JP7523691B2 - Use of norharman in the manufacture of a drug for preventing and treating acute pancreatitis - Google Patents
Use of norharman in the manufacture of a drug for preventing and treating acute pancreatitis Download PDFInfo
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- JP7523691B2 JP7523691B2 JP2023534209A JP2023534209A JP7523691B2 JP 7523691 B2 JP7523691 B2 JP 7523691B2 JP 2023534209 A JP2023534209 A JP 2023534209A JP 2023534209 A JP2023534209 A JP 2023534209A JP 7523691 B2 JP7523691 B2 JP 7523691B2
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Classifications
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、医薬技術分野に関し、具体的に急性膵炎を予防及び治療するための薬物の製造におけるノルハルマンの使用に関する。 The present invention relates to the field of pharmaceutical technology, specifically to the use of norharman in the manufacture of a drug for preventing and treating acute pancreatitis.
急性膵炎（ａｃｕｔｅ ｐａｎｃｒｅａｔｉｔｉｓ，ＡＰ）は、急性入院率の高い消化器系疾患で、全世界で年間の発症率が約１３～４５／１０万人である。急性膵炎の主な病理学的特徴は、膵臓の消化酵素の異常活性化による膵臓の浮腫、出血、壊死により急性炎症反応が引き起こされることである。約２０％の患者は重症急性膵炎に発展し、その早期に全身炎症反応症候群の病状が発生し、それに伴って多臓器機能障害が発生し、ひいては死亡に至ることもある。胆道系疾患、高脂血症、アルコール依存症、喫煙などは急性膵炎の主な病因で、膵腺房細胞の細胞質基質Ｃａ２＋が持続的に上昇し、早期かつ過度に活性化されたトリプシノーゲンによりＮＦ－κＢ炎症シグナルの経路が活性化されて、膵臓に実質的な損害をもたらす。現在、急性膵炎の治療指南によれば、膵臓の分泌と二次性疾患による損害の減少を目的とした西洋医学の通常の治療を優先的な治療法として推奨しているが、急性膵炎の致死率の顕著な低下が得られていない。そのため、効果的で低副作用の急性膵炎を予防及び治療するための薬物の開発は、依然として急務となっている。 Acute pancreatitis (AP) is a digestive disease with a high acute hospitalization rate, with an annual incidence rate of about 130,000 to 450,000 per 100,000 people worldwide. The main pathological feature of acute pancreatitis is that pancreatic edema, hemorrhage, and necrosis caused by abnormal activation of pancreatic digestive enzymes induces an acute inflammatory response. About 20% of patients develop severe acute pancreatitis, and symptoms of systemic inflammatory response syndrome occur early on, which can lead to multiple organ dysfunction and even death. Biliary disease, hyperlipidemia, alcoholism, smoking, etc. are the main causes of acute pancreatitis, and the cytoplasmic Ca 2+ of pancreatic acinar cells is continuously elevated, and the NF-κB inflammatory signal pathway is activated by early and excessive activation of trypsinogen, causing substantial damage to the pancreas. At present, according to the treatment guidelines for acute pancreatitis, the conventional treatment of Western medicine is recommended as the preferred treatment, aiming at reducing pancreatic secretion and damage caused by secondary diseases, but the mortality rate of acute pancreatitis has not been significantly reduced.Therefore, there is still an urgent need to develop effective and low-side-effect drugs for preventing and treating acute pancreatitis.
免疫機能障害は、急性膵炎の重症化、ひいては死亡を招く重要な原因となる。生体内の炎症反応と抗炎症反応は、全体の過程で相互の制限と均衡、交互の変化により、最終的にＡＰの重症度や予後を決定する。このような炎症と抗炎症の動的バランスが一旦崩れると、ＡＰの病状が悪化される恐れがある。マクロファージとは、膵臓組織、肝臓、肺、腹腔に存在する自然免疫細胞で、好中球、リンパ球、その他の免疫細胞とともに炎症カスケードを媒介して増幅させ、急性膵炎の重症化過程において重要な役割を果たしている。マクロファージは、その活性化状態と機能によって、Ｍ１型とＭ２型の２種類に分けられる。インターフェロン－γ、リポ多糖類、顆粒球／マクロファージのコロニー刺激因子又は他のＴｏｌｌ様受容体リガンドの刺激で、Ｍ１型マクロファージが炎症性サイトカインを放出し、Ｔｈ１型細胞の免疫反応と特定のケモカインを誘導することで、宿主の多種の細菌、寄生虫、ウイルスに対する防御反応を起こさせる。Ｍ２型マクロファージは、炎症反応を抑制し、断片とアポトーシス細胞を取り除き、組織の修復と創傷の治癒を促進し、免疫調節を改善し、血管の新生と線維化を促進する特性を有する。マクロファージのＭ１／Ｍ２への分極化のバランスは免疫応答におけるＴｈ１／Ｔｈ２のバランスに影響を与え、Ｍ１／Ｍ２への分極化の不均衡はＡＰの病状を悪化させる。 Immune dysfunction is an important cause of aggravation of acute pancreatitis and even death. In the body, inflammatory and anti-inflammatory responses are mutually restricted, balanced, and alternating throughout the entire process, ultimately determining the severity and prognosis of AP. Once this dynamic balance between inflammation and anti-inflammatory is disrupted, the condition of AP may worsen. Macrophages are innate immune cells present in pancreatic tissue, liver, lungs, and peritoneal cavity, and together with neutrophils, lymphocytes, and other immune cells, they mediate and amplify the inflammatory cascade, playing an important role in the aggravation process of acute pancreatitis. Macrophages are divided into two types, M1 and M2, depending on their activation state and function. When stimulated by interferon-γ, lipopolysaccharide, granulocyte/macrophage colony-stimulating factor, or other Toll-like receptor ligands, M1 macrophages release inflammatory cytokines, which induce the immune response of Th1 cells and certain chemokines, thereby triggering a defense response against various bacteria, parasites, and viruses in the host. M2 macrophages have the properties of suppressing inflammatory responses, clearing debris and apoptotic cells, promoting tissue repair and wound healing, improving immune regulation, and promoting angiogenesis and fibrosis. The balance of macrophage M1/M2 polarization affects the balance of Th1/Th2 in the immune response, and an imbalance in M1/M2 polarization aggravates the pathology of AP.
発明者らは、本発明の初期段階で、１６Ｓ ｒＤＮＡ配列決定－メタボノミクスの併用技術を用いて、急性膵炎ラットの糞便中の微生物及びその代謝物について研究を行ったところ、微生物の配列決定結果により、偽手術群と比較して、急性膵炎群の乳酸桿菌属（Ｌａｃｔｏｂａｃｉｌｌｕｓ）の相対存在度が顕著に低下することを見つけた。乳酸桿菌属は、トリプトファンの代謝調節に広く関与している。生体外実験において、異なる濃度のトリプトファンで３種の乳酸桿菌を予備処理し、非標的代謝物検出法で３種の乳酸桿菌のトリプトファン代謝物に対する影響を検出することで、有意差のある７種の代謝物を選別し、それらのマクロファージ分極化に対する影響をそれぞれ観察した。その結果、ノルハルマン（Ｎｏｒｈａｒｍａｎ，９Ｈ－Ｐｙｒｉｄｏ［３，４－ｂ］ｉｎｄｏｌｅ：９Ｈ－ピリド［３，４－ｂ］インドール，ＣＡＳ ２４４－６３－３）が、マクロファージの分極化への影響に関して、新たな化合物として研究の価値があることが明らかになった。 In the early stage of the present invention, the inventors used the combined technology of 16S rDNA sequencing-metabonomics to study microorganisms and their metabolites in the feces of rats with acute pancreatitis. The microbial sequencing results showed that the relative abundance of Lactobacillus was significantly decreased in the acute pancreatitis group compared with the sham-operated group. Lactobacillus is widely involved in the metabolic regulation of tryptophan. In in vitro experiments, three types of lactobacilli were pretreated with different concentrations of tryptophan, and the effects of the three types of lactobacilli on tryptophan metabolites were detected by a non-target metabolite detection method, and seven metabolites with significant differences were selected, and their effects on macrophage polarization were observed, respectively. As a result, it became clear that Norharman (9H-Pyrido[3,4-b]indole, CAS 244-63-3) is a new compound worthy of research in terms of its effect on macrophage polarization.
本発明は、上記の技術課題に鑑みてなされたもので、ノルハルマンの急性膵炎の改善におけるメカニズム及びその使用を提供する。本発明は、ノルハルマンが急性膵炎に対して顕著な改善作用があることを開示する。本発明により、ノルハルマンの、急性膵炎を改善させる面での更なる研究と開発における有用性が明らかになり、新薬の開発に実験データを提供する。 The present invention has been made in consideration of the above technical problems, and provides a mechanism for norharman in improving acute pancreatitis and its use. The present invention discloses that norharman has a significant improving effect on acute pancreatitis. The present invention reveals the usefulness of norharman in further research and development in improving acute pancreatitis, and provides experimental data for the development of new drugs.
本発明は、上記の技術課題に鑑みてなされたもので、急性膵炎を予防又は治療するための薬物の製造におけるノルハルマンの使用を提供する。 The present invention has been made in consideration of the above technical problems, and provides the use of norharman in the manufacture of a drug for preventing or treating acute pancreatitis.
さらに、好ましい態様として、ノルハルマンを単一の化学成分の薬物製剤として又は他の薬物ととともに複合剤として製造する。 In a further preferred embodiment, norharman is prepared as a single chemical component drug formulation or as a combination drug formulation with other drugs.
さらに、好ましい態様として、急性膵炎を予防又は治療するための前記薬物の用量はマウスで１００ｍｇ／ｋｇ以下、人（７０ｋｇ）で１１．０８ｍｇ／ｋｇ以下である。マウスへの用量と人への用量は、「漢方薬理学的研究方法科学」（（第３版）、陳奇編集、人民衛生出版社、２０１１年、第１２６１－１２６３頁）に記載の方法により換算される。 Furthermore, in a preferred embodiment, the dose of the drug for preventing or treating acute pancreatitis is 100 mg/kg or less in mice and 11.08 mg/kg or less in humans (70 kg). The doses for mice and humans are converted according to the method described in "Science of Chinese Pharmacological Research Methods" (3rd Edition, edited by Chen Qi, People's Health Publishing House, 2011, pages 1261-1263).
さらに、好ましい態様として、急性膵炎を予防又は治療するための前記薬物の剤型は、錠剤、丸剤、粉末剤、カプセル剤を含む。 Furthermore, in a preferred embodiment, the dosage form of the drug for preventing or treating acute pancreatitis includes tablets, pills, powders, and capsules.
さらに、好ましい態様として、ノルハルマンは、血清アミラーゼとリパーゼのレベルを低下させ、膵臓と腸組織の損傷を改善させる。 In addition, in a preferred embodiment, norharman reduces serum amylase and lipase levels and improves damage to pancreatic and intestinal tissue.
さらに、好ましい態様として、ノルハルマンは、マクロファージのＭ１型への分極化を制御することで、急性膵炎を改善する。 In a preferred embodiment, norharman ameliorates acute pancreatitis by controlling the polarization of macrophages into the M1 type.
本発明は、従来技術と比べると、以下のメリットがある。 Compared to conventional technology, the present invention has the following advantages:
本発明は、ノルハルマンが急性膵炎に対して顕著な改善作用を有することを開示し、具体的にはマクロファージのＭ１型への分極化を制御することで急性膵炎を改善する。本発明の結果により、ノルハルマンの、急性膵炎を改善する面での更なる研究と開発における有用性が明らかになり、本発明は、ノルハルマンの急性膵炎に対する改善効果を強化するための新たな方向やアイデアを提供し、急性膵炎を予防及び治療するための新薬の開発へ実験データと新たな研究方向を提供する。 The present invention discloses that norharman has a significant improving effect on acute pancreatitis, specifically, it improves acute pancreatitis by controlling the polarization of macrophages into M1 type. The results of the present invention reveal the usefulness of norharman in further research and development in improving acute pancreatitis, and the present invention provides new directions and ideas for strengthening the improving effect of norharman on acute pancreatitis, and provides experimental data and new research directions for the development of new drugs for preventing and treating acute pancreatitis.
下記の非制限性の実施例は、当業者が本発明を全面的に理解するように説明するためのものであり、いかなる形態で本発明を制限するものではない。 The following non-limiting examples are intended to allow those skilled in the art to fully understand the present invention, and are not intended to limit the present invention in any manner.
本発明の目的、技術手段及びメリットをより明らかにするために、以下、実施例と図面を参照しながら、本発明をさらに詳細に説明するが、本発明の例示的実施形態及びその説明は本発明を説明するためのものに過ぎず、本発明を限定するものではない。 In order to clarify the purpose, technical means and advantages of the present invention, the present invention will be described in more detail below with reference to examples and drawings. However, the exemplary embodiments of the present invention and their descriptions are merely for the purpose of explaining the present invention and are not intended to limit the present invention.
（実施例１）
本実施例の生体内実験では、腹腔投与によりセルレイン（Ｃａｅｒｕｌｅｉｎ）をＬＰＳ（リポ多糖類）とともに注射して急性膵炎を誘導して急性膵炎マウスモデルを作成する。１５匹のＣ５７ＢＬ／６マウスを、各群に６匹ずつなるように対照群、モデル群、ノルハルマン投与群にランダムで分ける。具体的には、実験前に１２時間断水せず断食し、インスリン針を用いて腹腔投与によりセルレイン（１００μｇ／ｋｇ）を注射し、１時間おきに、７回連続して実施し、最終回にＬＰＳ（１０ｍｇ／ｋｇ）とともに投与する。対照群では、モデリング薬の代わりに、生理食塩水を腹腔投与により注射する。ノルハルマン（１００ｍｇ／ｋｇ）を、胃内投与により、８時間おきに１回投与する。最終回の腹腔投与から２４時間後、ペントバルビタールナトリウムを使ってマウスを麻酔し、仰臥位になるように四肢をテープで固定する。腹壁を消毒した後に、１ｍＬの注射器の針を心尖拍動の箇所に挿入して約０．８－１ｍＬの血を取り、採取した全血を優しく２ｍＬの無菌遠心分離管に注入し、４℃で２時間静置すると、一部の血清の析出が見える。遠心機により、４℃、３０００ｒｐｍ下で１０ｍｉｎ遠心分離を行い、上清液を取って新しい無菌遠心分離管に入れ、－８０℃で保存し、ＥＬＩＳＡ検出に用いる。腹部を腹部正中線に沿って切り、右後方で胃の延長方向に沿って十二指腸を探し当て、膵臓と脾臓を十分に露出させる。脾臓を取ってＰＢＳ液に置き、脾臓細胞の採集に用いる。膵臓組織と一部分の腸管組織を取ってパラホルムアルデヒド組織固定液にそれぞれ保存し、ＨＥ染色による組織の病理的変化の観察に用いる。膵臓と腸の組織を、氷上において、低温ＰＢＳで腸内糞便を完全に洗い流した後、速やかに凍結保存管に入れ、液体窒素タンクに置いて保存し、ｑＲＴ－ＰＣＲ実験に用いる（腸管組織の分解を防ぐために、必ず低温のＰＢＳを使い、かつ素早く行うこと）。
Example 1
In the in vivo experiment of this embodiment, acute pancreatitis is induced by intraperitoneally injecting caerulein together with LPS (lipopolysaccharides) to create a mouse model of acute pancreatitis. 15 C57BL/6 mice are randomly divided into a control group, a model group, and a norharman-administered group, with six mice in each group. Specifically, the mice are fasted for 12 hours before the experiment without water deprivation, and caerulein (100 μg/kg) is intraperitoneally administered using an insulin needle, and is administered seven times consecutively at hourly intervals, with the final administration being administered together with LPS (10 mg/kg). In the control group, saline is injected intraperitoneally instead of the modeling drug. Norharman (100 mg/kg) is administered intragastrically once every 8 hours. 24 hours after the final intraperitoneal administration, the mice are anesthetized using sodium pentobarbital, and the four limbs are fixed with tape so that the mice are in a supine position. After disinfecting the abdominal wall, insert the needle of a 1mL syringe into the apical pulsation site to take about 0.8-1mL of blood, gently inject the collected whole blood into a 2mL sterile centrifuge tube, and leave it at 4℃ for 2 hours, after which some serum precipitation can be seen. Centrifuge for 10 minutes at 4℃ and 3000rpm in a centrifuge, take the supernatant and put it into a new sterile centrifuge tube, store it at -80℃, and use it for ELISA detection. Cut the abdomen along the abdominal midline, find the duodenum along the extension direction of the stomach at the right rear, and fully expose the pancreas and spleen. Take the spleen and place it in PBS solution to collect spleen cells. Take the pancreatic tissue and a part of the intestinal tissue, and store it in paraformaldehyde tissue fixative, respectively, and use it to observe the pathological changes of the tissue by HE staining. The pancreatic and intestinal tissues are placed on ice and thoroughly washed with cold PBS to remove any fecal matter from the intestines. They are then quickly placed in cryopreservation tubes and stored in a liquid nitrogen tank for use in qRT-PCR experiments (be sure to use cold PBS and wash quickly to prevent decomposition of the intestinal tissue).
ＥＬＩＳＡにより血清アミラーゼとリパーゼのレベルを検出し、ＨＥ染色により膵臓と腸組織の病理学的損傷の状況を観察する。 ELISA will be used to detect serum amylase and lipase levels, and HE staining will be used to observe the pathological damage of pancreatic and intestinal tissues.
分子メカニズムの研究では、生体内実験でフローサイトメトリーを用いてマウスの脾臓のマクロファージのＭ１への分極化を検出し、免疫蛍光染色法を用いて膵臓におけるＭ１型マクロファージの割合を観察する。 In research into the molecular mechanism, in vivo experiments will involve using flow cytometry to detect the polarization of mouse splenic macrophages into M1, and immunofluorescence staining will be used to observe the proportion of M1 macrophages in the pancreas.
生体内実験の結果から分かるように、対照群と比較して、モデル群のマウスの血清アミラーゼとリパーゼのレベルが著しく向上し、モデル群と比較して、ノルハルマン投与群のマウスの血清アミラーゼとリパーゼのレベルが著しく低下する。対照群と比較して、モデル群のマウスの膵臓組織には、浮腫、壊死、炎症性細胞浸潤が現れ、対照群と比較して、モデル群のマウスの腸組織の腸上皮下の隙間が大きくなり、絨毛が著しく薄くなったり欠けたりし、絨毛の先端の破れや抜け落ちが起こっている。モデル群と比較して、ノルハルマン投与群のマウスの膵臓と腸組織の損傷が顕著に改善される。 As can be seen from the results of in vivo experiments, compared with the control group, the serum amylase and lipase levels of the mice in the model group are significantly improved, and compared with the model group, the serum amylase and lipase levels of the mice in the norharman group are significantly reduced. Compared with the control group, the pancreatic tissue of the mice in the model group exhibits edema, necrosis, and inflammatory cell infiltration; compared with the control group, the subintestinal epithelial gaps of the intestinal tissue of the mice in the model group are larger, the villi are significantly thinned or missing, and the tips of the villi are torn or fallen off. Compared with the model group, the damage of the pancreatic and intestinal tissue of the mice in the norharman group is significantly improved.
図１の結果に示すように、ノルハルマンは、急性膵炎のマウスの血清アミラーゼとリパーゼのレベルを低下させることができ、図２の結果に示すように、ノルハルマンは、急性膵炎のマウスの膵臓と腸組織の損傷を改善させることができ、これはノルハルマンが急性膵炎のマウスに対して、顕著な改善作用を発揮していることを提示する。 As shown in Figure 1, norharman can reduce the serum amylase and lipase levels in mice with acute pancreatitis, and as shown in Figure 2, norharman can improve the damage of pancreatic and intestinal tissues in mice with acute pancreatitis, indicating that norharman has a significant ameliorative effect on mice with acute pancreatitis.
分子メカニズムの研究から分かるように、対照群と比較して、モデル群のマウスの脾臓におけるＭ１型マクロファージの割合が著しく向上し、モデル群と比較して、ノルハルマン投与群のマウスの脾臓におけるＭ１型マクロファージの割合が著しく低下する。対照群と比較して、モデル群のマウスの膵臓におけるＭ１型マクロファージの量が増加し、モデル群と比較して、ノルハルマン投与群のマウスの膵臓におけるＭ１型マクロファージの量が減少する。 As can be seen from the molecular mechanism research, the proportion of M1 type macrophages in the spleens of mice in the model group is significantly increased compared to the control group, and the proportion of M1 type macrophages in the spleens of mice in the norharman-administered group is significantly decreased compared to the model group. The amount of M1 type macrophages in the pancreas of mice in the model group is increased compared to the control group, and the amount of M1 type macrophages in the pancreas of mice in the norharman-administered group is decreased compared to the model group.
図３、図４の結果に示すように、ノルハルマンは、急性膵炎のマウスの脾臓におけるＭ１型マクロファージの割合を減少させることができ、これらの結果は、ノルハルマンは、Ｍ１型マクロファージへの分極化を調節することで、急性膵炎を軽減できることを表明する。 As shown in Figures 3 and 4, norharman can reduce the proportion of M1 macrophages in the spleens of mice with acute pancreatitis, and these results indicate that norharman can alleviate acute pancreatitis by regulating polarization into M1 macrophages.
ノルハルマンの急性膵炎のマクロファージの分極化の制御における作用をさらに明らかにするために、ｑＲＴ－ＰＣＲを用いて、マウスの膵臓と腸組織における炎症性因子ＩＬ－１βとＴＮＦ－αの遺伝子発現をそれぞれ検出したところ、対照群と比較して、モデル群のマウスの膵臓と腸組織の炎症性因子ＩＬ－１βとＴＮＦ－αの遺伝子発現が著しくアップ調節（ｕｐ ｒｅｇｕｌａｔｉｏｎ）され、モデル群と比較して、ノルハルマン投与群のマウスの膵臓と腸組織の炎症性因子ＩＬ－１βとＴＮＦ－αの遺伝子発現が著しくダウン調節（ｄｏｗｎ ｒｅｇｕｌａｔｉｏｎ）された。 To further clarify the effect of norharman in controlling macrophage polarization in acute pancreatitis, qRT-PCR was used to detect the gene expression of inflammatory factors IL-1β and TNF-α in the pancreatic and intestinal tissues of mice. Compared to the control group, the gene expression of inflammatory factors IL-1β and TNF-α in the pancreatic and intestinal tissues of mice in the model group was significantly up-regulated, and compared to the model group, the gene expression of inflammatory factors IL-1β and TNF-α in the pancreatic and intestinal tissues of mice in the norharman-administered group was significantly down-regulated.
図５の結果に示すように、ノルハルマンは、急性膵炎のマウスの膵臓と腸組織における炎症性因子ＩＬ－１βとＴＮＦ－αの遺伝子発現を抑制することができる。 As shown in the results in Figure 5, norharman can suppress gene expression of inflammatory factors IL-1β and TNF-α in pancreatic and intestinal tissues of mice with acute pancreatitis.
上記の内容は、本発明の実施例にすぎない。上記の実施例及び実施例における具体的なバラメータは、発明の検証過程を説明するためのものにすぎなく、本発明の保護の範囲を限定するものではない。本発明の保護の範囲は、特許請求の範囲に基づくものであるが、本発明の明細書及び図面に基づいて行われた同等な変更は、すべて本発明の請求の範囲に含まれるべきである。 The above content is merely an embodiment of the present invention. The above embodiment and the specific parameters in the embodiment are merely intended to explain the verification process of the invention, and do not limit the scope of protection of the present invention. The scope of protection of the present invention is based on the claims, but all equivalent modifications made based on the specification and drawings of the present invention should be included in the scope of the claims of the present invention.
［付記］
［付記１］
急性膵炎を予防又は治療するための薬物の製造におけるノルハルマンの使用。
[Additional Notes]
[Appendix 1]
23. Use of norharman in the manufacture of a medicament for preventing or treating acute pancreatitis.
［付記２］
ノルハルマンを単一の化学成分の薬物製剤として又は他の薬物とともに複合剤として製造する、ことを特徴とする付記１に記載の使用。
[Appendix 2]
The use according to claim 1, characterized in that norharman is prepared as a single chemical component drug formulation or as a combination drug formulation together with other drugs.
［付記３］
前記急性膵炎は、哺乳動物が罹る急性膵炎である、ことを特徴とする付記１に記載の使用。
[Appendix 3]
The use according to claim 1, wherein the acute pancreatitis is acute pancreatitis in a mammal.
［付記４］
前記哺乳動物は、人類である、ことを特徴とする付記３に記載の使用。
[Appendix 4]
The use according to claim 3, wherein the mammal is a human.
［付記５］
急性膵炎を予防又は治療するための前記薬物の用量は１１．０８ｍｇ／ｋｇ以下である、ことを特徴とする付記１に記載の使用。
[Appendix 5]
The use according to claim 1, wherein the dose of the drug for preventing or treating acute pancreatitis is 11.08 mg/kg or less.
［付記６］
急性膵炎を予防又は治療するための前記薬物は、錠剤、丸剤、粉末剤、カプセル剤を含む、ことを特徴とする付記１に記載の使用。
[Appendix 6]
The use according to claim 1, wherein the medicament for preventing or treating acute pancreatitis includes tablets, pills, powders, and capsules.
［付記７］
ノルハルマンは、血清アミラーゼとリパーゼのレベルを低下させ、膵臓及び腸組織の損傷を改善させる、ことを特徴とする付記１に記載の使用。
[Appendix 7]
The use described in Appendix 1, characterized in that norharman reduces serum amylase and lipase levels and improves damage to pancreatic and intestinal tissues.
［付記８］
ノルハルマンは、マクロファージのＭ１型への極性化を制御することで、急性膵炎を改善させる、ことを特徴とする付記１に記載の使用。
[Appendix 8]
The use described in Appendix 1, characterized in that norharman ameliorates acute pancreatitis by controlling the polarization of macrophages into M1 type.
Claims (8)
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