic, mixtures thereof and the like can be mentioned. Examples of lubricants include refined talc, stearate, borax, polyethylene glycol, and mixtures thereof. Examples of the binder include simple syrup, glucose solution, starch solution, gelatin solution, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, carboxymethylcellulose, shellac, methylcellulose, ethylcellulose, water, ethanol, potassium phosphate, and mixtures thereof. Can be mentioned.

  As the disintegrant, for example, dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose and mixtures thereof and the like. Is mentioned. Examples of the diluent include water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and mixtures thereof. Examples of the stabilizer include sodium pyrosulfite, ethylenediaminetetraacetic acid, thioglycolic acid, thiolactic acid, and a mixture thereof.

  The dose of curcumin and its analogs in the inhibitor of SAA-LDL and / or AT-LDL of the present invention and the lung function improving agent is preferably 10 mg to 10 g, more preferably 30 mg to 10 g, as an adult daily dose. Walmicun and its analogs may be administered once to several times a day in divided doses.

1. Human clinical study (double-blind, randomized, parallel group comparison study) (1) Subject Subject is in the 0 to II stage (COPD reserve) according to the classification criteria by the Japanese Respiratory Society while visiting the Kyoto Medical Center. The subjects were patients with chronic obstructive pulmonary disease (COPD) classified into groups to moderate, and those who had passed 4 months or more after smoking cessation. Although 48 patients were registered in this study, 39 subjects (22 in the active drug group (average age 69.6 years) and 17 in the placebo drug group (average age 69.9) due to dropouts and data deficiencies. Age group), and there is no difference in age and sex distribution between the two groups).

(2) Test drug The actual drug is a capsule in which ceracrumin (registered trademark), which is a superabsorbent curcumin preparation, and silicon dioxide and calcium stearate, which are excipients, are blended, and one capsule contains curcumin. It contains 30 mg. Note that the sera curmine (registered trademark) is composed of turmeric pigment (mainly curcumin, slightly including curcumin analogues), dextrin, maltose, gadhi gum, and citric acid.
On the other hand, the placebo drug is one obtained by removing the turmeric pigment from the above-mentioned seracurmin (registered trademark) and adding a coloring agent (edible yellow No. 4) in order to make the color tone the same as that of the actual drug, that is, dextrin, maltose, A capsule composed of gaddy gum, citric acid, silicon dioxide, calcium stearate and a colorant (Edible Yellow No. 4), which does not contain curcumin at all.

(3) Administration method 1. Subjects were randomly divided into 2 groups, and the above 2. 3 capsules of curcumin (90 mg as curcumin) or 3 placebo medications taken after breakfast and dinner (6 capsules per day, that is, 180 mg of curcumin per day in the case of the active drug) described in 1. The test was continued for 24 weeks (6 months). It was confirmed that the subject's symptoms were stable from the observation period (3 months or more) before the administration of the test drug.

(4) Observation / Test Items and Timing Before and after test sample administration, 12 and 24 weeks after administration, a) subjective symptoms, b) blood pressure, pulse rate, body weight and c) clinical examination (hematology) Inspection, biochemical test, urine test, etc.) and observation were carried out.
In the hematological examination, the red blood cell count, hemoglobin amount, hematocrit value, white blood cell count, platelet count and fibrinogen, and in the biochemical examination, total protein, total bilirubin, AST (GOT), ALT (GPT), Al-P, LDH, BUN, creatinine, uric acid, LDL-cholesterol, HDL-cholesterol, CPK, fasting blood glucose, triglyceride, Na, K, Cl and CRP, and urinalysis usually showed protein, occult blood and sugar (all qualitative). It measured according to the method.

(5) Method of measuring SAA-LDL and AT-LDL SAA-LDL and AT-LDL were entrusted to Igagaku Co., Ltd., a company that accepts and performs these measurements.

(6) Method for measuring lung function Lung function was measured using a spirometer according to a conventional method.

2. Results Regarding the age and sex distribution of the subjects, no difference was observed between the placebo group (17 people, 69.9 years old) and the curcumin group (22 people, 69.6 years old). Forty-eight subjects were registered in this study, and 39 subjects were included in the analysis due to dropouts and missing data.
Further, in both groups, changes in BMI, body weight, blood pressure, HbA1c, LDL-C, TG, and HDL-C were not observed before and after oral administration.

However, when the percent change in SAA-LDL from baseline for 6 months was examined, the percent change in SAA-LDL increased by 10.8 ± 47.4% in the placebo-administered group. In the curcumin administration group, there was a decrease of 2.0 ± 41.9%.
In addition, when the% change rate of AT-LDL was also examined in the same manner, the curcumin administration group (decrease by 1.6 ± 16.7%) was compared with the placebo administration group (14.8 ± 23.8% increase). ) Was significantly lower in the latter (p = 0.020).
Furthermore, in the curcumin administration group, the predicted 1-second rate improved significantly (p = 0.034) from before administration (67.5 ± 5.0%) to 6 months after administration (71.3 ± 8.8%). did. When the correlation was examined for changes before and after administration, a negative correlation was observed between the predicted one-second rate and AT-LDL in the curcumin group (r = -0.592, p = 0.008).
From the above results, it was found that orally ingesting curcumin reduces blood levels of SAA-LDL and AT-LDL and improves lung function.

  The preparation of the present invention that suppresses oxidatively modified LDL containing curcumin and / or an analog thereof as an active ingredient reduces blood SAA-LDL and AT-LDL concentrations by oral ingestion, and also reduces lung function in COPD patients. Has the effect of improving. Further, it may be linked to the suppression of future ischemic heart disease.

Claims (1)

Serum amyloid A / LDL complex and / or α ₁ − for suppressing the onset of ischemic heart disease in COPD patients , which comprises one or more selected from curcumin, desmethoxycurcumin, bisdesmethoxycurcumin and tetrahydrocurcumin as an active ingredient Inhibitor of antitrypsin-LDL complex .