WO2015137056A1 - Prevention or treatment of patent ductus arteriosus by glutamic acid - Google Patents

Prevention or treatment of patent ductus arteriosus by glutamic acid Download PDF

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WO2015137056A1
WO2015137056A1 PCT/JP2015/054277 JP2015054277W WO2015137056A1 WO 2015137056 A1 WO2015137056 A1 WO 2015137056A1 JP 2015054277 W JP2015054277 W JP 2015054277W WO 2015137056 A1 WO2015137056 A1 WO 2015137056A1
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glutamic acid
ductus arteriosus
patent ductus
salt
treatment
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French (fr)
Japanese (ja)
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詩子 横山
石川　義弘
秀次郎 藤田
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公立大学法人横浜市立大学
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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Abstract

　Provided is a novel agent for the prevention or treatment of patent ductus arteriosus. An agent for the prevention or treatment of patent ductus arteriosus, the agent containing glutamic acid or a salt thereof as an active ingredient.

Description

グルタミン酸による動脈管開存症の予防又は治療Prevention or treatment of patent ductus arteriosus with glutamate
　本発明は、グルタミン酸による動脈管開存症の予防又は治療に関し、より詳細には、動脈管開存症の予防薬又は治療薬としてのグルタミン酸の使用に関する。 The present invention relates to the prevention or treatment of patent ductus arteriosus with glutamic acid, and more particularly to the use of glutamic acid as a preventive or therapeutic drug for patent ductus arteriosus.
　近年、高齢出産の増加や不妊治療による多胎妊娠の増加などの影響により、総出生数に対する低出生体重児の割合は徐々に増加している。平成24年度の厚生労働省の統計によれば、特に慎重な管理を要する1000g未満の超低出生体重児は総出生数の約0.3％（3195人）である。 In recent years, the ratio of low birth weight infants to the total number of births has gradually increased due to the effects of increased births and increased multiple pregnancy due to infertility treatment. According to statistics from the Ministry of Health, Labor and Welfare in FY2012, the number of extremely low birth weight infants of less than 1000 g, which requires particularly careful management, is about 0.3% (3195) of the total number of births.
　新生児医療が長足の進歩を遂げた昨今でも、超低出生体重児の急性期管理には難渋することが少なくない。なかでも未熟児動脈管開存症は心不全、呼吸不全、壊死性腸炎など生命予後を左右する合併症の要因となるため、その治療は最重要課題の一つである。 Even nowadays when neonatal medical care has made great strides, it is often difficult to manage the acute phase of very low birth weight infants. Among them, patent ductus arteriosus in premature infants is a factor of complications that affect life prognosis such as heart failure, respiratory failure, and necrotizing enterocolitis, and its treatment is one of the most important issues.
　超低出生体重児のおおむね4割程度が動脈管開存症の治療を必要とする。従来の治療法としては、外科手術による動脈管結紮術とインドメタシンを使用する内科治療（非特許文献１）の2種があるが、いずれも循環動態の不安定な低出生体重児では生命に関わる合併症のリスクも少なくない。 About 40% of very low birth weight infants require treatment for patent ductus arteriosus. There are two conventional therapies: arterial ligation by surgery and internal medicine using indomethacin (Non-patent Document 1), both of which are life-threatening in low birth weight infants with unstable circulatory dynamics There is also a considerable risk of complications.
　本発明は、新規な動脈管開存症予防薬又は治療薬を提供することを目的とする。 An object of the present invention is to provide a novel preventive or therapeutic agent for patent ductus arteriosus.
　本発明者らは、グルタミン酸レセプター（GluR1）の発現がラットでは大動脈に比べて動脈管で多く、また、ヒト動脈管でもGluR1が多く発現していることを見出した。さらに、グルタミン酸は血管周囲神経から血管収縮作用のあるノルアドレナリンを放出させることで動脈管を収縮させ、閉鎖に導く作用があることを明らかにした。本発明は、これらの知見に基づいて、完成されたものである。 The present inventors have found that the glutamate receptor (GluR1) is expressed more in the arterial duct in rats than in the aorta, and more GluR1 is expressed in the human arterial duct. Furthermore, it was clarified that glutamate has the action of constricting the arterial duct by releasing noradrenaline, which has vasoconstrictive action, from the perivascular nerve, leading to closure. The present invention has been completed based on these findings.
　本発明の要旨は以下の通りである。
（１）グルタミン酸又はその塩を有効成分として含有する、動脈管開存症の予防薬又は治療薬。
（２）医薬的に有効な量のグルタミン酸又はその塩を被験者に投与することを含む、動脈管開存症を予防及び/又は治療する方法。
（３）動脈管開存症の予防及び/又は治療のためのグルタミン酸又はその塩の使用。
（４）動脈管開存症を予防及び/又は治療する方法に使用するためのグルタミン酸又はその塩。 The gist of the present invention is as follows.
(1) A prophylactic or therapeutic agent for patent ductus arteriosus comprising glutamic acid or a salt thereof as an active ingredient.
(2) A method for preventing and / or treating patent ductus arteriosus comprising administering to a subject a pharmaceutically effective amount of glutamic acid or a salt thereof.
(3) Use of glutamic acid or a salt thereof for the prevention and / or treatment of patent ductus arteriosus.
(4) Glutamic acid or a salt thereof for use in a method for preventing and / or treating patent ductus arteriosus.
　グルタミン酸又はその塩を投与することで、未熟児における動脈管開存症を抑制することができる。
　本明細書は、本願の優先権の基礎である日本国特許出願、特願2014‐050206の明細書および／または図面に記載される内容を包含する。 By administering glutamic acid or a salt thereof, patent ductus arteriosus in premature infants can be suppressed.
This specification includes the contents described in the specification and / or drawings of Japanese Patent Application No. 2014-050206 which is the basis of the priority of the present application.
4種のAMPA型グルタミン酸受容体GluR1～R4の胎齢19(e19、未熟児)及び胎齢21(e21、成熟児)での大動脈組織(AO)および動脈管組織(DA)での発現の比較を示す。未熟児、成熟児ともにGluR1の発現が動脈管で大動脈に比べて多い。Comparison of the expression of four AMPA-type glutamate receptors GluR1 to R4 in aortic tissue (AO) and arterial duct tissue (DA) at fetal age 19 (e19, premature infant) and fetal age 21 (e21, mature infant) . In both premature and mature infants, GluR1 expression is higher in the arterial duct than in the aorta. 抗GluR1抗体を用いたヒト動脈管免疫染色の結果を示す。図上側が血管内腔、下側が血管外膜となる。動脈管血管外膜側に、血管に分布する神経と同じ場所にGluR1の発現を認めた。The result of human arterial tract immunostaining using anti-GluR1 antibody is shown. The upper side of the figure is the blood vessel lumen and the lower side is the outer blood vessel membrane. On the adventitia side of the arterial vessel, GluR1 expression was observed at the same location as the nerve distributed in the blood vessel. 生理食塩水(NS)、0.7%グルタミン酸（Glu）,グルタミン酸受容体阻害薬(NASPM)およびGluを投与した際の動脈管管腔径と肺動脈管腔径の比を示す。右二枚の写真はNS投与、Glu投与を行った際の一例を示す。グルタミン酸投与により有意に動脈管が収縮し、グルタミン酸受容体阻害薬でその効果が抑制されたことを示す。The ratio of the arterial lumen diameter to the pulmonary artery lumen diameter when physiological saline (NS), 0.7% glutamic acid (Glu), glutamate receptor inhibitor (NASPM) and Glu are administered is shown. The two photographs on the right show an example when NS and Glu were administered. It is shown that the arterial duct contracted significantly by administration of glutamate, and its effect was suppressed by a glutamate receptor inhibitor. double distilled water(DDW)および0.7％グルタミン酸(Glu)腹腔内投与後の、ラット血清中のグルタミン酸濃度測定結果を示す。グルタミン酸投与により有意にラットの血清中のグルタミン酸濃度が上昇していることが示された。The measurement result of glutamic acid concentration in rat serum after intraperitoneal administration of double distilled water (DDW) and 0.7% glutamic acid (Glu) is shown. It was shown that the glutamic acid concentration in the rat serum was significantly increased by the administration of glutamic acid. 生理食塩水(NS)、0.7%グルタミン酸（Glu）,アドレナリン受容体阻害薬(prazosin)およびGluを投与した際の動脈管管腔径と肺動脈管腔径の比を示す。グルタミン酸投与により有意に動脈管が収縮し、アドレナリン受容体阻害薬でその効果が抑制されたことを示す。ノルアドレナリンはアドレナリン受容体を刺激することで血管を収縮させるため、グルタミン酸投与によりノルアドレナリンを介して動脈管が収縮したことが示された。The ratio of the arterial lumen diameter to the pulmonary artery lumen diameter when physiological saline (NS), 0.7% glutamic acid (Glu), adrenergic receptor inhibitor (prazosin) and Glu are administered is shown. It is shown that the arterial duct contracted significantly by administration of glutamic acid, and its effect was suppressed by an adrenergic receptor inhibitor. Since noradrenaline contracts the blood vessels by stimulating the adrenergic receptor, it was shown that administration of glutamate contracted the arterial duct via noradrenaline.
　以下、本発明の実施の形態についてより詳細に説明する。 Hereinafter, embodiments of the present invention will be described in more detail.
　本発明は、グルタミン酸又はその塩を有効成分として含有する、動脈管開存症の予防薬又は治療薬を提供する。
　また、本発明は、医薬的に有効な量のグルタミン酸又はその塩を被験者に投与することを含む、動脈管開存症を予防及び/又は治療する方法を提供する。
　さらに、本発明は、動脈管開存症の予防及び/又は治療のためのグルタミン酸又はその塩の使用を提供する。
　さらにまた、本発明は、動脈管開存症を予防及び/又は治療する方法に使用するためのグルタミン酸又はその塩を提供する。 The present invention provides a preventive or therapeutic agent for patent ductus arteriosus containing glutamic acid or a salt thereof as an active ingredient.
The present invention also provides a method for preventing and / or treating patent ductus arteriosus comprising administering to a subject a pharmaceutically effective amount of glutamic acid or a salt thereof.
Furthermore, the present invention provides the use of glutamic acid or a salt thereof for the prevention and / or treatment of patent ductus arteriosus.
Furthermore, the present invention provides glutamic acid or a salt thereof for use in a method for preventing and / or treating patent ductus arteriosus.
　グルタミン酸は、下記の式で表される。 Glutamic acid is represented by the following formula.
Figure JPOXMLDOC01-appb-C000001
Figure JPOXMLDOC01-appb-C000001
　グルタミン酸は公知の方法で製造することができ、また、市販のものを用いることもできる。 Glutamic acid can be produced by a known method, and commercially available products can also be used.
　グルタミン酸は、動脈管を収縮させ、閉鎖に導く作用があるので、未熟児における動脈管開存症の予防薬又は治療薬として利用することができる。 Glutamic acid can be used as a preventive or therapeutic agent for patent ductus arteriosus in premature infants because it contracts the arterial duct and leads to closure.
　グルタミン酸又はその塩は、動脈管開存症に対する予防又は治療効果のある非経口補給物として、又は他の栄養液との組み合わせによる完全非経口補給物として、特に、未熟児、新生児に適する。例えば、有効成分の量に換算して、１日あたり約　5～　10000　 mg/kg（体重）、好ましくは、約　50～　1000　 mg/kg（体重）の投与量で、１回または数回に分けて、輸液法により、静脈内に持続点滴注入するとよいが、その投与量や投与回数は、臨床症状、臨床検査値等により、適宜増減するとよい。グルタミン酸又はその塩と組み合わせる他の栄養液中に含まれる成分としては、グルコース、アミノ酸（例えば、イソロイシン、ロイシン、リシン、メチオニン、フェニルアラニン、トレオニン、トリプトファン、バリン、アルギニン、ヒスチジン、グリシン、アラニン、アスパラギン酸、プロリン、セリン、チロシン、システイン、タウリンなど）、脂肪などを例示することができるが、これらに限定されるわけではない。本明細書において、光学異性体を有するアミノ酸（グルタミン酸を含む）は、特に断りがない限りＬ体である。また、アミノ酸は塩の形態（例えば、グルタミン酸ナトリウム）をとってもよく、アミノ酸又はその塩は水などの溶媒を含む溶媒和物の形態であってもよい。塩や溶媒和物は、医薬的に許容されるものであるとよい。グルタミン酸又はその塩を注射剤に製剤化する場合には、蒸留水、生理食塩水などの担体を用いるとよく、亜硫酸水素ナトリウム、pH調節剤などの添加物を加えてもよい。製剤中の有効成分の含有率は、１～９９重量％の間で変動させることができ、例えば、注射剤の場合には、有効成分を１～１０重量％含有させるのが好ましい。 Glutamic acid or a salt thereof is particularly suitable for premature infants and newborns as a parenteral supplement having a preventive or therapeutic effect on patent ductus arteriosus or as a complete parenteral supplement in combination with other nutrient solutions. For example, in terms of the amount of the active ingredient, it is divided into 1 or several times at a dose of about 5 to 10000 mg / kg (body weight), preferably about 50 to 1000 mg / kg (body weight) per day. Thus, continuous infusion is preferably performed intravenously by an infusion method, but the dose and the number of administrations may be appropriately increased or decreased depending on clinical symptoms, laboratory test values, and the like. Ingredients contained in other nutrient solutions combined with glutamic acid or a salt thereof include glucose, amino acids (for example, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, arginine, histidine, glycine, alanine, aspartic acid , Proline, serine, tyrosine, cysteine, taurine, etc.), fat and the like, but are not limited thereto. In this specification, amino acids (including glutamic acid) having optical isomers are L-isomers unless otherwise specified. In addition, the amino acid may take the form of a salt (for example, sodium glutamate), and the amino acid or salt thereof may be in the form of a solvate containing a solvent such as water. Salts and solvates are preferably pharmaceutically acceptable. When formulating glutamic acid or a salt thereof into an injection, a carrier such as distilled water or physiological saline may be used, and additives such as sodium bisulfite and a pH regulator may be added. The content of the active ingredient in the preparation can be varied between 1 to 99% by weight. For example, in the case of an injection, it is preferable to contain 1 to 10% by weight of the active ingredient.
　グルタミン酸又はその塩は、市販の小児用アミノ酸輸液（例えば、プレアミン-P注射液（扶桑薬品工業株式会社、Trophamine（B. Braun Medical Inc.）、Aminosyn（Hospira, Inc.）、Primene（Baxter Healthcare Pty Ltd）など）に添加して、用いてもよい。未熟児のための適切なアミノ酸溶液は、成熟新生児用または成人用のアミノ酸溶液とは、アミノ酸パターンに求められる事項において大きく相違している。さらに未熟児は動脈管開存症を発症するリスクが高く、この発症を予防するようなアミノ酸組成が必要である。現在日本において新生児に使用されているアミノ酸輸液（プレアミン-P注射液（扶桑薬品工業株式会社））は、成熟新生児が外科手術を受けた際に補充されるべきアミノ酸の構成成分をもとに作製されている。したがって、未熟児（出生時体重2kg未満）が必要とするアミノ酸組成を有したアミノ酸輸液は存在せず、このため適切ではないアミノ酸組成を投与される未熟児において、栄養状態の改善や動脈管開存症の発症抑制が妨げられている可能性がある。本発明により、従来のアミノ酸輸液に加えてグルタミン酸又はその塩を投与することで未熟児動脈管開存症の予後改善をはかることが可能となる。 Glutamic acid or its salts are commercially available amino acid transfusions for pediatric use (for example, preamine-P injection (Fuso Pharmaceutical Co., Ltd., Trophamine (B. Braun Medical Inc.), Aminosyn (Hospira, Inc.), Primene (Baxter Healthcare Pty) A suitable amino acid solution for premature babies differs greatly from the amino acid solution for mature newborns or adults in matters required for amino acid patterns. In addition, premature infants are at high risk of developing patent ductus arteriosus and need an amino acid composition that prevents this from happening.Amino acid infusion currently used in newborns in Japan (preamine-P injection (fuso medicine) Kogyo Co., Ltd.) is based on amino acid components that should be replenished when a mature newborn undergoes surgery. There is no amino acid infusion solution with the amino acid composition required (under 2 kg), which prevents improvement of nutritional status and suppression of patent ductus arteriosus in premature babies receiving an inappropriate amino acid composition. According to the present invention, it is possible to improve the prognosis of premature infant patent ductus arteriosus by administering glutamic acid or a salt thereof in addition to the conventional amino acid infusion.
　以下、実施例に基づいて本発明を具体的に説明するが、本発明はこれらの実施例に限定されるものではない。
〔実施例１〕定量RT-PCR（図１）
　交配日が確定されている妊娠ラットを日本エスエルシーより購入し、交配日より算出された日程（胎生１９日及び２１日）で全身麻酔の後、帝王切開で胎仔を摘出した。胎仔動脈管(DA)組織および大動脈(AO)組織から作製したcDNAをテンプレートとしてRT-PCRによりグルタミン酸AMPA型受容体の4種のサブユニットGluR1、GluR2、GluR3およびGluR4の発現解析を行った。
GluR1:Forward: 5’- tcctgttgacacatccaatca-3’（配列番号１）　 Reverse: 5’- ccgttacctgccagttcttc-3’ （配列番号２）
GluR2:Forward: 5’- cagtcaccaatgctttctgc-3’ （配列番号３）　 Reverse: 5’- tgctcctttgaggtcaggtc -3’ （配列番号４）
GluR3:Forward: 5’- gcttcgttttaggcgtagca -3’ （配列番号５）　 Reverse: 5’- gctcctgaaccgtgtttctc -3’ （配列番号６）
GluR4:Forward: 5’ - cgatttggagggcataaaaa-3’ （配列番号７）　 Reverse: 5’- agaggcattgaagacgatgg -3’ （配列番号８） EXAMPLES Hereinafter, although this invention is demonstrated concretely based on an Example, this invention is not limited to these Examples.
[Example 1] Quantitative RT-PCR (Figure 1)
Pregnant rats whose mating dates were confirmed were purchased from Japan SLC, and the fetuses were removed by cesarean section after general anesthesia on the schedule calculated from the mating date (fetal days 19 and 21). Expression analysis of 4 subunits of glutamate AMPA type receptors GluR1, GluR2, GluR3 and GluR4 was performed by RT-PCR using cDNA prepared from fetal artery duct (DA) tissue and aorta (AO) tissue as a template.
GluR1: Forward: 5'- tcctgttgacacatccaatca-3 '(SEQ ID NO: 1) Reverse: 5'- ccgttacctgccagttcttc-3' (SEQ ID NO: 2)
GluR2: Forward: 5'-cagtcaccaatgctttctgc-3 '(SEQ ID NO: 3) Reverse: 5'- tgctcctttgaggtcaggtc -3' (SEQ ID NO: 4)
GluR3: Forward: 5'-gcttcgttttaggcgtagca -3 '(SEQ ID NO: 5) Reverse: 5'- gctcctgaaccgtgtttctc -3' (SEQ ID NO: 6)
GluR4: Forward: 5 '-cgatttggagggcataaaaa-3' (SEQ ID NO: 7) Reverse: 5'- agaggcattgaagacgatgg -3 '(SEQ ID NO: 8)
　結果を図１に示す。グラフの縦軸は18S ribosomal RNAの発現を1とした場合の各サブユニットの発現の比を表している。実験より得られた値は平均値±標準誤差(mean±SEM)で示し、二群間の有意差検定にはt-testを用い、有意水準はP<0.05とした。ラット動脈管ではGluR1サブユニットが多く発現していた。 The results are shown in FIG. The vertical axis of the graph represents the expression ratio of each subunit when the expression of 18S ribosomal RNA is 1. The value obtained from the experiment was expressed as mean ± standard error (mean ± SEM), t-test was used for the significance test between the two groups, and the significance level was P <0.05. In rat arterial ducts, many GluR1 subunits were expressed.
〔実施例２〕ヒト動脈管および大動脈の抗GluR1抗体を用いた免疫染色（図２）
　学内倫理委員会の同意を得て、外科手術で摘除されたヒト動脈管大動脈移行部をホルマリン固定した後にパラフィン切片を作製した。作製したパラフィン切片から脱パラフィン操作を行った後に抗GluR1抗体(Sigma-Aldrich,USA)を反応させた後に二次抗体で標識し、動脈管でのGluR1サブユニットの発現を検討した。大動脈に比べて血管に厚みがあることなどで動脈管組織であることがわかる。この血管外膜側の血管周囲神経に一致してGluR1サブユニットが発現していることを確認した。 [Example 2] Immunostaining of human arterial duct and aorta using anti-GluR1 antibody (FIG. 2)
With the consent of the in-house ethics committee, paraffin sections were prepared after formalin fixation of the human arterial duct aorta transition site removed by surgery. Deparaffinization was performed from the prepared paraffin sections, followed by reaction with an anti-GluR1 antibody (Sigma-Aldrich, USA), followed by labeling with a secondary antibody, and the expression of GluR1 subunit in the arterial duct was examined. It can be seen that it is an arterial duct tissue because the blood vessel is thicker than the aorta. It was confirmed that the GluR1 subunit was expressed in accordance with the perivascular nerve on the outer membrane side.
〔実施例３〕ラット動脈管および肺動脈のグルタミン酸およびグルタミン酸受容体阻害薬1-naphthyl acetylspermine (NASPM)投与後の管腔測定（図３）
　胎生21日のWistar ratを麻酔下で開腹し、以下の4群の肺動脈管腔径、動脈管(DA)腔径の計測を行った。
(1)子宮外からラット胎仔に生理食塩水(NS)200μlを胎仔腹腔内に投与したのちに一旦閉腹し30分後にラット胎仔を娩出。
(2)子宮外からラット胎仔に0.7%グルタミン酸水溶液(Glu)200μlを胎仔腹腔内に投与したのちに一旦閉腹し30分後にラット胎仔を娩出。
(3)子宮外からラット胎仔にAMPA型グルタミン酸受容体阻害薬NASPM(1μg/50μl)を投与し、更に15分後に0.7%グルタミン酸水溶液(Glu)200μlを胎仔腹腔内に投与したのちに一旦閉腹し30分後にラット胎仔を娩出。
(4)子宮外からラット胎仔にAMPA型グルタミン酸受容体阻害薬NASPM (10μg/50μl)を投与し、更に15分後に0.7%グルタミン酸水溶液(Glu)200μlを胎仔腹腔内に投与したのちに一旦閉腹し30分後にラット胎仔を娩出。 [Example 3] Measurement of luminal volume after administration of glutamic acid and glutamate receptor inhibitor 1-naphthyl acetylspermine (NASPM) in rat arterial duct and pulmonary artery (FIG. 3)
Wistar rats on the 21st day of gestation were opened under anesthesia, and the pulmonary artery lumen diameter and arterial duct (DA) cavity diameter of the following 4 groups were measured.
(1) From the outside of the uterus, 200 μl of physiological saline (NS) was intraperitoneally administered to the rat fetus, then the abdomen was temporarily closed, and the rat fetus was delivered 30 minutes later.
(2) From the outside of the uterus, 200 μl of 0.7% glutamic acid aqueous solution (Glu) was intraperitoneally administered to the rat fetus, and then the abdomen was temporarily closed, and the rat fetus was delivered 30 minutes later.
(3) The AMPA-type glutamate receptor inhibitor NASPM (1 μg / 50 μl) was administered to the rat fetus from outside the uterus. 30 minutes later, the rat fetus was delivered.
(4) The AMPA glutamate receptor inhibitor NASPM (10 μg / 50 μl) was administered to the rat fetus from outside the uterus. 30 minutes later, the rat fetus was delivered.
　すべての群で胎仔を娩出後、自発呼吸の生じないうちに液体窒素で急速に凍結した。凍結した胎仔のサンプルを滑走式ミクロトームで薄切し、その前額面で動脈管の中間位径と肺動脈径を顕微鏡用デジタルカメラセットで計測した。 In all groups, the fetuses were delivered and rapidly frozen in liquid nitrogen before spontaneous breathing occurred. The frozen fetal sample was sliced with a sliding microtome, and the medial diameter of the arterial canal and the pulmonary artery diameter were measured with a digital camera set for microscopes on the front face.
　結果を図３に示す。グラフの縦軸は肺動脈径を1とした場合の動脈管中間位の径を表している。各二群間の有意差検定にはt-testを用い、有意水準はP<0.05とした。 The results are shown in FIG. The vertical axis of the graph represents the diameter of the intermediate position of the arterial duct when the pulmonary artery diameter is 1. The t-test was used for the significant difference test between each two groups, and the significance level was P <0.05.
〔実施例４〕ラット胎仔血清グルタミン酸濃度測定（図４）
　胎生21日のWistar ratを麻酔し、帝王切開で胎仔を摘出した。摘出した胎仔に200μlの0.7%グルタミン酸(Glu)水溶液またはdouble distilled water(DDW)を腹腔内投与した後に37℃のホットプレートで30分間観察した。その後心腔穿刺によりラット血液を採取し血漿分離を行った後に、血中アミノ酸分析をhigh-performance liquid chromatography/electrospray ionization/ mass spectrometry methodを用いて行った。 [Example 4] Measurement of rat fetal serum glutamate concentration (FIG. 4)
Wistar rats on the 21st day of gestation were anesthetized, and the fetuses were removed by caesarean section. 200 μl of 0.7% glutamic acid (Glu) aqueous solution or double distilled water (DDW) was intraperitoneally administered to the removed fetus and then observed on a hot plate at 37 ° C. for 30 minutes. Thereafter, rat blood was collected by cardiac puncture and plasma separation was performed, followed by blood amino acid analysis using high-performance liquid chromatography / electrospray ionization / mass spectrometry method.
　結果を図４に示す。グラフはDDW腹腔内投与群と0.7%Glu投与群の血漿グルタミン酸濃度の比較である。二群間の有意差検定にはt-testを用いた。 The results are shown in FIG. The graph is a comparison of plasma glutamate concentration in DDW intraperitoneal administration group and 0.7% Glu administration group. T-test was used for the test of significant difference between the two groups.
〔実施例５〕ラット動脈管および肺動脈のグルタミン酸およびアドレナリン受容体阻害薬prazosin投与後の管腔測定（図５）
　胎生21日のWistar ratを麻酔下で開腹し、以下の4群の肺動脈管腔径、動脈管腔径の計測を行った。
(1)子宮外からラット胎仔に生理食塩水(NS)200μlを胎仔腹腔内に投与したのちに一旦閉腹し30分後にラット胎仔を娩出。
(2)子宮外からラット胎仔に0.7%グルタミン酸水溶液(Glu)200μlを胎仔腹腔内に投与したのちに一旦閉腹し30分後にラット胎仔を娩出。
(3)子宮外からラット胎仔にアドレナリン受容体阻害薬prazosin(1μg/50μl)を投与し、更に15分後に0.7%グルタミン酸水溶液(Glu)200μlを胎仔腹腔内に投与したのちに一旦閉腹し30分後にラット胎仔を娩出。
　実施例３と同様の方法で評価した。結果を図５に示す。グラフの縦軸は動脈管管腔径と肺動脈管腔径の比を表している。各二群間の有意差検定にはt-testを用い、有意水準はP<0.001とした。
　本明細書で引用した全ての刊行物、特許および特許出願をそのまま参考として本明細書にとり入れるものとする。 [Example 5] Measurement of lumen in rat arterial duct and pulmonary artery after administration of glutamate and adrenergic receptor inhibitor prazosin (Fig. 5)
Wistar rats on the 21st day of gestation were opened under anesthesia, and the following 4 groups of pulmonary artery lumen diameter and artery lumen diameter were measured.
(1) From the outside of the uterus, 200 μl of physiological saline (NS) was intraperitoneally administered to the rat fetus, then the abdomen was temporarily closed, and the rat fetus was delivered 30 minutes later.
(2) From the outside of the uterus, 200 μl of 0.7% glutamic acid aqueous solution (Glu) was intraperitoneally administered to the rat fetus, and then the abdomen was temporarily closed, and the rat fetus was delivered 30 minutes later.
(3) The adrenoreceptor inhibitor prazosin (1 μg / 50 μl) was administered to the rat fetus from outside the uterus, and after 15 minutes later, 200 μl of a 0.7% glutamic acid aqueous solution (Glu) was administered into the fetal abdominal cavity, and then the abdomen was temporarily closed 30 The rat fetus was delivered after a minute.
Evaluation was performed in the same manner as in Example 3. The results are shown in FIG. The vertical axis of the graph represents the ratio of the arterial lumen diameter to the pulmonary artery lumen diameter. The t-test was used for the significant difference test between each two groups, and the significance level was P <0.001.
All publications, patents and patent applications cited herein are incorporated herein by reference in their entirety.
　本発明は、未熟児の動脈管開存症の予防又は治療に利用可能である。 The present invention can be used for the prevention or treatment of patent ductus arteriosus in premature infants.

Claims (4)

  1. グルタミン酸又はその塩を有効成分として含有する、動脈管開存症の予防薬又は治療薬。 A prophylactic or therapeutic agent for patent ductus arteriosus comprising glutamic acid or a salt thereof as an active ingredient.
  2. 医薬的に有効な量のグルタミン酸又はその塩を被験者に投与することを含む、動脈管開存症を予防及び/又は治療する方法。 A method for preventing and / or treating patent ductus arteriosus comprising administering to a subject a pharmaceutically effective amount of glutamic acid or a salt thereof.
  3. 動脈管開存症の予防及び/又は治療のためのグルタミン酸又はその塩の使用。 Use of glutamic acid or a salt thereof for the prevention and / or treatment of patent ductus arteriosus.
  4. 動脈管開存症を予防及び/又は治療する方法に使用するためのグルタミン酸又はその塩。 Glutamic acid or a salt thereof for use in a method for preventing and / or treating patent ductus arteriosus.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007106698A (en) * 2005-10-13 2007-04-26 Yokohama City Univ Tunica intima tylosis by accelerating hyaluronic acid synthesis and utilization of the same
WO2011059075A1 (en) * 2009-11-13 2011-05-19 味の素株式会社 Glutamic acid-rich and arginine-rich preparation

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007106698A (en) * 2005-10-13 2007-04-26 Yokohama City Univ Tunica intima tylosis by accelerating hyaluronic acid synthesis and utilization of the same
WO2011059075A1 (en) * 2009-11-13 2011-05-19 味の素株式会社 Glutamic acid-rich and arginine-rich preparation

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RYCKMAN, KELLI K. ET AL.: "Association of amino acids with common complications of prematurity", PEDIATRIC RESEARCH, vol. 73, no. 6, 2013, pages 700 - 705 *
TOSHIO KAWANO: "The use for an indometacin intravenous infusion for patent ductus arterious", CLINICS & DRUG THERAPY, vol. 15, no. 11, 1996, pages 977 - 979 *
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