WO2006035706A1 - 薬効評価用動物、薬効評価用動物の慢性閉塞性肺疾患発症方法及びその動物を用いた薬効評価方法 - Google Patents
薬効評価用動物、薬効評価用動物の慢性閉塞性肺疾患発症方法及びその動物を用いた薬効評価方法 Download PDFInfo
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- chronic obstructive
- obstructive pulmonary
- pulmonary disease
- drug efficacy
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
- A61K49/0008—Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
- A01K2267/03—Animal model, e.g. for test or diseases
- A01K2267/035—Animal model for multifactorial diseases
Definitions
- the present invention relates to a medicinal evaluation animal that has developed chronic obstructive pulmonary disease in which inflammation is not observed in the nasal cavity and pharynx, a method for developing chronic obstructive pulmonary disease in the animal for evaluating the medicinal effect, and an animal for such medicinal evaluation.
- the present invention relates to a method for evaluating the efficacy of a drug using.
- Cigarette 1R1 force Main smoke generated is inhaled for 1 to 4 hours Z days, 5 days, Z weeks for a total of 6 months. There was a defect that could not be evaluated.
- the method of inhaling cigarette smoke passes through the oral cavity or nasal cavity, which may cause an inflammatory reaction in areas other than chronic obstructive pulmonary disease, and selectively evaluate the efficacy of the affected area. It was difficult to develop animals.
- Patent Document 1 Japanese Patent Application Laid-Open No. 2004-105173
- An object of the present invention is to provide, for example, an animal for evaluating drug efficacy that develops only chronic obstructive pulmonary disease in which inflammation is not observed in the nasal cavity and pharynx, and a method for developing only chronic obstructive pulmonary disease in such animal for evaluating drug efficacy At the same time, it is intended to provide a method for evaluating selective drug efficacy against chronic obstructive pulmonary disease by administering a drug to such an animal for drug efficacy evaluation.
- the present invention provides an aqueous solution obtained by dissolving tobacco smoke in water or physiological saline.
- a medicinal evaluation animal characterized by causing chronic obstructive pulmonary disease by direct administration to the lower respiratory tract.
- the present invention also provides a method for developing chronic obstructive pulmonary disease in an animal for drug efficacy evaluation, which comprises directly administering an aqueous solution in which tobacco smoke is dissolved in water or physiological saline to the lower respiratory tract of animals other than humans. To do.
- the present invention provides a drug efficacy evaluation method for administering a drug to the drug efficacy evaluation animal and evaluating the action and effect.
- the present invention it is possible to reliably provide an animal for evaluation of drug efficacy that selectively develops only chronic obstructive pulmonary disease, which is useful for drug development, particularly for screening anti-chronic obstructive pulmonary disease substance. Therefore, it is possible to quickly provide an animal for evaluation of drug efficacy in order to carry out various evaluation methods.
- model production required a device that generated cigarette smoke and an exposure chamber that allowed animals to inhale smoke.
- an animal for evaluation of drug efficacy can be produced reliably.
- FIG. 1 is a schematic view showing a method for producing a tobacco smoke liquid used in the present invention.
- FIG. 2 In Example 1, the disease developed after administration of only the physiological saline as a comparison target! FIG.
- FIG. 3 is an external view of a guinea pig lung that developed in Example 1.
- Example 1 In Example 1, only the physiological saline as a comparison target was administered to develop symptoms! This is a photomicrograph of the lung tissue of the pupa / porcine guinea pig.
- FIG. 5 is a photomicrograph of lung tissue of the guinea pig lung that developed in Example 1.
- chronic obstructive pulmonary disease model animals animals for evaluating drug efficacy that have developed chronic obstructive pulmonary disease.
- Chronic obstructive pulmonary disease is a pulmonary disease including chronic bronchitis and emphysema.
- Chronic obstructive pulmonary disease although partially reversible, is generally characterized as progressive irreversible airway obstruction and is often associated with airway hyperresponsiveness.
- Chronic bronchitis is characterized by a chronic wet cough that lasts for more than 3 months in each year for 2 consecutive years.
- Emphysema is also associated with destructive changes in the alveolar wall, with no obvious fibrosis, distal to the terminal bronchiole. An abnormal permanent swelling of the cavity. Destruction is defined as an irregular enlargement of the respiratory airspace
- Chronic obstructive pulmonary disease as described above is characterized by irreversible airway obstruction and has a different disease concept from asthma, which is a reversible airway obstruction disease. Furthermore, as a drug therapy for bronchial asthma, inhalation was conducted in the Guideline for the Diagnosis and Management of Asthma (NHLBI, 2002), which is a global guideline for asthma treatment. Steroid is recommended as a first-line drug and has proven to be of great use, but for chronic obstructive pulmonary disease, a similar global guideline, Global Initiative for Chronic Obstructive Lang for chronic obstructive lung disease) (GOLD; NHLBl / WHO, 1998), the effects of steroids are limited and their use is not recommended. Thus, the responsiveness to drugs differs between chronic obstructive pulmonary disease and bronchial asthma.
- the animal model of chronic obstructive pulmonary disease of the present invention uses an aqueous solution (hereinafter referred to as "cigarette smoke”) obtained by dissolving tobacco smoke in water or physiological saline to the lower respiratory tract of animals other than humans.
- aqueous solution hereinafter referred to as "cigarette smoke”
- Direct administration or administration of tobacco smoke and an aqueous solution containing endotoxin (hereinafter, an aqueous solution containing endotoxin is simply referred to as an “endotoxin-containing aqueous solution”) Either directly administered to the lower respiratory tract of animals, or an aqueous solution of tobacco smoke and endotoxin dissolved in water or physiological saline (hereinafter referred to as “tobacco smoke / endotoxin-containing solution”! Produced by direct administration to the respiratory tract.
- the “lower airway” here is defined as the airway, trachea, bronchi, bronchiole, alveoli, and the like.
- directly administered refers to administering tobacco smoke liquid, endotoxin-containing aqueous solution, and tobacco smoke endotoxin-containing aqueous solution directly to the lower respiratory tract without touching the nasal cavity.
- the tobacco smoke liquid is produced, for example, by the method shown in the schematic diagram of FIG. That is, the filter suction port of the tobacco 1 is joined to one end of the introduction pipe 4, and the other end of the introduction pipe 4 is submerged in the water in the container 3 or physiological saline 2.
- the suction pump 6 and the suction pipe 7 are joined, and the container 3 and the other end of the suction pipe 7 are joined so as not to touch the water surface.
- the suction pipe 7 is provided with a valve 5. After the cigarette 1 is ignited, the suction pump 6 is operated, and the tobacco smoke liquid is made by bubbling the cigarette smoke into the water while opening and closing the valve 5 appropriately.
- Tobacco smoke and tobacco smoke •
- the concentration of tobacco smoke in the endotoxin-containing aqueous solution is sufficient to cause chronic obstructive pulmonary disease in the applied animal.
- one or more cigarettes per 10 mL Preferably, it can be brought about by inhaling 5 or more smokes.
- the amount of the tobacco smoke used may be any amount as long as it is sufficient to cause chronic obstructive pulmonary disease in the applied animal.
- the aqueous solution may contain water, physiological saline, and a water-soluble organic solvent that does not adversely affect animals other than humans.
- examples of the organic solvent that can be used include organic solvents such as ethanol and dimethyl sulfoxide, and the ratio of the organic solvents such as ethanol and dimethyl sulfoxide varies depending on the animal used.
- the concentration is about 10% by weight.
- the endotoxin produced by Gram-negative bacteria is used in combination with cigarettes as the main cause of chronic obstructive pulmonary disease, but secondary factors such as infection It is said to make the condition worse, and by adding this secondary factor, it is to create a disease model that is closer to the actual symptoms.
- the endotoxin produced by the gram-negative bacterium here refers to an endotoxin that releases the cell wall force of the gram-negative bacterium, such as lipopolysaccharide.
- the powerful endotoxin is preferably administered in a solution, for example, dissolved in physiological saline.
- the concentration of endotoxin produced by the gram-negative bacterium can be any concentration that is sufficient to cause chronic obstructive pulmonary disease in the animal to which it is applied.
- concentration for example, against water or physiological saline or tobacco smoke , Preferably gZmL or more, more preferably gZmL to 2 g / mL.
- the endotoxin produced by the gram-negative bacterium may not be contained, but for the reasons described above, it is preferable to contain the endotoxin in water, physiological saline or tobacco smoke.
- the number of administrations and the administration period of the tobacco smoke liquid, the endotoxin-containing aqueous solution, and the tobacco smoke / endotoxin-containing aqueous solution can be determined according to the degree of onset of chronic obstructive pulmonary disease.
- the degree of onset is evaluated by peak expiratory flow (mLZsec), and the number and duration of decrease by 10% or more are set for the physiological saline administration group as the control group.
- the endotoxin-containing aqueous solution is preferably administered between the tobacco smoke liquids.
- the thus obtained animal model for chronic obstructive pulmonary disease has a characteristic that it can selectively cause inflammation at a target site of chronic obstructive pulmonary disease.
- Evans Blue solution was administered to the lower respiratory tract, which is a feature of the present invention, and the colored part of the living body was confirmed, the colored part was not observed in the nasal part and nasal cavity, but was limited to the mouth and lower respiratory tract. The percentage is almost 100 %Met.
- a method for directly administering tobacco smoke liquid, tobacco smoke liquid and endotoxin-containing aqueous solution or tobacco smoke / endotoxin-containing aqueous solution to the lower respiratory tract of animals other than humans will be described.
- a metal sonde can be used, but a commonly used stainless steel sonde can be used, and a preferred metal sonde such as size and shape can be selected according to the type of animal used in the experiment. it can.
- a processing method for example, there is a method of bending the tip of a stainless steel sonde so that it can be easily administered directly to the lower respiratory tract.
- Degree of curvature The shape varies depending on the type and shape of the animal used, but in general, the angle between the portion corresponding to the curved tip and the portion corresponding to the base of the sonde is 90 to 150 °. It is preferable to bend.
- direct administration a curved sonde is inserted from the mouth, and the tip is applied to the upper lower respiratory tract of the animal's pharynx. .
- an animal having a lower respiratory tract and performing pulmonary respiration can be used.
- dentates such as guinea pigs, mice, rats, and hamsters, and heavy teeth such as rabbits.
- mammals such as eyes, goats, hidges, pigs and other cloven-hoofed animals, horses, donkeys, etc., carrots such as inu and cats, monkeys, chimpanzees, etc.
- Advantages of experimental operation due to the shape preferred by guinea pigs, mice, rats, mice, mice, rabbits, monkeys, chimpanzees, nu, goats, hidges, pigs, etc.
- rodents such as guinea pigs, mice, rats and hamsters are particularly preferable.
- a drug is administered to the animal model of chronic obstructive pulmonary disease, and its effect is evaluated. What is necessary is just to perform evaluation with a change of respiratory function in an effect.
- Evaluation of chronic obstructive pulmonary disease in the animal model of chronic obstructive pulmonary disease of the present invention is performed by evaluating changes in respiratory function normally used as an evaluation parameter for the disease, that is, specific airway resistance, peak expiratory flow, once Ventilation volume, number of minute breaths, and minute ventilation volume are measured, and these can be measured by known methods.
- specific airway resistance is described by Pennock BE, et al, J. Nanoreb Applied Physiology. (J. Appl.
- Penock et al. It can be measured by a comprehensive breathing function measurement system (for example, PULMOS-I; MIPS, etc.).
- the peak expiratory flow, tidal volume, number of minute breaths, and minute ventilation can be measured using, for example, PULMOS-I; MIPS.
- Chronic obstructive pulmonary disease is characterized by neutrophils infiltrating into the cell membrane among inflammatory cells. Therefore, the degree of inflammation should be confirmed by measuring the number of neutrophil cells. Is also possible.
- Tobacco smoke was prepared using the apparatus shown in the schematic diagram of FIG.
- a solution using ribopolysaccharide as endotoxin produced by Gram-negative bacteria was prepared as follows. That is, 50 mg of lipopolysaccharide was dissolved in 10 mL of physiological saline to prepare a 500 ⁇ g ZmL lipopolysaccharide solution.
- Cigarette smoke solution 200 ⁇ LZ animals were administered Z once a day for 4 consecutive days, and lipopolysaccharide solution 500 ⁇ LZ animals were administered on the fifth day. With this as one cycle, the same operation was repeated on the 6th and 11th days, and on the 16th and 19th days, Tanoku Smoke 200 LZ animals were administered Z times.
- the disease model was evaluated by measuring specific airway resistance, peak expiratory flow, tidal volume, minute ventilation, and minute ventilation on the 20th day for the animals developed in 3. It was.
- the affected animals showed increased specific airway resistance, decreased peak expiratory flow, decreased tidal volume, decreased minute expiration, and decreased minute ventilation. It was confirmed that obstructive pulmonary disease developed.
- Example 1 an experimental chronic obstructive pulmonary disease model animal having a strong reaction in a short period of time without causing inflammation in other sites such as the oral cavity and nasal cavity, It was revealed that it can be produced without using a heavy force device such as an exposure chamber.
- FIG. 2 is an external view of the lungs of a guinea pig that does not develop after administration of only physiological saline
- FIG. 3 is an external view of the lungs of a guinea pig that has developed according to this example.
- the hyperinflation of the lung which is a characteristic of chronic obstructive pulmonary disease
- Fig. 4 is a micrograph of the guinea pig lung tissue developed by administration of physiological saline alone
- Fig. 5 is a micrograph of the guinea pig lung tissue developed in this example.
- the guinea pigs that developed in the examples were confirmed to have a hollow cavity in the alveolar wall, which is characteristic of chronic obstructive pulmonary disease, compared to normal guinea pigs.
- the BALF 25 L obtained in step 5 was stained with 100 L of Turku's solution, and the total white blood cell count was counted using a Birker Turk hemocytometer (Elma sales).
- Cell smear preparation method and neutrophil measurement Adjust the white blood cell concentration of BALF to 3 X 10 5 cellZmL with physiological saline based on the total white blood cell count of 6. Collect 25 ⁇ L from it, sediment the cells on a slide glass, and Diff-Quick staining Samples were prepared and neutrophils were counted under a microscope.
- the effect was confirmed using theophylline which is known as a therapeutic drug for chronic obstructive pulmonary disease.
- tobacco smoke liquid preparation preparation of tobacco smoke and lipopolysaccharide preparation, diseased animal onset, and disease evaluation were performed in the same manner as in Example 1.
- Theophylline was orally administered (lOmgZkg) 1 hour before the administration of tobacco smoke and LPS solution.
- the theophylline was confirmed to have an effect of improving respiratory function in the evaluation method according to the present invention, and it was revealed that it is useful as a method for evaluating chronic obstructive pulmonary disease.
- Example 1 In the same manner as in Example 1, a model animal for chronic obstructive pulmonary disease was prepared using experimental animals such as Inu, Hedge, and monkeys. As confirmation of the onset, the neutrophil count was measured in the same manner as in Example 1.
- the animal model of chronic obstructive pulmonary disease of the present invention is useful because it can be used for screening compounds in the development of pharmaceuticals, particularly in the development of anti-chronic obstructive pulmonary disease therapeutic agents.
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Abstract
Description
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Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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US11/576,137 US20080072338A1 (en) | 2004-09-28 | 2005-09-26 | Animal for Drug Efficacy Evaluation, Method for Developing Chronic Obstructive Pulmonary Disease in Animal for Drug Efficacy Evaluation, and Method for Evaluating Drug Efficacy Using the Animal |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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JP2004-281461 | 2004-09-28 | ||
JP2004281461 | 2004-09-28 |
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WO2006035706A1 true WO2006035706A1 (ja) | 2006-04-06 |
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PCT/JP2005/017619 WO2006035706A1 (ja) | 2004-09-28 | 2005-09-26 | 薬効評価用動物、薬効評価用動物の慢性閉塞性肺疾患発症方法及びその動物を用いた薬効評価方法 |
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US (1) | US20080072338A1 (ja) |
TW (1) | TW200616536A (ja) |
WO (1) | WO2006035706A1 (ja) |
Cited By (1)
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RU2714679C1 (ru) * | 2019-03-21 | 2020-02-19 | Федеральное государственное бюджетное научное учреждение "Томский национальный исследовательский медицинский центр Российской академии наук" (Томский НИМЦ) | Способ моделирования сочетанной патологии метаболического синдрома и хронической обструктивной болезни легких |
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WO2008040080A1 (en) * | 2006-10-05 | 2008-04-10 | Waratek Pty Limited | Silent memory reclamation |
US8541645B2 (en) * | 2009-10-22 | 2013-09-24 | University Of Calcutta | Animal model for cigarette-smoke-induced atherosclerosis and related methods |
CN106770246A (zh) * | 2016-12-26 | 2017-05-31 | 重庆中烟工业有限责任公司 | 一种烟草制品溶出液中的烟碱检测系统 |
CN109601471B (zh) * | 2018-10-26 | 2021-07-27 | 中国人民解放军第二军医大学 | 一种评价卷烟烟气对小鼠免疫损伤的动物模型的构建方法及其应用 |
CN109601472B (zh) * | 2018-10-26 | 2021-07-27 | 中国人民解放军第二军医大学 | 一种评价卷烟烟气对小鼠免疫损伤动物模型的构建方法 |
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DE2828447C2 (de) * | 1978-06-29 | 1980-05-14 | Willy Ruesch Gmbh & Co Kg, 7053 Kernen | Laryngealtubus |
US4502482A (en) * | 1983-05-23 | 1985-03-05 | Deluccia Victor C | Endotracheal tube complex |
US5850840A (en) * | 1995-11-15 | 1998-12-22 | Alteon Inc. | Methods for measurement and treatment predicated on the presence of advanced glycosylation endproducts in tobacco and its combustion byproducts |
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JP2002539072A (ja) * | 1998-08-18 | 2002-11-19 | ザ・レジェンツ・オブ・ザ・ユニバーシティー・オブ・カリフォルニア | Egf−rアンタゴニストの投与による気道粘液産生の防止 |
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RU2714679C1 (ru) * | 2019-03-21 | 2020-02-19 | Федеральное государственное бюджетное научное учреждение "Томский национальный исследовательский медицинский центр Российской академии наук" (Томский НИМЦ) | Способ моделирования сочетанной патологии метаболического синдрома и хронической обструктивной болезни легких |
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