WO2011083718A1 - Agent for promoting lung regeneration - Google Patents
Agent for promoting lung regeneration Download PDFInfo
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- WO2011083718A1 WO2011083718A1 PCT/JP2010/073586 JP2010073586W WO2011083718A1 WO 2011083718 A1 WO2011083718 A1 WO 2011083718A1 JP 2010073586 W JP2010073586 W JP 2010073586W WO 2011083718 A1 WO2011083718 A1 WO 2011083718A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
Definitions
- the present invention relates to a lung regeneration accelerator.
- Residual lung function after pulmonary resection is an important factor in the evaluation of pulmonary resection, and the risk of complications due to low pulmonary function after pulmonary resection becomes an important issue in considering pulmonary resection. ing.
- compensatory regeneration after unilateral total pneumonectomy is a long-known phenomenon. Therefore, it is considered that residual lung function can be enhanced by promoting compensatory regeneration after lung resection.
- An object of the present invention is to provide a novel lung regeneration promoter.
- the present invention is as follows. (1) A pulmonary regeneration promoter containing a steroid, which is administered while performing a treatment to increase cAMP concentration in the lung. (2) A lung regeneration promoting agent containing a steroid, wherein the cAMP concentration is increased by administering an intracellular cAMP concentration increasing agent to the lung. (3) A lung regeneration promoting agent containing an intracellular cAMP concentration increasing agent, characterized by being administered together with a steroid. (4) A lung regeneration promoter containing a steroid and an intracellular cAMP concentration increasing agent. (5) The lung regeneration promoter according to any one of (2) to (4), wherein the intracellular cAMP concentration increasing agent contains at least one of a phosphodiesterase inhibitor, cAMP, and a cAMP analog.
- 4 is a graph showing the examination results of the doses of dexamethasone, 8-bromo-cAMP, and 3-isobutyl-1-methylxanthine effective in promoting compensatory lung regeneration in an embodiment of the present invention.
- FIG. 4 is a micrograph (A) of a lung tissue on day 4 after DCI administration to an emphysema-induced model mouse and a graph (B) showing the number of alveoli per unit area in a lung tissue section in an embodiment of the present invention. .
- pulmonary regeneration can be promoted by administering a steroid while performing a treatment to increase the cAMP concentration in the lung.
- steroids are administered to patients suffering from pulmonary diseases accompanied by a decrease in the number of alveoli, while increasing the cAMP concentration in the lungs. It can increase the number of alveoli and promote lung regeneration.
- an intracellular cAMP concentration increasing drug for example, a phosphodiesterase inhibitor, cAMP, cAMP analog and the like can be used.
- Phosphodiesterase inhibitors include caffeine, isobutylmethylxanthine, rolipram (4- [3- (cyclopentyloxy) -4-methoxyphenyl] -2- pyrrolidinone), theophylline (1,3-dimethylxanthine), cilomilast, Roflumilast, Arofylline, OPC-6535, ONO-6126, IC-485, AWD-12-281, CC-10004, CC-1088, KW-4490, Irimilast, ZK-117137, YM-976, BY-61-9987, CC-7085, CDC-998, MEM-1414, ND-1251, Bay19-8004, D-4396, PD-168787, Atizolam, cipamfylline, Rolipram, NIK -6 16, SCH-351591, V-11294A, Besnanoline, R020-1724, Vinpocetine, Zaprinast,
- the steroid to be administered is not particularly limited, for example, cortisone acetate, hydrocortisone, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, fludrocortisone acetate, prednisolone, prednisolone acetate, prednisolone sodium succinate, prednisolone butyl acetate, prednisolone sodium phosphate , Halopredon acetate, methylprednisolone acetate, methylprednisolone acetate, methylprednisolone sodium succinate, triamcinolone, triamcinolone acetate, triamcinolone acetonide, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, dexamethasone palmitate, paramethasone acetate, metamethasone acetate , Fluticasone Use fluticasone propionate, budesonide,
- the administration method is not particularly limited and may be systemically administered by internal use. However, in order to suppress side effects, it is preferable to spray from the throat or nose so that it can be locally administered to the lungs through the respiratory tract. Spray is preferred as the shape.
- the intracellular cAMP concentration increasing drug may be administered together with the steroid as a lung regeneration promoting agent, or the steroid may be administered as the lung regeneration promoting agent while increasing the intracellular cAMP concentration.
- “co-administer” does not only mean that they are administered at the same time, but also means that the other is administered while one drug remains, so even if there is a difference in administration time I do not care.
- the administration method is not particularly limited, but it is preferable to spray from the throat or nose so that it can act directly on the lungs through the respiratory tract. Therefore, spray is preferable as the dosage form.
- Vertebrates to be treated include human and non-human vertebrates.
- the circumstances of the loss of the lung are not particularly limited, and may be caused by traffic injury or artificially caused by surgery. Moreover, even if it is a defect
- examples of pulmonary diseases accompanied by a decrease in the number of alveoli include emphysema, interstitial lung disease, and diffuse alveolar disorder.
- the severity of the disease to be treated is not limited, and it may be a decrease in the number of alveoli in either the left or right lung, or a decrease in the number of alveoli in both the left and right lungs.
- the alveolar number may be decreased only in a part of the lung, or the alveolar number may be decreased in the entire lung.
- the lung regeneration promoter may contain a carrier and an excipient in addition to an active ingredient such as an intracellular cAMP concentration increasing drug or a steroid, and can be produced by a method well known to those skilled in the art.
- an active ingredient such as an intracellular cAMP concentration increasing drug or a steroid
- the lung surfactant to be contained is not particularly limited, Infasurf and Surfacten have been developed as artificial lung surfactants, and these may be used.
- mice 8-week-old mice (male, C57 / BL6) were anesthetized by subcutaneous injection of ketamine (125 mg / kg) and xylazine (10 mg / kg), and then an 18G Surfflow needle was placed in the trachea and breathed through a ventilator. Managed. The skin of the mouse in the right lateral position was incised about 2 cm, and the muscle layer was further incised, and thoracotomy was performed from the fifth rib. The left hilar (left main bronchus, left pulmonary artery, and left pulmonary vein) was dissected by lumping together with 3-0 silk, and the left lung was removed. The thoracotomy was sutured with 3-0 silk thread.
- ketamine 125 mg / kg
- xylazine 10 mg / kg
- Example 1 In this example, when dexamethasone, 8-bromo-cAMP, and 3-isobutyl-1-methylxanthine are administered to mice undergoing left pneumonectomy surgery, compensatory lung regeneration is promoted in the right lung. Show.
- a drug was administered to an individual who had not undergone total left pneumonectomy, and this was designated as a DCI group.
- FIG. 1 shows changes in LDWI after surgery in each group. There was no significant change in the LDWI of the DCI group from 48 hours to 28 days after surgery. This indicates that the LDWI of the right lung is not changed by DCI in an individual who does not have a lung defect due to the left pneumonectomy operation.
- LDWI increased after 7 days compared to 48 hours after surgery.
- Example 2 In this example, the results of studying effective doses of dexamethasone, 8-bromo-cAMP, and 3-isobutyl-1-methylxanthine administered in Example 1 for promoting compensatory lung regeneration are shown.
- PNX left pneumonectomy surgery
- mice compensatory lungs when the doses of dexamethasone, 8-bromo-cAMP, and 3-isobutyl-1-methylxanthine per gram of body weight were 500 ng, 5 ⁇ g, and 12.5 ⁇ g or more in order. It was shown to have a regeneration promoting effect.
- Example 3 This example shows that when dexamethasone, 8-bromo-cAMP, 3-isobutyl-1-methylxanthine is administered to mice undergoing total left pneumonectomy, the number of alveoli in the right lung tissue increases. .
- the number of alveoli in the PNX + DCI group was significantly higher than that in the PNX + INF group after the second day after total left pneumonectomy (Mann-Whitney U test. In any group). As in Example 1, no histological abnormalities were detected.
- Example 4 it is shown that the number of alveoli increases when dexamethasone, 8-bromo-cAMP, and 3-isobutyl-1-methylxanthine are administered in the lungs of emphysema-induced model mice.
- VEGF vascular endothelial growth factor
- siVEGF # 2 UAGGAAGCUCAUCUCUCCUAUGUGC (SEQ ID NO: 1)
- siVEGF # 3 AAGUACGUUCGUUUAACUCAAGCUG (SEQ ID NO: 2)
- dexamethasone 500 ng / g
- 8-bromo-cAMP 5 ⁇ g / g
- 3-isobutyl-1-methylxanthine 12.5 ⁇ g / g
- the siVEGF # 2 group and the siVEGF # 3 group significantly decreased the number of alveoli per area compared to the control group (FIG. 4A, NoTx ) (Mann-Whitney U test). ), The alveolar space in the lung tissue was enlarged, and it was confirmed that emphysematous tissue changes were induced.
- the siVEGF # 2 + DCI group and the siVEGF # 3 + DCI group have significantly more alveoli per area than the siVEGF # 2 group and the siVEGF # 3 group, respectively (Mann ⁇ Whitney® U test) and the same level as the control group. In any group, histological abnormalities were not detected.
- dexamethasone, 8-bromo-cAMP, and 3-isobutyl-1-methylxanthine can be administered to pulmonary emphysema-induced model mice in which the number of alveoli is reduced, thereby restoring the number of alveoli.
- dexamethasone has an action of inhibiting the alveolar septum division (see, for example, Japanese Patent Application Laid-Open No. 2007-302689). Therefore, in Examples 3 and 4, the increase in the number of alveoli due to the administration of the drug containing dexamethasone can be said to be a remarkable and advantageous effect beyond the expectation for those skilled in the art.
- a novel lung regeneration promoting agent can be provided.
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Abstract
Disclosed is a novel agent for promoting lung regeneration.
Lung regeneration is promoted by administering a steroid, while carrying out treatment of increasing the cAMP concentration in a lung. Consequently, a medical agent that contains a steroid and/or an agent for increasing the cAMP concentration can be used as an agent for promoting lung regeneration.
Description
本発明は、肺再生促進剤に関する。
The present invention relates to a lung regeneration accelerator.
肺切除後の残存肺機能は、肺切除術の評価における重要な要素であって、肺切除後の低肺機能による合併症などのリスクは、肺切除術を考える上での重要な問題になっている。一方、マウスなどの脊椎動物において、片側肺全摘手術後の代償性再生は、古くから知られている現象である。従って、肺切除後に、代償性再生を促進することによって、残存肺機能を高めることができると考えられる。
Residual lung function after pulmonary resection is an important factor in the evaluation of pulmonary resection, and the risk of complications due to low pulmonary function after pulmonary resection becomes an important issue in considering pulmonary resection. ing. On the other hand, in vertebrates such as mice, compensatory regeneration after unilateral total pneumonectomy is a long-known phenomenon. Therefore, it is considered that residual lung function can be enhanced by promoting compensatory regeneration after lung resection.
これまで、この代償性再生を促進する効果を有する薬剤として、オールトランスレチノイン酸（例えば、横堀直子著「肺の再生医学 レチノイン酸、アラキドン酸と肺の再生」、Lung Perspect, vol. 11, 47-50, 2003 参照）やＨＧＦ（例えば、特開２００６－１３１６４９号公報参照）などが知られているが、いまだ実用化されていない。
Until now, all-trans retinoic acid (for example, Naoko Yokobori, “Regenerative Medicine of Lungs, Retinoic acid, Arachidonic acid and Lung Regeneration”, Lung Perspect, vol. 11, 47) -50, 2003) and HGF (see, for example, JP-A-2006-131649) are known, but have not yet been put into practical use.
本発明は、新規な肺再生促進剤を提供することを目的とする。
An object of the present invention is to provide a novel lung regeneration promoter.
本発明は、以下の通りである。
（１）肺におけるｃＡＭＰ濃度を上昇させる処置を行いながら投与されることを特徴とする、ステロイドを含有する肺再生促進剤。
（２）細胞内ｃＡＭＰ濃度上昇剤を肺に投与することによりｃＡＭＰ濃度を上昇させることを特徴とする、ステロイドを含有する肺再生促進剤。
（３）ステロイドと共に投与されることを特徴とする、細胞内ｃＡＭＰ濃度上昇剤を含有する肺再生促進剤。
（４）ステロイドと細胞内ｃＡＭＰ濃度上昇剤とを含有する肺再生促進剤。
（５）前記細胞内ｃＡＭＰ濃度上昇剤が、ホスホジエステラーゼ阻害薬、ｃＡＭＰ、及びｃＡＭＰアナログのうちの少なくとも一つを含有する前記（２）～（４）のいずれかに記載の肺再生促進剤。
（６）前記ステロイドがデキサメタゾンであることを特徴とする前記（１）～（５）のいずれかに記載の肺再生促進剤。
（７）前記ホスホジエステラーゼ阻害薬が、イソブチルメチルキサンチンであることを特徴とする前記（５）に記載の肺再生促進剤。
（８）前記肺再生が、肺除去手術後の代償性肺再生であることを特徴とする前記（１）～（７）のいずれかに記載の肺再生促進剤。
（９）肺欠損患者において肺再生を促進する方法であって、ｃＡＭＰ濃度を上昇させる処置を行う工程と、前記患者にステロイドを投与する工程を含む方法。
（１０）前記代償性肺再生が、肺の増量によることを特徴とする前記（８）に記載の肺再生促進剤。
（１１）前記代償性肺再生が、肺胞形成によることを特徴とする前記（８）に記載の肺再生促進剤。
（１２）前記肺再生が、肺胞数の減少を伴う肺疾患に罹患した肺における、肺胞形成による肺再生であることを特徴とする前記（１）～（７）のいずれかに記載の肺再生促進剤。
（１３）前記肺疾患が、肺気腫であることを特徴とする、前記（１２）に記載の肺再生促進剤。
（１４）肺胞数の減少を伴う肺疾患に罹患した患者において肺再生を促進する方法であって、ｃＡＭＰ濃度を上昇させる処置を行う工程と、前記患者にステロイドを投与する工程を含む方法。 The present invention is as follows.
(1) A pulmonary regeneration promoter containing a steroid, which is administered while performing a treatment to increase cAMP concentration in the lung.
(2) A lung regeneration promoting agent containing a steroid, wherein the cAMP concentration is increased by administering an intracellular cAMP concentration increasing agent to the lung.
(3) A lung regeneration promoting agent containing an intracellular cAMP concentration increasing agent, characterized by being administered together with a steroid.
(4) A lung regeneration promoter containing a steroid and an intracellular cAMP concentration increasing agent.
(5) The lung regeneration promoter according to any one of (2) to (4), wherein the intracellular cAMP concentration increasing agent contains at least one of a phosphodiesterase inhibitor, cAMP, and a cAMP analog.
(6) The lung regeneration promoter according to any one of (1) to (5), wherein the steroid is dexamethasone.
(7) The lung regeneration promoter according to (5), wherein the phosphodiesterase inhibitor is isobutylmethylxanthine.
(8) The lung regeneration promoter according to any one of (1) to (7), wherein the lung regeneration is compensatory lung regeneration after lung removal surgery.
(9) A method of promoting lung regeneration in a lung-deficient patient, the method comprising a step of increasing the cAMP concentration and a step of administering a steroid to the patient.
(10) The lung regeneration promoter according to (8), wherein the compensatory lung regeneration is based on an increase in lung volume.
(11) The lung regeneration promoter according to (8), wherein the compensatory lung regeneration is based on alveoli formation.
(12) The lung regeneration according to any one of (1) to (7), wherein the lung regeneration is lung regeneration by alveoli formation in a lung affected by a lung disease accompanied by a decrease in the number of alveoli. Lung regeneration promoter.
(13) The lung regeneration promoter according to (12), wherein the lung disease is emphysema.
(14) A method for promoting lung regeneration in a patient suffering from a lung disease accompanied by a decrease in the number of alveoli, comprising a step of performing a treatment for increasing cAMP concentration and a step of administering a steroid to the patient.
（１）肺におけるｃＡＭＰ濃度を上昇させる処置を行いながら投与されることを特徴とする、ステロイドを含有する肺再生促進剤。
（２）細胞内ｃＡＭＰ濃度上昇剤を肺に投与することによりｃＡＭＰ濃度を上昇させることを特徴とする、ステロイドを含有する肺再生促進剤。
（３）ステロイドと共に投与されることを特徴とする、細胞内ｃＡＭＰ濃度上昇剤を含有する肺再生促進剤。
（４）ステロイドと細胞内ｃＡＭＰ濃度上昇剤とを含有する肺再生促進剤。
（５）前記細胞内ｃＡＭＰ濃度上昇剤が、ホスホジエステラーゼ阻害薬、ｃＡＭＰ、及びｃＡＭＰアナログのうちの少なくとも一つを含有する前記（２）～（４）のいずれかに記載の肺再生促進剤。
（６）前記ステロイドがデキサメタゾンであることを特徴とする前記（１）～（５）のいずれかに記載の肺再生促進剤。
（７）前記ホスホジエステラーゼ阻害薬が、イソブチルメチルキサンチンであることを特徴とする前記（５）に記載の肺再生促進剤。
（８）前記肺再生が、肺除去手術後の代償性肺再生であることを特徴とする前記（１）～（７）のいずれかに記載の肺再生促進剤。
（９）肺欠損患者において肺再生を促進する方法であって、ｃＡＭＰ濃度を上昇させる処置を行う工程と、前記患者にステロイドを投与する工程を含む方法。
（１０）前記代償性肺再生が、肺の増量によることを特徴とする前記（８）に記載の肺再生促進剤。
（１１）前記代償性肺再生が、肺胞形成によることを特徴とする前記（８）に記載の肺再生促進剤。
（１２）前記肺再生が、肺胞数の減少を伴う肺疾患に罹患した肺における、肺胞形成による肺再生であることを特徴とする前記（１）～（７）のいずれかに記載の肺再生促進剤。
（１３）前記肺疾患が、肺気腫であることを特徴とする、前記（１２）に記載の肺再生促進剤。
（１４）肺胞数の減少を伴う肺疾患に罹患した患者において肺再生を促進する方法であって、ｃＡＭＰ濃度を上昇させる処置を行う工程と、前記患者にステロイドを投与する工程を含む方法。 The present invention is as follows.
(1) A pulmonary regeneration promoter containing a steroid, which is administered while performing a treatment to increase cAMP concentration in the lung.
(2) A lung regeneration promoting agent containing a steroid, wherein the cAMP concentration is increased by administering an intracellular cAMP concentration increasing agent to the lung.
(3) A lung regeneration promoting agent containing an intracellular cAMP concentration increasing agent, characterized by being administered together with a steroid.
(4) A lung regeneration promoter containing a steroid and an intracellular cAMP concentration increasing agent.
(5) The lung regeneration promoter according to any one of (2) to (4), wherein the intracellular cAMP concentration increasing agent contains at least one of a phosphodiesterase inhibitor, cAMP, and a cAMP analog.
(6) The lung regeneration promoter according to any one of (1) to (5), wherein the steroid is dexamethasone.
(7) The lung regeneration promoter according to (5), wherein the phosphodiesterase inhibitor is isobutylmethylxanthine.
(8) The lung regeneration promoter according to any one of (1) to (7), wherein the lung regeneration is compensatory lung regeneration after lung removal surgery.
(9) A method of promoting lung regeneration in a lung-deficient patient, the method comprising a step of increasing the cAMP concentration and a step of administering a steroid to the patient.
(10) The lung regeneration promoter according to (8), wherein the compensatory lung regeneration is based on an increase in lung volume.
(11) The lung regeneration promoter according to (8), wherein the compensatory lung regeneration is based on alveoli formation.
(12) The lung regeneration according to any one of (1) to (7), wherein the lung regeneration is lung regeneration by alveoli formation in a lung affected by a lung disease accompanied by a decrease in the number of alveoli. Lung regeneration promoter.
(13) The lung regeneration promoter according to (12), wherein the lung disease is emphysema.
(14) A method for promoting lung regeneration in a patient suffering from a lung disease accompanied by a decrease in the number of alveoli, comprising a step of performing a treatment for increasing cAMP concentration and a step of administering a steroid to the patient.
＝＝クロスリファレンス＝＝
本出願は、平成２２年１月５日付で出願した日本国特許出願第２０１０－６８０に基づく優先権を主張するものであり、当該基礎出願を引用することにより、本明細書に含めるものとする。 == Cross reference ==
This application claims priority based on Japanese Patent Application No. 2010-680 filed on January 5, 2010, and is incorporated herein by reference. .
本出願は、平成２２年１月５日付で出願した日本国特許出願第２０１０－６８０に基づく優先権を主張するものであり、当該基礎出願を引用することにより、本明細書に含めるものとする。 == Cross reference ==
This application claims priority based on Japanese Patent Application No. 2010-680 filed on January 5, 2010, and is incorporated herein by reference. .
以下、上記知見に基づき完成した本発明の実施の形態を、実施例を挙げながら詳細に説明する。なお、本発明の目的、特徴、利点、および、そのアイデアは、本明細書の記載により、当業者には明らかであり、本明細書の記載から、当業者であれば容易に本発明を再現できる。以下に記載された発明の実施の形態及び具体的な実施例などは、本発明の好ましい実施態様を示すものであり、例示又は説明のために示されているのであって、本発明をそれらに限定するものではない。本明細書で開示されている本発明の意図並びに範囲内で、本明細書の記載に基づき、様々な改変並びに修飾ができることは、当業者にとって明らかである。
Hereinafter, embodiments of the present invention completed based on the above knowledge will be described in detail with reference to examples. The objects, features, advantages, and ideas of the present invention will be apparent to those skilled in the art from the description of the present specification, and those skilled in the art can easily reproduce the present invention from the description of the present specification. it can. The embodiments and specific examples of the invention described below show preferred embodiments of the present invention and are shown for illustration or explanation, and the present invention is not limited to them. It is not limited. It will be apparent to those skilled in the art that various modifications and variations can be made based on the description of the present specification within the spirit and scope of the present invention disclosed herein.
脊椎動物は、肺を欠損すると、その代償として、残りの肺が再生し、肺胞が増えるとともに、増量して乾燥重量も増える。この現象は代償性肺再生と呼ばれている。このとき、肺におけるｃＡＭＰ濃度を上昇させる処置を行いながらステロイドを投与することで、肺再生を促進することができる。
When vertebrates lack a lung, the remaining lungs regenerate, the alveoli increase, and the dry weight increases as the alveoli increase. This phenomenon is called compensatory lung regeneration. At this time, pulmonary regeneration can be promoted by administering a steroid while performing a treatment to increase the cAMP concentration in the lung.
また、肺胞数の減少を伴う肺疾患に罹患した患者に対し、肺におけるｃＡＭＰ濃度を上昇させる処置を行いながらステロイドを投与することで、肺胞数が減少した肺において肺胞を形成させて肺胞数を増加させ、肺再生を促進することができる。
In addition, steroids are administered to patients suffering from pulmonary diseases accompanied by a decrease in the number of alveoli, while increasing the cAMP concentration in the lungs. It can increase the number of alveoli and promote lung regeneration.
ｃＡＭＰ濃度を上昇させるためには、当業者に公知の処置を行えばよいが、簡便さの点で、細胞内ｃＡＭＰ濃度上昇薬を肺に投与するのが好ましい。細胞内ｃＡＭＰ濃度上昇薬として、例えば、ホスホジエステラーゼ阻害薬、ｃＡＭＰ、ｃＡＭＰアナログなどを用いることができる。ホスホジエステラーゼ阻害薬として、カフェイン、イソブチルメチルキサンチン、ロリプラム（4-[3-(シクロペンチルオキシ)-4-メトキシフェニル]-2- ピロリジノン）、テオフィリン（1,3-ジメチルキサンチン）、シロミラスト（cilomilast）、ロフルミラスト（Roflumilast）、アロフィリン（Arofylline）、ＯＰＣ－６５３５、ＯＮＯ－６１２６、ＩＣ－４８５、ＡＷＤ－１２－２８１、ＣＣ－１０００４、ＣＣ－１０８８、ＫＷ－４４９０、Ｉｉｒｉｍｉｌａｓｔ、ＺＫ－１１７１３７、ＹＭ－９７６、ＢＹ－６１－９９８７、ＣＣ－７０８５、ＣＤＣ－９９８、ＭＥＭ－１４１４、ＮＤ－１２５１、Ｂａｙ１９－８００４、Ｄ－４３９６、ＰＤ－１６８７８７、アチゾラム（Atizoram）、シパムフィリン（cipamfylline）、ロリプラム（Rolipram）、ＮＩＫ－６１６、ＳＣＨ－３５１５９１、Ｖ－１１２９４Ａ、ベスナノリン、Ｒ０２０－１７２４、ビンポセチン、ザプリナスト、ジピリダモール、ミルリノン、アムリノン、ピモベンダン、シロスタミド、エノキシモン、ペルオキシモンなどを用いることができ、ｃＡＭＰアナログとして、フォルスコリン、８－ブロモｃＡＭＰ、ジブチリルｃＡＭＰ、Ｎ６－ベンゾイルｃＡＭＰ、８－チオメチルｃＡＭＰなどを用いることができる。投与方法は、特に限定されないが、気道を通じて肺に直接作用できる様に、喉や鼻から噴霧することが好ましく、したがって、剤形としてスプレーが好ましい。
In order to increase the cAMP concentration, a treatment known to those skilled in the art may be performed, but it is preferable to administer an intracellular cAMP concentration increasing drug to the lung in terms of simplicity. As an intracellular cAMP concentration increasing drug, for example, a phosphodiesterase inhibitor, cAMP, cAMP analog and the like can be used. Phosphodiesterase inhibitors include caffeine, isobutylmethylxanthine, rolipram (4- [3- (cyclopentyloxy) -4-methoxyphenyl] -2- pyrrolidinone), theophylline (1,3-dimethylxanthine), cilomilast, Roflumilast, Arofylline, OPC-6535, ONO-6126, IC-485, AWD-12-281, CC-10004, CC-1088, KW-4490, Irimilast, ZK-117137, YM-976, BY-61-9987, CC-7085, CDC-998, MEM-1414, ND-1251, Bay19-8004, D-4396, PD-168787, Atizolam, cipamfylline, Rolipram, NIK -6 16, SCH-351591, V-11294A, Besnanoline, R020-1724, Vinpocetine, Zaprinast, Dipyridamole, Milrinone, Amrinone, Pimobendan, Cilostamide, Enoximone, Peroximone and the like, and forskolin, 8- Bromo cAMP, dibutyryl cAMP, N6-benzoyl cAMP, 8-thiomethyl cAMP and the like can be used. The administration method is not particularly limited, but it is preferably sprayed from the throat or nose so that it can act directly on the lungs through the respiratory tract. Therefore, spray is preferred as the dosage form.
投与するステロイドは、特に限定されないが、例えば、酢酸コルチゾン、ヒドロコルチゾン、リン酸ヒドロコルチゾンナトリウム、コハク酸ヒドロコルチゾンナトリウム、酢酸フルドロコルチゾン、プレドニゾロン、酢酸プレドニゾロン、コハク酸プレドニゾロンナトリウム、ブチル酢酸プレドニゾロン、リン酸プレドニゾロンナトリウム、酢酸ハロプレドン、メチルプレドニゾロン、酢酸メチルプレドニゾロン、コハク酸メチルプレドニゾロンナトリウム、トリアムシノロン、酢酸トリアムシノロン、トリアムシノロンアセトニド、デキサメサゾン、酢酸デキサメタゾン、リン酸デキサメタゾンナトリウム、パルミチン酸デキサメタゾン、酢酸パラメサゾン、ベタメタゾン、ベクロメタゾン、プロピオン酸ベクロメタゾン、フルチカゾン、プロピオン酸フルチカゾン、ブデソニド、フルニソリド、トリアムシノロン、ＳＴ－１２６Ｐ、シクレソニド、デキサメタゾン、デキサメタゾンパロミチオネート、モメタゾンフランカルボネート、プラステロンスルホネート、デフラザコート、メチルプレドニゾロンスレプタネート、メチルプレドニゾロンナトリウムスクシネートなどを用いることができる。投与方法は、特に限定されず、内服によって全身投与しても構わないが、副作用を抑えるためには、気道を通じて肺に局所投与できる様に、喉や鼻から噴霧することが好ましく、したがって、剤形としてスプレーが好ましい。
The steroid to be administered is not particularly limited, for example, cortisone acetate, hydrocortisone, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, fludrocortisone acetate, prednisolone, prednisolone acetate, prednisolone sodium succinate, prednisolone butyl acetate, prednisolone sodium phosphate , Halopredon acetate, methylprednisolone acetate, methylprednisolone acetate, methylprednisolone sodium succinate, triamcinolone, triamcinolone acetate, triamcinolone acetonide, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, dexamethasone palmitate, paramethasone acetate, metamethasone acetate , Fluticasone Use fluticasone propionate, budesonide, flunisolide, triamcinolone, ST-126P, ciclesonide, dexamethasone, dexamethasone paromithionate, mometasone furan carbonate, plasterone sulfonate, deflazacoat, methylprednisolone streptinate, methylprednisolone sodium succinate, etc. be able to. The administration method is not particularly limited and may be systemically administered by internal use. However, in order to suppress side effects, it is preferable to spray from the throat or nose so that it can be locally administered to the lungs through the respiratory tract. Spray is preferred as the shape.
このように、細胞内ｃＡＭＰ濃度上昇薬を肺再生促進剤として、ステロイドと一緒に投与してもよく、ステロイドを肺再生促進剤として、細胞内ｃＡＭＰ濃度を上昇させながら投与しても構わないが、簡便さの点で、細胞内ｃＡＭＰ濃度上昇薬とステロイドを共投与することが好ましい。ここで、「共投与する」とは、同時に投与することだけを意味するのではなく、一方の薬効が残る間に、他方を投与することを意味し、従って、投与時間にずれがあっても構わない。しかし、最も好ましいのは、肺再生促進剤として一種以上の細胞内ｃＡＭＰ濃度上昇薬と一種以上のステロイドを両方含む単一剤にすることである。この場合も、投与方法は、特に限定されないが、気道を通じて肺に直接作用できる様に、喉や鼻から噴霧することが好ましく、したがって、剤形としてスプレーが好ましい。
As described above, the intracellular cAMP concentration increasing drug may be administered together with the steroid as a lung regeneration promoting agent, or the steroid may be administered as the lung regeneration promoting agent while increasing the intracellular cAMP concentration. From the viewpoint of simplicity, it is preferable to co-administer an intracellular cAMP concentration increasing drug and a steroid. Here, “co-administer” does not only mean that they are administered at the same time, but also means that the other is administered while one drug remains, so even if there is a difference in administration time I do not care. However, it is most preferable to use a single agent containing both one or more intracellular cAMP level-elevating drugs and one or more steroids as the lung regeneration promoter. In this case as well, the administration method is not particularly limited, but it is preferable to spray from the throat or nose so that it can act directly on the lungs through the respiratory tract. Therefore, spray is preferable as the dosage form.
治療対象とする脊椎動物は、ヒト及びヒト以外の脊椎動物を含む。肺が欠損した経緯は、特に限定されず、交通外傷などによって生じたものであっても、外科手術などによる人為的なものであっても構わない。また、肺の一部の欠損であっても、片側全肺の欠損であっても構わない。
Vertebrates to be treated include human and non-human vertebrates. The circumstances of the loss of the lung are not particularly limited, and may be caused by traffic injury or artificially caused by surgery. Moreover, even if it is a defect | deletion of a part of lungs, the defect | deletion of one side whole lungs may be sufficient.
また、肺胞数の減少を伴う肺疾患とは、例えば、肺気腫、間質性肺疾患、びまん性肺胞障害が挙げられる。なお、治療対象となる疾患の重症度は限定されず、左右どちらかの肺において肺胞数の減少を呈していても、あるいは、左右両方の肺において肺胞数の減少を呈していてもよく、また、肺の一部分のみにおいて肺胞数の減少を呈していても、あるいは肺全体で肺胞数の減少を呈していてもよい。
In addition, examples of pulmonary diseases accompanied by a decrease in the number of alveoli include emphysema, interstitial lung disease, and diffuse alveolar disorder. The severity of the disease to be treated is not limited, and it may be a decrease in the number of alveoli in either the left or right lung, or a decrease in the number of alveoli in both the left and right lungs In addition, the alveolar number may be decreased only in a part of the lung, or the alveolar number may be decreased in the entire lung.
肺再生促進剤は、細胞内ｃＡＭＰ濃度上昇薬やステロイドという有効成分以外に、キャリアや賦型剤を含んでも構わず、当業者に周知の方法で、製造することができる。特に、肺サーファクタントを含有させることが好ましい。含有させる肺サーファクタントは特に限定されないが、人工の肺サーファクタントとして、現在、InfasurfやSurfactenなどが開発されており、これらを用いてもよい。
The lung regeneration promoter may contain a carrier and an excipient in addition to an active ingredient such as an intracellular cAMP concentration increasing drug or a steroid, and can be produced by a method well known to those skilled in the art. In particular, it is preferable to contain a lung surfactant. Although the lung surfactant to be contained is not particularly limited, Infasurf and Surfacten have been developed as artificial lung surfactants, and these may be used.
以下、実施例により本発明をさらに具体的に説明する
Hereinafter, the present invention will be described more specifically with reference to examples.
＝＝マウスの左肺全摘出手術＝＝
８週齢のマウス（オス、Ｃ５７／ＢＬ６）にケタミン（１２５ｍｇ／ｋｇ）およびキシラジン（１０ｍｇ／ｋｇ）を皮下注射して麻酔した後、１８Ｇサーフロー針を気管内に留置して人工呼吸器によって呼吸管理を行った。右側臥位としたマウスの皮膚を約２ｃｍ切開し、さらに筋層を切開して、第五肋骨より開胸した。左肺門（左主気管支、左肺動脈、および左肺静脈）を３－０絹糸で一括結紮することにより切離し、左肺を摘出した。３－０絹糸で開胸部位を縫合した。 == Surgery to remove the left lung of the mouse ==
8-week-old mice (male, C57 / BL6) were anesthetized by subcutaneous injection of ketamine (125 mg / kg) and xylazine (10 mg / kg), and then an 18G Surfflow needle was placed in the trachea and breathed through a ventilator. Managed. The skin of the mouse in the right lateral position was incised about 2 cm, and the muscle layer was further incised, and thoracotomy was performed from the fifth rib. The left hilar (left main bronchus, left pulmonary artery, and left pulmonary vein) was dissected by lumping together with 3-0 silk, and the left lung was removed. The thoracotomy was sutured with 3-0 silk thread.
８週齢のマウス（オス、Ｃ５７／ＢＬ６）にケタミン（１２５ｍｇ／ｋｇ）およびキシラジン（１０ｍｇ／ｋｇ）を皮下注射して麻酔した後、１８Ｇサーフロー針を気管内に留置して人工呼吸器によって呼吸管理を行った。右側臥位としたマウスの皮膚を約２ｃｍ切開し、さらに筋層を切開して、第五肋骨より開胸した。左肺門（左主気管支、左肺動脈、および左肺静脈）を３－０絹糸で一括結紮することにより切離し、左肺を摘出した。３－０絹糸で開胸部位を縫合した。 == Surgery to remove the left lung of the mouse ==
8-week-old mice (male, C57 / BL6) were anesthetized by subcutaneous injection of ketamine (125 mg / kg) and xylazine (10 mg / kg), and then an 18G Surfflow needle was placed in the trachea and breathed through a ventilator. Managed. The skin of the mouse in the right lateral position was incised about 2 cm, and the muscle layer was further incised, and thoracotomy was performed from the fifth rib. The left hilar (left main bronchus, left pulmonary artery, and left pulmonary vein) was dissected by lumping together with 3-0 silk, and the left lung was removed. The thoracotomy was sutured with 3-0 silk thread.
[実施例１]
本実施例では、左肺全摘出手術を受けたマウスに対し、デキサメタゾン、８－ブロモ－ｃＡＭＰ、３－イソブチル－１－メチルキサンチンを投与すると、右肺において代償性肺再生が促進されることを示す。 [Example 1]
In this example, when dexamethasone, 8-bromo-cAMP, and 3-isobutyl-1-methylxanthine are administered to mice undergoing left pneumonectomy surgery, compensatory lung regeneration is promoted in the right lung. Show.
本実施例では、左肺全摘出手術を受けたマウスに対し、デキサメタゾン、８－ブロモ－ｃＡＭＰ、３－イソブチル－１－メチルキサンチンを投与すると、右肺において代償性肺再生が促進されることを示す。 [Example 1]
In this example, when dexamethasone, 8-bromo-cAMP, and 3-isobutyl-1-methylxanthine are administered to mice undergoing left pneumonectomy surgery, compensatory lung regeneration is promoted in the right lung. Show.
＝＝薬剤投与＝＝
マウスの左肺全摘出手術終了後に抜管した直後、デキサメタゾン（Dexamethasone、５００ｎｇ／ｇ、Sigma社）、８－ブロモ－ｃＡＭＰ（8-Bromo-cAMP、５μｇ／ｇ、Santa Cruz社）、３－イソブチル－１－メチルキサンチン（3-isobutyl-1-methylxanthine、１２．５μｇ／ｇ、Calbiochem社）をInfasurf（ONY, Inc社）と混合し、マイクロピペッターを用いてマウスの鼻腔に３回に分けて投与した。（ＰＮＸ＋ＤＣＩ群）。対照群には、左肺全摘出手術を行ったが、上記薬剤投与を行わなかった（ＰＮＸ群）。また、左肺全摘出手術を受けていない個体に対し同様に薬剤投与を行い、これをＤＣＩ群とした。これらの各群（ｎ＝４～５）について、左肺全摘出手術から４８時間、７日、１４日、あるいは２８日間飼育を続け、以下のＬＤＷＩ測定あるいは、形態学的測定に供した。 == Drug administration ==
Immediately after extubation after completion of the left pneumonectomy for mice, dexamethasone (Dexamethasone, 500 ng / g, Sigma), 8-bromo-cAMP (8-Bromo-cAMP, 5 μg / g, Santa Cruz), 3-isobutyl- 1-methylxanthine (3-isobutyl-1-methylxanthine, 12.5 μg / g, Calbiochem) was mixed with Infasurf (ONY, Inc.) and administered to the nasal cavity of mice using a micropipettor in three times. . (PNX + DCI group). In the control group, the left pneumonectomy was performed, but the drug administration was not performed (PNX group). In addition, a drug was administered to an individual who had not undergone total left pneumonectomy, and this was designated as a DCI group. Each of these groups (n = 4 to 5) was kept for 48 hours, 7 days, 14 days, or 28 days after the left pneumonectomy and subjected to the following LDWI measurement or morphological measurement.
マウスの左肺全摘出手術終了後に抜管した直後、デキサメタゾン（Dexamethasone、５００ｎｇ／ｇ、Sigma社）、８－ブロモ－ｃＡＭＰ（8-Bromo-cAMP、５μｇ／ｇ、Santa Cruz社）、３－イソブチル－１－メチルキサンチン（3-isobutyl-1-methylxanthine、１２．５μｇ／ｇ、Calbiochem社）をInfasurf（ONY, Inc社）と混合し、マイクロピペッターを用いてマウスの鼻腔に３回に分けて投与した。（ＰＮＸ＋ＤＣＩ群）。対照群には、左肺全摘出手術を行ったが、上記薬剤投与を行わなかった（ＰＮＸ群）。また、左肺全摘出手術を受けていない個体に対し同様に薬剤投与を行い、これをＤＣＩ群とした。これらの各群（ｎ＝４～５）について、左肺全摘出手術から４８時間、７日、１４日、あるいは２８日間飼育を続け、以下のＬＤＷＩ測定あるいは、形態学的測定に供した。 == Drug administration ==
Immediately after extubation after completion of the left pneumonectomy for mice, dexamethasone (Dexamethasone, 500 ng / g, Sigma), 8-bromo-cAMP (8-Bromo-cAMP, 5 μg / g, Santa Cruz), 3-isobutyl- 1-methylxanthine (3-isobutyl-1-methylxanthine, 12.5 μg / g, Calbiochem) was mixed with Infasurf (ONY, Inc.) and administered to the nasal cavity of mice using a micropipettor in three times. . (PNX + DCI group). In the control group, the left pneumonectomy was performed, but the drug administration was not performed (PNX group). In addition, a drug was administered to an individual who had not undergone total left pneumonectomy, and this was designated as a DCI group. Each of these groups (n = 4 to 5) was kept for 48 hours, 7 days, 14 days, or 28 days after the left pneumonectomy and subjected to the following LDWI measurement or morphological measurement.
＝＝ＬＤＷＩ測定＝＝
左肺全摘出手術から４８時間、７日、１４日、あるいは２８日間飼育を続けた後、マウスを屠殺して右肺を摘出した。摘出した肺について、ＬＤＷＩ（lung dry weight index、肺乾燥重量／被検体体重）の測定を行った。 == LDWI measurement ==
After 48 hours, 7 days, 14 days, or 28 days after the left pneumonectomy, the mice were sacrificed and the right lung was removed. The extracted lung was measured for LDWI (lung dry weight index, lung dry weight / subject weight).
左肺全摘出手術から４８時間、７日、１４日、あるいは２８日間飼育を続けた後、マウスを屠殺して右肺を摘出した。摘出した肺について、ＬＤＷＩ（lung dry weight index、肺乾燥重量／被検体体重）の測定を行った。 == LDWI measurement ==
After 48 hours, 7 days, 14 days, or 28 days after the left pneumonectomy, the mice were sacrificed and the right lung was removed. The extracted lung was measured for LDWI (lung dry weight index, lung dry weight / subject weight).
図１に、各群における術後のＬＤＷＩの変化を示す。術後４８時間から２８日までにわたり、ＤＣＩ群のＬＤＷＩには有意な変化がなかった。これは、左肺全摘出手術による肺欠損のない個体では、ＤＣＩによって右肺のＬＤＷＩが変化しないことを示す。
FIG. 1 shows changes in LDWI after surgery in each group. There was no significant change in the LDWI of the DCI group from 48 hours to 28 days after surgery. This indicates that the LDWI of the right lung is not changed by DCI in an individual who does not have a lung defect due to the left pneumonectomy operation.
一方、ＰＮＸ群では、術後４８時間と比較して術後７日以後にＬＤＷＩが有意に（Mann-Whitney U検定、p=0.0209）増加した。そして、このＰＮＸ群のＬＤＷＩは、術後７日以後にはＤＣＩ群に比較して有意に（Mann-Whitney U検定、7日 p=0.0143 14日p=0.0143 28日 p=0.009）高かった。これらの結果は、左肺全摘出手術を行うことにより、右肺のＬＤＷＩが増加することを示す。
On the other hand, in the PNX group, LDWI increased significantly (Mann-Whitney U test, p = 0.0209) after 7 days after surgery compared with 48 hours after surgery. The LDWI of the PNX group was significantly higher than that of the DCI group after 7 days after the operation (Mann-Whitney U test, 7 days p = 0.0143, 14 days p = 0.0143, 28 days p = 0.009). These results indicate that the LDWI of the right lung is increased by performing a left pneumonectomy operation.
ＰＮＸ＋ＤＣＩ群では、術後４８時間と比較し、７日以後ではＬＤＷＩが増加していた。また、術後４８時間～２８日にわたり、ＤＣＩ群およびＰＮＸ群に比較してＬＤＷＩが有意に（Mann-Whitney U検定、48時間 p=0.009、 7日 p=0.009、 14日p=0.009、 28日 p=0.009 （ＤＣＩ群と比較）、 48時間 p=0.0143、 7日 p=0.0143、14日 p=0.0143、 28日 p=0.009（ＰＮＸ群と比較））高かった。
In the PNX + DCI group, LDWI increased after 7 days compared to 48 hours after surgery. In addition, LDWI was significantly higher than that of DCI group and PNX group for 48 hours to 28 days after operation (Mann-Whitney U test, 48 hours p = 0.009, 7 days p = 0.009, 14 days p = 0.009, 28) Day p = 0.009 (compared with DCI group), 48 hours (p = 0.0143), day 7 (p = 0.0143), day 14 (p = 0.0143), day 28 (p = 0.009 (compared with PNX group)).
以上の結果は、左肺全摘出をすることにより、右肺のＬＤＷＩが増加すること、そして、このＬＤＷＩの増加は、術後にデキサメタゾン、８－ブロモ－ｃＡＭＰ、および３－イソブチル－１－メチルキサンチンを投与することによって促進されたことを示している。
The above results indicate that the removal of the left lung completely increases the LDWI of the right lung, and this increase in LDWI is postoperatively caused by dexamethasone, 8-bromo-cAMP, and 3-isobutyl-1-methyl. It shows that it was promoted by administering xanthine.
＝＝肺組織の形態学的観察＝＝
ＰＮＸ＋ＤＣＩ群およびＰＮＸ群のマウスについて、左肺全摘出手術から１２時間、４８時間、７日、１４日、あるいは２８日間飼育を続けた後、左肺全摘出手術時と同様に麻酔した後開腹し、下大静脈切開によって失血させて屠殺した。このマウスを開胸して右肺を摘出し、２０ｃｍＨ２Ｏで１０％ホルマリンを注入して肺組織を固定した（ｎ＝４）。この組織のパラフィン切片をＨＥ染色してプレパラートを作製し、正常肺と比較したところ、両群とも、組織学的異常は検出されなかった。 == Morphological observation of lung tissue ==
The mice in the PNX + DCI group and the PNX group were kept for 12 hours, 48 hours, 7 days, 14 days, or 28 days after the left pneumonectomy, then anesthetized in the same manner as in the left pneumonectomy and then laparotomized. Blood was sacrificed by inferior vena cava incision. The mouse was opened and the right lung was removed, and 10% formalin was injected with 20 cmH 2 O to fix the lung tissue (n = 4). When a paraffin section of this tissue was stained with HE to prepare a preparation and compared with normal lung, no histological abnormality was detected in either group.
ＰＮＸ＋ＤＣＩ群およびＰＮＸ群のマウスについて、左肺全摘出手術から１２時間、４８時間、７日、１４日、あるいは２８日間飼育を続けた後、左肺全摘出手術時と同様に麻酔した後開腹し、下大静脈切開によって失血させて屠殺した。このマウスを開胸して右肺を摘出し、２０ｃｍＨ２Ｏで１０％ホルマリンを注入して肺組織を固定した（ｎ＝４）。この組織のパラフィン切片をＨＥ染色してプレパラートを作製し、正常肺と比較したところ、両群とも、組織学的異常は検出されなかった。 == Morphological observation of lung tissue ==
The mice in the PNX + DCI group and the PNX group were kept for 12 hours, 48 hours, 7 days, 14 days, or 28 days after the left pneumonectomy, then anesthetized in the same manner as in the left pneumonectomy and then laparotomized. Blood was sacrificed by inferior vena cava incision. The mouse was opened and the right lung was removed, and 10% formalin was injected with 20 cmH 2 O to fix the lung tissue (n = 4). When a paraffin section of this tissue was stained with HE to prepare a preparation and compared with normal lung, no histological abnormality was detected in either group.
[実施例２]
本実施例では、実施例１において投与されたデキサメタゾン、８－ブロモ－ｃＡＭＰ、および３－イソブチル－１－メチルキサンチンの、代償性肺再生促進に有効な投与量の検討結果を示す。 [Example 2]
In this example, the results of studying effective doses of dexamethasone, 8-bromo-cAMP, and 3-isobutyl-1-methylxanthine administered in Example 1 for promoting compensatory lung regeneration are shown.
本実施例では、実施例１において投与されたデキサメタゾン、８－ブロモ－ｃＡＭＰ、および３－イソブチル－１－メチルキサンチンの、代償性肺再生促進に有効な投与量の検討結果を示す。 [Example 2]
In this example, the results of studying effective doses of dexamethasone, 8-bromo-cAMP, and 3-isobutyl-1-methylxanthine administered in Example 1 for promoting compensatory lung regeneration are shown.
上記「マウスの左肺全摘出手術」に記載の方法に従って左肺を摘出した直後のマウスに対し、表１に示す量のデキサメタゾン、８－ブロモ－ｃＡＭＰ、および３－イソブチル－１－メチルキサンチンを投与した。１４日間飼育した後、実施例１の記載に従ってＬＤＷＩを測定した（ｎ＝４～５）。
The amount of dexamethasone, 8-bromo-cAMP, and 3-isobutyl-1-methylxanthine shown in Table 1 was added to the mouse immediately after the left lung was removed according to the method described in the above “total left pneumonectomy operation of mice”. Administered. After rearing for 14 days, LDWI was measured as described in Example 1 (n = 4-5).
図２に示すように、ＤＣＩあるいはＤＣＩｘ２のいずれの投与量においても、左肺全摘出手術後薬剤投与を行わない場合（ＰＮＸ）に比較してＬＤＷＩが有意に（Mann-Whitney U検定、p=0.0143（ＤＣＩ群と比較） 、p=0.0143 （ＤＣＩｘ２群と比較））高く、ＤＣＩとＤＣＩｘ２には有意な差が認められなかった。一方で、ＤＣＩｘ１／４およびＤＣＩｘ１／２の投与量では、ＰＮＸに比較してＬＤＷＩの有意な（Mann-Whitney U検定、p=0.0143 （ＤＣＩｘ１／４群と比較)）、p=0.0143（ＤＣＩｘ１／２群と比較））上昇が認められたが、その増加は小さく、ＤＣＩ群と比較してＬＤＷＩは有意に低かった（Mann-Whitney U検定、p=0.0472 （ＤＣＩとＤＣＩｘ１／４群とを比較）、p=0.009（ＤＣＩ群とＤＣＩ１／２群とを比較））。
As shown in FIG. 2, at any dose of DCI or DCIx2, LDWI is significantly higher (Mann-Whitney U test, p = p) than when no drug administration is performed after left pneumonectomy surgery (PNX) 0.0143 (compared to the DCI group), p = 0.0143 (compared to the DCIx2 group))), and no significant difference was observed between DCI and DCIx2. On the other hand, at doses of DCIx1 / 4 and DCIx1 / 2, LDWI was significantly higher than PNX (Mann-WhitneyhU test, p = 0.0143 (compared to DCIx1 / 4 group)), p = 0.0143 (DCIx1 / 1). 2) Compared to the DCI group, the increase was small, but the LDWI was significantly lower than the DCI group (Mann-Whitney U test, p = 0.0472 (comparison between DCI and DCIx1 / 4 group) ), P = 0.009 (comparison between DCI group and DCI1 / 2 group)).
以上の結果から、マウスにおいては、体重１ｇ当たりのデキサメタゾン、８－ブロモ－ｃＡＭＰ、および３－イソブチル－１－メチルキサンチンの投与量が、順に５００ｎｇ、５μｇ、１２．５μｇ以上の場合に代償性肺再生促進効果を有することが示された。
Based on the above results, in mice, compensatory lungs when the doses of dexamethasone, 8-bromo-cAMP, and 3-isobutyl-1-methylxanthine per gram of body weight were 500 ng, 5 μg, and 12.5 μg or more in order. It was shown to have a regeneration promoting effect.
[実施例３]
本実施例では、左肺全摘出手術を受けたマウスに対し、デキサメタゾン、８－ブロモ－ｃＡＭＰ、３－イソブチル－１－メチルキサンチンを投与すると、右肺組織の肺胞数が増加することを示す。 [Example 3]
This example shows that when dexamethasone, 8-bromo-cAMP, 3-isobutyl-1-methylxanthine is administered to mice undergoing total left pneumonectomy, the number of alveoli in the right lung tissue increases. .
本実施例では、左肺全摘出手術を受けたマウスに対し、デキサメタゾン、８－ブロモ－ｃＡＭＰ、３－イソブチル－１－メチルキサンチンを投与すると、右肺組織の肺胞数が増加することを示す。 [Example 3]
This example shows that when dexamethasone, 8-bromo-cAMP, 3-isobutyl-1-methylxanthine is administered to mice undergoing total left pneumonectomy, the number of alveoli in the right lung tissue increases. .
実施例１の方法と同様にマウスの左肺全摘出および薬剤投与を行ったＰＮＸ＋ＤＣＩ群、マウスの左肺全摘出後にＤＣＩの担体（Infasurf）のみを２０μｌ投与したＰＮＸ＋ＩＮＦ群、および、左肺全摘出も薬剤投与も受けていない対照群（図ではＮｏＴｘ）について、実施例１の「肺組織の形態学的観察」に従い、右肺組織を摘出し、プレパラートを作製した（各群ｎ＝４）。各個体の右肺組織について、０．１９６ｍｍ２の視野面積について、５視野ずつ観察し、視野当たりの肺胞個数を計測し、群ごとの平均値を算出した。
The PNX + DCI group in which mice were subjected to total pneumonectomy and drug administration in the same manner as in Example 1, the PNX + INF group in which only 20 μl of DCI carrier (Infasurf) was administered after total pneumonectomy of mice, and total pneumonectomy For the control group (NoTx in the figure) that received no drug administration, the right lung tissue was excised and prepared in accordance with “morphological observation of lung tissue” in Example 1 (each group n = 4). With respect to the right lung tissue of each individual, five fields of view were observed for a field area of 0.196 mm 2 , the number of alveoli per field was measured, and the average value for each group was calculated.
図３Ａ、Ｂに示すように、左肺全摘出後２日目以降、ＰＮＸ＋ＩＮＦ群と比較して、ＰＮＸ＋ＤＣＩ群では肺胞数が有意に多かった（Mann-Whitney U検定。なお、いずれの群においても、実施例１と同様、組織学的異常は検出されなかった。
As shown in FIGS. 3A and 3B, the number of alveoli in the PNX + DCI group was significantly higher than that in the PNX + INF group after the second day after total left pneumonectomy (Mann-Whitney U test. In any group). As in Example 1, no histological abnormalities were detected.
このように、左肺全摘出後にデキサメタゾン、８－ブロモ－ｃＡＭＰ、３－イソブチル－１－メチルキサンチンを投与することにより、右肺組織において有意に肺胞数が増加する。
Thus, the administration of dexamethasone, 8-bromo-cAMP, and 3-isobutyl-1-methylxanthine after total removal of the left lung significantly increases the number of alveoli in the right lung tissue.
[実施例４]
本実施例では、肺気腫誘発モデルマウスの肺において、デキサメタゾン、８－ブロモ－ｃＡＭＰ、３－イソブチル－１－メチルキサンチンを投与することにより肺胞数が増加することを示す。 [Example 4]
In this example, it is shown that the number of alveoli increases when dexamethasone, 8-bromo-cAMP, and 3-isobutyl-1-methylxanthine are administered in the lungs of emphysema-induced model mice.
本実施例では、肺気腫誘発モデルマウスの肺において、デキサメタゾン、８－ブロモ－ｃＡＭＰ、３－イソブチル－１－メチルキサンチンを投与することにより肺胞数が増加することを示す。 [Example 4]
In this example, it is shown that the number of alveoli increases when dexamethasone, 8-bromo-cAMP, and 3-isobutyl-1-methylxanthine are administered in the lungs of emphysema-induced model mice.
８週齢のマウス（オス、Ｃ５７／ＢＬ６）にケタミン（３０ｍｇ／ｋｇ）およびキシラジン（３ｍｇ／ｋｇ）を皮下注射して麻酔した後２０分以内に、ＶＥＧＦ（血管内皮細胞増殖因子）ｍＲＮＡに対する以下のｓｉＲＮＡのいずれかをマイクロピペッターを用いてマウスの鼻腔に３回に分けて投与し（体重１ｇあたり計３５μｇをInfasurfに溶解し、２０μｌとして投与）、肺気腫誘発モデルマウスとした（ｓｉＶＥＧＦ＃２群、ｓｉＶＥＧＦ＃３群、各群ｎ＝４）。なお、ＶＥＧＦの発現低下により肺気腫が誘発されることが知られている（例えば、Kasahara, Y. et al., Am. J. Respir. Crit. Care Med. 163:737-744, 2001; Kasahara, Y. et al., J. Clin. Invest. 106:1309-1310, 2000; Tuder, R. M. et al., Am. J. Respir. Cell Mol. Biol. 29:88-97, 2003 参照）。
ｓｉＶＥＧＦ＃２：UAGGAAGCUCAUCUCUCCUAUGUGC（配列番号１）
ｓｉＶＥＧＦ＃３：AAGUACGUUCGUUUAACUCAAGCUG（配列番号２） Within 20 minutes after anesthesia by subcutaneous injection of ketamine (30 mg / kg) and xylazine (3 mg / kg) into 8-week-old mice (male, C57 / BL6), VEGF (vascular endothelial growth factor) mRNA One of these siRNAs was administered to a mouse's nasal cavity in 3 portions using a micropipette (total 35 μg per gram of body weight was dissolved in Infasurf and administered as 20 μl) to give an emphysema-induced model mouse (siVEGF # 2 group) , SiVEGF # 3 group, each group n = 4). It is known that pulmonary emphysema is induced by decreased expression of VEGF (for example, Kasahara, Y. et al., Am. J. Respir. Crit. Care Med. 163: 737-744, 2001; Kasahara, Y. et al., J. Clin. Invest. 106: 1309-1310, 2000; Tuder, RM et al., Am. J. Respir. Cell Mol. Biol. 29: 88-97, 2003).
siVEGF # 2: UAGGAAGCUCAUCUCUCCUAUGUGC (SEQ ID NO: 1)
siVEGF # 3: AAGUACGUUCGUUUAACUCAAGCUG (SEQ ID NO: 2)
ｓｉＶＥＧＦ＃２：UAGGAAGCUCAUCUCUCCUAUGUGC（配列番号１）
ｓｉＶＥＧＦ＃３：AAGUACGUUCGUUUAACUCAAGCUG（配列番号２） Within 20 minutes after anesthesia by subcutaneous injection of ketamine (30 mg / kg) and xylazine (3 mg / kg) into 8-week-old mice (male, C57 / BL6), VEGF (vascular endothelial growth factor) mRNA One of these siRNAs was administered to a mouse's nasal cavity in 3 portions using a micropipette (total 35 μg per gram of body weight was dissolved in Infasurf and administered as 20 μl) to give an emphysema-induced model mouse (
siVEGF # 2: UAGGAAGCUCAUCUCUCCUAUGUGC (SEQ ID NO: 1)
siVEGF # 3: AAGUACGUUCGUUUAACUCAAGCUG (SEQ ID NO: 2)
このｓｉＲＮＡ投与と同時に、デキサメタゾン（５００ｎｇ／ｇ）、８－ブロモ－ｃＡＭＰ（５μｇ／ｇ）、および３－イソブチル－１－メチルキサンチン（１２．５μｇ／ｇ）をマウス鼻腔内に投与した（ｓｉＶＥＧＦ＃２＋ＤＣＩ群、ｓｉＶＥＧＦ＃３＋ＤＣＩ群、各群ｎ＝４）。
Simultaneously with this siRNA administration, dexamethasone (500 ng / g), 8-bromo-cAMP (5 μg / g), and 3-isobutyl-1-methylxanthine (12.5 μg / g) were administered intranasally (siVEGF #). 2 + DCI group, siVEGF # 3 + DCI group, each group n = 4).
ｓｉＲＮＡおよび薬剤投与から４日後に、薬剤投与時と同様に麻酔して開腹し、下大静脈切開によって失血させて屠殺した。このマウスを開胸して肺を摘出し、２０ｃｍＨ２Ｏで１０％ホルマリンを注入して肺組織を固定した。この肺組織のパラフィン切片をＨＥ染色してプレパラートを作製し、実施例３の記載と同様にして組織における視野当たりの肺胞個数を計測した。なお、いずれのｓｉＲＮＡも薬剤も投与しない対照群についても、同様の解析を行った（ｎ＝４）。
Four days after the administration of siRNA and drug, anesthesia was performed and the abdomen was opened in the same manner as during drug administration. The mouse was opened to remove the lung, and 10% formalin was injected with 20 cmH 2 O to fix the lung tissue. A paraffin section of this lung tissue was stained with HE to prepare a preparation, and the number of alveoli per visual field in the tissue was measured in the same manner as described in Example 3. The same analysis was performed for the control group to which neither siRNA nor drug was administered (n = 4).
図４Ａ、Ｂに示すように、ｓｉＶＥＧＦ＃２群、およびｓｉＶＥＧＦ＃３群では、対照群（図４Ａ、ＮｏＴｘ）と比較し、面積当たりの肺胞数が有意に減少し（Mann-Whitney U検定）、肺組織において肺胞道のスペースが拡大しており、肺気腫性組織変化が誘発されていることが確認できた。
As shown in FIGS. 4A and B, the siVEGF # 2 group and the siVEGF # 3 group significantly decreased the number of alveoli per area compared to the control group (FIG. 4A, NoTx ) (Mann-Whitney U test). ), The alveolar space in the lung tissue was enlarged, and it was confirmed that emphysematous tissue changes were induced.
これに対し、図４Ａ、Ｂに示すように、ｓｉＶＥＧＦ＃２＋ＤＣＩ群とｓｉＶＥＧＦ＃３＋ＤＣＩ群では、それぞれｓｉＶＥＧＦ＃２群とｓｉＶＥＧＦ＃３群よりも、面積当たりの肺胞数が有意に多く（Mann-Whitney U検定）、対照群と同程度であった。なお、いずれの群においても、組織学的異常は検出されなかった。
In contrast, as shown in FIGS. 4A and 4B, the siVEGF # 2 + DCI group and the siVEGF # 3 + DCI group have significantly more alveoli per area than the siVEGF # 2 group and the siVEGF # 3 group, respectively (Mann− Whitney® U test) and the same level as the control group. In any group, histological abnormalities were not detected.
このように、肺胞数が減少した肺気腫誘発モデルマウスに対し、デキサメタゾン、８－ブロモ－ｃＡＭＰ、３－イソブチル－１－メチルキサンチンを投与することにより、肺胞数を回復させることができる。
Thus, dexamethasone, 8-bromo-cAMP, and 3-isobutyl-1-methylxanthine can be administered to pulmonary emphysema-induced model mice in which the number of alveoli is reduced, thereby restoring the number of alveoli.
これまで、デキサメタゾンが肺胞隔膜区分を阻害する作用を有することが報告されている（例えば、特開２００７－３０２６８９公報参照）。従って、実施例３、４において、デキサメタゾンを含む薬剤の投与によって肺胞数が増加したことは、当業者にとって予測を超えた、顕著で有利な効果であるといえる。
So far, it has been reported that dexamethasone has an action of inhibiting the alveolar septum division (see, for example, Japanese Patent Application Laid-Open No. 2007-302689). Therefore, in Examples 3 and 4, the increase in the number of alveoli due to the administration of the drug containing dexamethasone can be said to be a remarkable and advantageous effect beyond the expectation for those skilled in the art.
本発明によって、新規な肺再生促進剤を提供することができる。
According to the present invention, a novel lung regeneration promoting agent can be provided.
Claims (6)
- デキサメタゾンとイソブチルメチルキサンチンとを含有する肺再生促進剤。 肺 Lung regeneration promoter containing dexamethasone and isobutylmethylxanthine.
- 前記肺再生が、肺除去手術後の代償性肺再生であることを特徴とする請求項１に記載の肺再生促進剤。 The lung regeneration promoter according to claim 1, wherein the lung regeneration is compensatory lung regeneration after lung removal surgery.
- 前記代償性肺再生が、肺胞形成による肺再生であることを特徴とする請求項２に記載の肺再生促進剤。 The lung regeneration promoter according to claim 2, wherein the compensatory lung regeneration is lung regeneration by alveolar formation.
- 前記代償性肺再生が、肺の増量によることを特徴とする請求項２に記載の肺再生促進剤。 The lung regeneration promoter according to claim 2, wherein the compensatory lung regeneration is based on an increase in lung volume.
- 前記肺再生が、肺胞数の減少を伴う肺疾患に罹患した肺組織における、肺胞形成による肺再生であることを特徴とする請求項１に記載の肺再生促進剤。 The lung regeneration accelerator according to claim 1, wherein the lung regeneration is lung regeneration by alveoli formation in lung tissue affected by a lung disease accompanied by a decrease in the number of alveoli.
- 前記肺胞数の減少を伴う肺疾患が、肺気腫であることを特徴とする、請求項５に記載の肺再生促進剤。 The lung regeneration promoting agent according to claim 5, wherein the lung disease accompanied by a decrease in the number of alveoli is emphysema.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| KR20190031209A (en) * | 2016-06-03 | 2019-03-25 | 더 트러스티스 오브 컬럼비아 유니버시티 인 더 시티 오브 뉴욕 | How to treat Prader-Willi Syndrome |
| JP2019522045A (en) * | 2016-06-03 | 2019-08-08 | ザ・トラスティーズ・オブ・コロンビア・ユニバーシティ・イン・ザ・シティ・オブ・ニューヨーク | How to treat Prader-Willi syndrome |
| US10842775B2 (en) | 2016-06-03 | 2020-11-24 | The Trustees Of Columbia University In The City Of New York | Methods of treating Prader-Willi syndrome |
| JP7044768B2 (en) | 2016-06-03 | 2022-03-30 | ザ・トラスティーズ・オブ・コロンビア・ユニバーシティ・イン・ザ・シティ・オブ・ニューヨーク | How to Treat Prader-Willi Syndrome |
| JP2022058673A (en) * | 2016-06-03 | 2022-04-12 | ザ・トラスティーズ・オブ・コロンビア・ユニバーシティ・イン・ザ・シティ・オブ・ニューヨーク | Methods of treating prader-willi syndrome |
| KR102478186B1 (en) | 2016-06-03 | 2022-12-15 | 더 트러스티스 오브 컬럼비아 유니버시티 인 더 시티 오브 뉴욕 | How to treat Prader-Willi syndrome |
| JP7329634B2 (en) | 2016-06-03 | 2023-08-18 | ザ・トラスティーズ・オブ・コロンビア・ユニバーシティ・イン・ザ・シティ・オブ・ニューヨーク | How to Treat Prader-Willi Syndrome |
| US11957656B2 (en) | 2016-06-03 | 2024-04-16 | The Trustees Of Columbia University In The City Of New York | Methods of treating Prader-Willi syndrome |
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