KR101333089B1 - Pharmaceutical composition for the prevention or treatment of smoking-induced chronic obstructive pulmonary disease comprising Rosiglitazone as an active ingredient - Google Patents

Abstract

The present invention by containing rosiglitazone (Rosiglitazone) as an active ingredient, the prevention of smoking-induced emphysema pulmonary parenchyma destruction and pulmonary hypertension and inhibiting the infiltration of inflammatory cells to prevent and treat smoking-induced chronic obstructive pulmonary disease To a pharmaceutical composition provided.

Rosiglitazone, smoking, chronic obstructive pulmonary disease, emphysema, pulmonary arterial hypertension

Description

Pharmaceutical composition for the prevention or treatment of smoking-induced chronic obstructive pulmonary disease comprising Rosiglitazone as an active ingredient

1 is a graph showing the results of measuring pulmonary artery pressure in each test group;

2 is a micrograph of representative lungs of rats in each group;

Figure 3 is a micrograph of lung tissue that can confirm the degree of lung inflammation in each group;

4 is a graph showing the quantification of lung inflammation; And

5 is a graph quantifying the muscle degree of pulmonary blood vessels in rats numerically.

<Technical Field>

The present invention relates to pharmaceutical compositions for the prevention and treatment of smoking-induced chronic obstructive pulmonary disease. In particular, the present invention relates to a pharmaceutical composition for the prevention and treatment of smoking-induced chronic obstructive pulmonary disease containing rosiglitazone as an active ingredient.

Conventional Technology

The obstructive changes in airways due to smoking and the reduction of elastic recoils due to the destruction of emphysema pulmonary parenchyma lead to chronic airflow restriction, which leads to the so-called chronic obstructive pulmonary disease, which is irreversible and progressively characterized. However, no treatment has yet prevented its progression. (National Heart, Lung, and Blood Institute.Morbidity & Mortality: Chart book on Cardiovascular, Lung, and Blood Diseases.Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, 2003.) Inflammation, and many types of oxidants and proteases caused by inflammation are thought to play an important role in the destruction of lung parenchyma. (Sethi JM, Rochester CL. Smoking and chronic obstructive pulmonary disease.Clin Chest Med 2000; 21: 67-86 .; D'Armiento J, Dalal SS, Okada Y, Berg RA, Chada K. Collagenase expression in the lungs of transgenic mice causes pulmonary emphysema.Cell 1992; 71: 955-61 .; Selman M, Montano M, Ramos C, Vanda B, Becerril C, Delgado J, et al.Tobacco smoke induced lung emphysema in guinea pigs is associated with increased interstitial collagenase Am J Physiol 1996; 271: L734-43 .; Segura-Valdez L, Pardo A, Gaxiola M, Uhal BD, Becerril C, Selman M. Upregulation of gelatinases A and B, collagenases 1 and 2, and increased parenchymal cell death. in COPD.Chest 2000; 117: 684-94 .; Finlay GA, O'criscoll LR, Russell KJ, D'arcy EM, Masterson JB, FitzGerald MX, et al. Matrix metalloproteinase expression and production by alveolar macrophages in emphysema.Am J Respir Crit Care Med 1997; 156: 240-7 .; Hautamaki RD, Kobayashi DK, Senior RM, Shapiro SD.Requirement for macrophage elastase for cigarette smoke-induce d emphysema in mice. Science 1997; 277: 2002-4.)

In addition, chronic obstructive pulmonary disease, in which smoking is the most important risk factor, causes abnormal pulmonary vasoconstriction and structural changes in the small pulmonary artery, which is known to cause pulmonary hypertension as a complication. (Pierson DJ. Pathophysiology and clinical effects of chronic hypoxia.Respir Care 2000; 45: 39-51.)

PPARγ (Peroγsome proliferator-activated receptor) is a kind of nuclear hormone receptor (insulin sensitizing effect) that is used as a therapeutic agent for diabetes due to insulin sensitization, in addition to metabolism of lipids and proteins, inflammatory reactions, angiogenesis, cell death, It is known to be involved in the movement and proliferation of vascular smooth muscle, and rosiglitazone, a PPARγ agonist, has been reported to have an effect of inhibiting vascular smooth muscle proliferation. (Haffner SM, Greenberg AS, Weston WM, Chen H, Williams K, Freed MI. Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation. 2002; 106 (6): 679-84. Law RE, Meehan WP, Xi XP, Graf K, Wuthrich DA, Coats W, et al.Troglitazone inhibits Law vascular smooth muscle cell growth and intimal hyperplasia.J Clin Invest 1996; 98 (8): 1897-905; de Dios ST, Bruemmer D, Dilley RJ, Ivey ME, Jennings GL, Law RE, et al. Inhibitory activity of clinical thiazolidinedione peroxisome proliferator activating receptor-gamma ligands toward internal mammary artery, radial artery, and saphenous vein smooth muscle cell proliferation.Circulation 2003 107 (20): 2548-50.) In addition, PPARγ inhibits nuclear factor-kappaB (NF-kB), signal transducer and activator of transcription, and modulates the production of substances that mediate inflammatory responses. It is known to have an inflammatory effect. (Yip EC, Liu AM, Wong JT, Wong YH.An aqueous extract of the popular Chinese nutraceutical Kwei Ling Ko (Tortoise shell-Rhizome jelly) activates the PPARgamma pathway and down-regulates the NFkappaB activity.Phytomedicine. 2005; 12 (10 : 748-59 .; Blanquart C, Barbier O, Fruchart JC, Staels B, Glineur C. Peroxisome proliferator-activated receptors: regulation of transcriptional activities and roles in inflammation.J Steroid Biochem Mol Biol. 2003 Jun; 85 (2- 5): 267-73.)

Recently, it has been reported that administration of PPARγ agonists alleviates bronchial inflammatory responses in animal asthma models (Serhan CN, Devchand PR. Novel antiinflammatory targets for asthma.A role for PPARgamma® Am J Respir Cell Mol Biol. 2001 Jun; 24 (6): 658-61; Lee KS, Park SJ, Hwang PH, Yi HK, Song CH, Chai OH, Kim JS, Lee MK, Lee YC.PPAR-gamma modulates allergic inflammation through up-regulation of PTEN.FASEB J 2005 Jun; 19 (8): 1033-5 Epub 2005 Mar 23), The effect of smoking-induced lung changes is unknown.

Since the PPARγ agonist has effects of anti-inflammatory response, vascular smooth muscle proliferation, and cell death, the present inventors assume that administration of rosiglitazone, a PPARγ agonist, may alleviate the occurrence of emphysema caused by smoking and pulmonary vascular hypertension. The present invention was completed by verifying its potential as a prophylactic and therapeutic agent for smoking-induced chronic obstructive pulmonary disease.

The present invention is to provide a smoking-induced chronic obstructive pulmonary disease prevention and treatment containing rosiglitazone (Rosiglitazone) as an active ingredient.

The present invention provides a pharmaceutical composition for the prevention and treatment of smoking-induced chronic obstructive pulmonary disease containing rosiglitazone as an active ingredient.

As a result of the present study, the administration of rosiglitazone during smoking in the rat model suppressed the occurrence of emphysema pulmonary parenchyma and pulmonary hypertension due to smoking, and it is thought that the mechanism by which rosiglitazone inhibits the invasion of inflammatory cells in this process. .

The present invention is particularly meaningful in that rosiglitazone is used for the first time as a treatment method for chronic obstructive pulmonary disease caused by smoking.

The composition of the present invention may contain not only rosiglitazone as an active ingredient but also components having the same or similar functions, and may further contain other active ingredients as necessary.

The composition of the present invention, in addition to the active ingredient, may be prepared using a pharmaceutically suitable and physiologically acceptable adjuvant, and the adjuvant may be a solvent, a disintegrant, a sweetener, a binder, a coating agent, an expanding agent, a lubricant, a lubricant. Solubilizers, such as an agent or a flavoring agent, can be used.

The pharmaceutical composition of the composition of the present invention may be formulated to include one or more additional pharmaceutically acceptable carriers, in addition to the active ingredients described above for administration.

Pharmaceutically acceptable carriers may be used in combination with saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol and one or more of these components, as necessary, including antioxidants, buffers, Other conventional additives such as bacteriostatic agents can be added. In addition, diluents, dispersants, surfactants, binders, and lubricants may be additionally added to formulate into injectable solutions, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like. Furthermore, it may be preferably formulated according to each disease or component by a suitable method in the art or using a method disclosed in Remington's Pharmaceutical Science (Recent Edition), Mack Publishing Company, Easton PA.

Formulation forms of the pharmaceutical compositions of the present invention may be granules, powders, coated tablets, tablets, capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions and sustained release preparations of the active compounds, and the like. Can be.

The pharmaceutical compositions of the present invention may be administered intravenously, intraarterally, intraperitoneally, intramuscularly, intraarterally, intraperitoneally, intrasternally, percutaneously, nasal, inhaled, topical, rectal, oral, intraocular or intradermal Administration can be by conventional routes.

The dosage of the pharmaceutical composition of the present invention is preferably adjusted within the range of 0.5 to 5 mg / day per adult, the type of disease, the severity of the disease, the type and content of the active ingredients and other ingredients contained in the composition It can be adjusted according to various factors including the type of formulation and the age, weight, general health state, sex and diet of the patient, the time of administration, the route of administration and the ratio of the composition, the duration of treatment, the drug used concurrently.

The pharmaceutical composition of the present invention may be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy and biological response modifiers.

Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided to further understand the present invention, and the present invention is not limited by the examples.

EXAMPLES Confirmation of the Effect of the Compositions of the Present Invention on Chronic Obstructive Pulmonary Disease

Example 1 Preparation of Experimental Animals

Smoking exposure and treatment: 35 Sprague-Dawley rats weighing 350 g were divided into four groups. Smoking exposure allowed rats to smoke 10 cigarettes per day for 5 days a week using a specially designed instrument. (Pittilo RM, Bull HA, Gulati S, Rowles PM, Blow CM, Machin SJ, et al. Nicotine and cigarette smoking: effects on the ultrastructure of aortic endothelium.Int J Exp Pathol 1990; 71: 573-86.) The animals were divided as follows and all animals followed the guidelines for treatment of experimental animals from the Asan Life Science Institute. :

SM: smoking group smoked by the above method for 16 weeks (n = 10);

SMRG: smoking-logiglitazone group (n = 10) administered rosiglitazone (4 mg / kg / d) orally (gavage) 5 days a week for 16 weeks of smoking;

CTL: control breathed for 16 weeks at atmospheric (n = 10); And

-RG: rosiglitazone group orally administered rosiglitazone for 16 weeks with atmospheric breathing (n = 5)

Data are expressed as mean and standard error. The number of rats used in each experiment is indicated by the numbers in parentheses. Statistical analysis was performed using Statistical Package for the Social Science, SPSS Inc, Version 10.0, USA. For the comparison of three groups or more, the difference was tested using the one-way ANOVA test, and the statistical significance (P <0.05) between the two groups was verified using the Mann-Whitney U test.

Example 2. Hemodynamic  Measurement of indicators

After 4 weeks, each group received an intraperitoneal administration of ketamine (ketamine 90 mg / kg) and silazine (xylazine 7 mg / kg), followed by tracheostomy and then connected to the ventilator (Servo 300, Simens). It was. After exposing the internal jugular vein, a silastic catheter (0.7mm external diameter) was inserted and placed in the pulmonary artery through the right ventricle. Catheter was perfused with <2 ml of heparin (1,000 IU / ml) to prevent coagulation. Pulmonary arterial pressure was measured using a pressure transducer (AP 620G; Nihon Kohden; Tokyo, Japan).

1 is a graph showing the results of measuring pulmonary artery pressure in each test group. ( ^* P <0.01 compared to CTL group; ^** P <0.01 compared to SM group) As a result of pulmonary artery pressure measurement, as shown in FIG. 1, the mean pulmonary artery pressure in the smoking group (SM) was increased compared to the control group (CTL) Pulmonary arterial pressure in SMRG) and rosiglitazone group (RG) was significantly decreased (P <0.01).

As a result, it was confirmed that the administration of rosiglitazone can alleviate pulmonary vascular hypertension caused by smoking.

Example 3 Acquisition of Samples and Observation of Lung Tissue for Observation

After pulmonary artery pressure measurement, thoracotomy was performed, 200 units of heparin were injected through the right ventricle, the lungs were perfused with PBS (phosphate-buffered saline), and both lungs and heart were removed. The left lung was excised and the left lung was excised and stored frozen in liquid nitrogen for biochemical examination. The right lung was injected with agarose gelatin at a pressure of 25 cmH ₂ O through the trachea, followed by a formalin tube (formalin). tube), fixed for 24 hours, followed by midsagittal section, paraffin block, hematoxylin and eosin stain, elastic Van Gieson stain, and immunohistochemical staining on 5μm tissue sections. .

Example 4. Average Alveolar wall  Street( interalveolar wall distance Observation

The mean alveolar wall distance was measured using the method of Thurlbeck (Thurlbeck WM. Measurement of pulmonary emphysema. Am Rev Respir Dis 1967; 95: 752-64.) While observing at a 100-fold field of view. In other words, 30 lines per slide were drawn at randomly defined visual fields without blood vessels or airways, and the number of lines meeting lung tissue was counted and the length of the drawn lines was divided by this and this was defined as mean linear intercept (Lm).

Table 1 is a table showing the measured value of Lm measured in each test group, Figure 2 is a micrograph of a typical lung of the rat of each group.

Morphometry of emphysema CTL SM SMRG RG Lm (μm) 74.2 ± 2.23 99.4 ± 2.7 ^* 78.6 ± 1.8 ^** 78.7 ± 1.7 ^**

Lm: mean linear intercept,

CTL: control group, SM: smoking group, SMRG: smoking- rosiglitazone group, RG: rosiglitazone alone group.

^* P <0.01, compared to CTL group

^** p <0.01 compared to SM group

As shown in Table 1 and FIG. 2, Lm, an indicator of mean alveolar wall distance, was significantly increased in the smoking group (SM) who smoked for 4 months compared to the control group, and that of the smoking-logiglitazone group (SMRG) and rosiglitazone group (RG) was significantly increased. Lm was decreased compared to the smoking group (P <0.01)

Therefore, the administration of rosiglitazone was found to reduce the degree of emphysema caused by smoking.

Example 5 Observation of Inflammation Around the Bronchus and Blood Vessels

5 μm of lung tissue was stained with hematoxylin and eosin, and the inflammation level around the bronchus and surrounding blood vessels was divided from 0 to 4, with 0 being no inflammation and 4 for severe inflammation. Obtained. (Sur S, Wild JS, Choudhury BK, Sur N, Alam R, Klinman DM.Long term prevention of allergic lung inflammation in a mouse model of asthma by CpG oligodeoxynucleotides.J Immunol. 1999 May 15; 162 (10): 6284- 93.)

Figure 3 is a micrograph of lung tissue to determine the degree of inflammation of each group (A: artery <arteriole>, Br: bronchus <Bronchiole>. The wedge-shaped arrow is inflammation around the bronchus, Inflammation around the blood vessels are indicated.), Figure 4 is a graph showing the quantification of lung inflammation. (* P <0.01 compared to CTL group; ** P <0.01) compared to SM group

As shown in Figures 3 to 4, as a result of observing the degree of inflammation around the bronchus and blood vessels, the degree of inflammation around the bronchus and blood vessels was more severe in the SM group than in the CTL group and the SMRG group was reduced in comparison with the SM group. .

Therefore, it was confirmed that the administration of rosiglitazone reduces the inflammation around the bronchus and blood vessels induced by smoking.

Example 6. Pulmonary blood vessels  Shape measurement vascular morphometry )

Hematoxylin and eosin stains and elastic Van Gieson stains were performed on 5 μm thick tissue sections. By randomly extracting blood vessels with an outer diameter of 50-200 μm, two layers of elastic lamina are> 75% of the muscular and elastic plates. 26-75% partial muscle type and 0-25% non-muscular type (Girgis RE, Li D, Zhan X, Garcia JG, Tuder RM, Hassoun PM, et al.Attenuation of chronic hypoxic pulmonary hypertension by simvastatin. Am J Physiol Heart Circ Physiol 2003; 285 (3): H938-45.) 500-600 blood vessels were sequentially observed in each group, and two observers were randomly measured independently of each other by blind method.

Table 2 is a quantified quantitative degree of muscle pulmonary blood vessels of the rat in the same manner as above, Figure 5 is a graph illustrating this. ( ^* P <0.01 compared to CTL group; ^** P <0.01 compared to SM group)

Quantification of the Muscle Density of Pulmonary Vascular in Rats CTL SM SMRG RG Muscular
(Muscular)% 7.4 ± 1.3 41.2 ± 4.1 * 15.7 ± 1.4 ** 12.0 ± 1.6 ** Partial muscle type
(Partially muscular),% 19.5 ± 2.1 28.1 ± 1.8 * 14.0 ± 1.9 ** 9.1 ± 0.8 ** Non-muscular
(Nonmuscular)% 73.1 ± 2.4 30.7 ± 3.9 * 70.3 ± 2.3 ** 78.9 ± 1.6 ** Total blood vessel count 600 600 500 500

Each value (mean ± SE) is the percentage of vessels classified by vessel type in each group.

CTL: control group, SM: smoking group, SMRG: smoking-logiglitazone group, RG: rojiglitazone alone group.

^* Compared to CTL groupsP <0.01;^** Compared to SM GroupP <0.01.

As shown in Table 2 and Figure 5, as a result of observation of pulmonary vascular changes in each group was subjected to elastic Van Gieson stain to observe the elastic plate of the two layers in the pulmonary blood vessels when divided into muscle type, partial muscle type, non-muscular type SM group Muscle pulmonary vessels were significantly higher than the control group (7.4 ± 1.3%) (41.2 ± 4.1%) and the SMRG group was 15.7 ± 1.4% (p <0.01).

The proportion of partial muscle vessels was also higher in the SM group than in the control group and lower in the SMRG group than in the SM group. The non-muscular vessels were 73.1 ± 2.4% in the control group, 30.7 ± 3.9% in the SM group, 70.3 ± 2.3% in the SMRG group, which was lower in the SM group than in the CTL group and higher in the SMRG group than in the SM group (P <0.01).

As a result, it was confirmed that the administration of rosiglitazone reduced the vascularization of pulmonary blood vessels caused by smoking.

Therefore, by confirming that the composition containing the rosiglitazone of the present invention as an active ingredient is administered to a test animal during smoking to suppress the occurrence of emphysema, pulmonary hypertension and inflammation due to smoking, the composition of the present invention is a chronic obstructive lung caused by smoking. It has been proved to be useful as a medicament for the prevention and treatment of diseases.

The administration of rosiglitazone suppressed the occurrence of emphysema caused by smoking and pulmonary arterial hypertension. Therefore, the pharmaceutical composition containing the pharmaceutically acceptable carrier of the present invention and rosiglitazone as an active ingredient can be used for the prevention and treatment of smoking-induced chronic obstructive pulmonary disease.

Claims (1)

Pharmaceutical composition for the prevention and treatment of smoking-induced pulmonary arterial hypertension and emphysema containing rosiglitazone as an active ingredient.

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