WO2023123834A1 - Norharman在制备预防或治疗急性胰腺炎药物中的应用 - Google Patents

Norharman在制备预防或治疗急性胰腺炎药物中的应用 Download PDF

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WO2023123834A1
WO2023123834A1 PCT/CN2022/094667 CN2022094667W WO2023123834A1 WO 2023123834 A1 WO2023123834 A1 WO 2023123834A1 CN 2022094667 W CN2022094667 W CN 2022094667W WO 2023123834 A1 WO2023123834 A1 WO 2023123834A1
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acute pancreatitis
norharman
preventing
present
preparation
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项红
尚东
陶旭锋
周琪
郭方悦
吴昱
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大连医科大学附属第一医院
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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
    • A61K31/435—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
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    • 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
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    • 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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  • the invention relates to the application of Norharman in the preparation of medicines for preventing or treating acute pancreatitis, and belongs to the field of medicine.
  • Acute pancreatitis is a kind of digestive system disease with a high acute hospitalization rate, and the global annual incidence is about 13-45 people/100,000 people.
  • the main pathological features of acute pancreatitis are pancreatic edema, hemorrhage, and necrosis caused by abnormal activation of pancreatic digestive enzymes, leading to acute inflammatory response.
  • Immune dysfunction is an important cause of severe acute pancreatitis and even death.
  • the pro-inflammatory and anti-inflammatory responses in the body check and balance each other and change alternately throughout the process, which ultimately determines the severity and prognosis of AP. Once this pro-inflammatory/anti-inflammatory dynamic balance is broken, it may lead to the deterioration of AP condition.
  • Macrophages are an innate immune cell located in the pancreas, liver, lung and peritoneal cavity, mediate and amplify the inflammatory cascade with neutrophils, lymphocytes and other immune cells, during the severe acute pancreatitis process play an important role in. According to the activation state and function of macrophages, they can be roughly divided into two types, M1 type and M2 type.
  • M1-type macrophages release pro-inflammatory cytokines, induce Th1-type cellular immune responses and specific Chemokines, which induce host defense responses against a variety of bacteria, parasites, and viruses.
  • M2 macrophages suppress inflammatory responses, remove debris and apoptotic cells, promote tissue repair and wound healing, improve immune regulation, and possess pro-angiogenic and pro-fibrotic properties.
  • the balance of M1/M2 polarization of macrophages affects the balance of Th1/Th2 in the immune response, and the imbalance of M1/M2 polarization will lead to the deterioration of AP.
  • the present invention provides the mechanism and application of Norharman for improving acute pancreatitis.
  • the present invention reveals that Norharman has a significant improvement effect on acute pancreatitis.
  • the present invention shows that Norharman has the value of further research and development in improving acute pancreatitis. For Provide experimental data for innovative drug research and development.
  • the present invention provides the application of Norharman in the preparation of medicines for preventing or treating acute pancreatitis.
  • Norharman is prepared into a single chemical composition pharmaceutical preparation, or prepared in combination with other drugs into a compound pharmaceutical preparation.
  • the dose of the drug for preventing or treating acute pancreatitis is no more than 100 mg/kg for mice, and no more than 11.08 mg/kg for humans (70 kg).
  • the mouse dose and the human dose were converted according to the method described in "Chinese Medicine Pharmacological Research Methodology” ((3rd edition), edited by Chen Qi, People's Health Publishing House, 2011, pp. 1261-1263).
  • the dosage forms of the drug for preventing or treating acute pancreatitis include tablets, pills, powders, and capsules.
  • Norharman reduces serum amylase and lipase levels and improves pancreatic and intestinal tissue damage.
  • Norharman improves acute pancreatitis by regulating the M1 polarization of macrophages.
  • the beneficial effect of the present invention is: the present invention reveals that Norharman has obvious improvement effect on acute pancreatitis, and this effect is to improve acute pancreatitis by regulating macrophage M1 type polarization.
  • the achievement of the present invention shows that Norharman has the value of in-depth research and development in acute pancreatitis.
  • the achievement of the present invention provides a new direction and idea for strengthening the improvement effect of Norharman on acute pancreatitis, and provides a new direction and idea for the development of innovative drugs in acute pancreatitis. Experimental materials and new research and development directions are provided.
  • Fig. 2 is a graph showing the effect of Norharman in Example 1 of the present invention on the histopathology of pancreas and intestines in mice with acute pancreatitis.
  • Example 4 is a diagram showing the effect of Norharman in Example 1 of the present invention on the M1 polarization of macrophages in the pancreas of mice with acute pancreatitis.
  • a mouse model of acute pancreatitis was induced by intraperitoneal injection of cerulein combined with LPS (lipopolysaccharide).
  • LPS lipopolysaccharide
  • C57BL/6 mice were randomly divided into control group, model group, and Norharman administration group, with 6 mice in each group.
  • the specific operation is: fasting without food and water for 12 hours before the experiment, extracting cerulein (100 ⁇ g/kg) with an insulin needle for intraperitoneal injection, once every 1 hour, and injecting 7 times in a row, and the last time needs to be combined with LPS (10mg/kg).
  • normal saline was used instead of modeling drugs for intraperitoneal injection.
  • Norharman (100mg/kg) was administered by gavage, once every 8 hours. Twenty-four hours after the last intraperitoneal injection, the mice were anesthetized with pentobarbital sodium, and their limbs were fixed with adhesive tape in a supine position. After disinfecting the abdominal wall, use a 1mL syringe to draw about 0.8-1mL of blood at the apex of the heart. Gently inject the collected whole blood into a 2mL sterile centrifuge tube and place it at 4°C for 2 hours, and some serum can be seen to precipitate.
  • the abdomen was incised along the midline of the abdomen, and the duodenum was found at the right rear along the direction of the stomach, and the pancreas and spleen were fully exposed.
  • Pancreatic tissue and part of intestinal tissue were taken and placed in paraformaldehyde tissue fixative solution for HE staining to observe histopathological changes.
  • Pancreas and intestinal tissues were taken, and the intestinal cavity and feces were thoroughly rinsed on ice with low-temperature PBS, then quickly put into cryopreservation tubes and stored in liquid nitrogen tanks for subsequent qRT-PCR experiments. (Note that low-temperature PBS must be used, and the action must be rapid to avoid degradation of intestinal tissue).
  • ELISA was used to detect serum amylase and lipase levels
  • HE staining was used to observe the pathological damage of pancreas and intestinal tissue.
  • qRT-PCR was used to detect the gene expressions of inflammatory factors IL-1 ⁇ and TNF- ⁇ in mouse pancreas and intestinal tissues, respectively.
  • the gene expressions of inflammatory factors IL-1 ⁇ and TNF- ⁇ in the pancreas and intestinal tissues of the mice in the model group were significantly up-regulated.
  • the inflammatory factors IL-1 1 ⁇ and TNF- ⁇ gene expressions were significantly down-regulated.

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Abstract

本发明公开了Norharman在制备预防或治疗急性胰腺炎药物中的应用，属于医药领域。Norharman使血清淀粉酶、脂肪酶水平降低，改善胰腺和肠组织损伤。Norharman通过调控巨噬细胞M1型极化改善急性胰腺炎。本发明的成果表明Norharman在急性胰腺炎方面具有深入研究和开发的价值，本发明的成果为加强Norharman对急性胰腺炎的改善作用提供了新的方向和思路，为急性胰腺炎方面的创新药研发提供了实验资料和新的研发方向。

Description

Norharman在制备预防或治疗急性胰腺炎药物中的应用 技术领域
本发明涉及Norharman在制备预防或治疗急性胰腺炎药物中的应用，属于医药领域。
背景技术
急性胰腺炎(acute pancreatitis,AP)是一类具有高急性住院率的消化系统疾病，全球年发病率约13-45人/10万人。急性胰腺炎的主要病理特征为胰腺消化酶异常激活引起的胰腺水肿、出血、坏死，导致急性炎症反应。约20％的患者发展成重症急性胰腺炎，早期即可发生全身炎症反应综合征，伴多器官功能损害甚至死亡。胆系疾病，高脂血症，酗酒，吸烟等是急性胰腺炎的主要致病因素，导致胰腺腺泡细胞胞浆Ca 2+持续升高，过早过度激活的胰蛋白酶原，活化NF-κB炎症信号通路，进而对胰腺实质造成损害。目前急性胰腺炎诊治指南将西医常规治疗推荐为首选疗法，旨在减少胰腺分泌和继发性病损，但急性胰腺炎的病死率并未得到明显降低。因此，研发防治急性胰腺炎的高效低副作用药物仍然是一个重大且亟待解决的问题。
免疫功能障碍是导致急性胰腺炎重症化甚至死亡的重要原因。机体内的促炎反应与抗炎反应在整个过程中相互制衡、交替变化，最终决定着AP的严重程度及预后。这种促炎/抗炎动态平衡一旦被打破可能造成AP病情的恶化。巨噬细胞是一种定位于胰腺组织，肝脏，肺和腹腔的先天免疫细胞，与中性粒细胞、淋巴细胞和其他免疫细胞共同介导和放大炎症级联反应，在急性胰腺炎重症化过程中发挥重要作用。根据巨噬细胞活化状态及功能不同大致分为2种，M1型和M2型。在干扰素-γ、脂多糖、粒细胞/巨噬细胞集落刺激因子或其他Toll样受体配体的刺激下，M1型巨噬细胞释放促炎细胞因子，诱导Th1型细胞免疫反应和特定的趋化因子，使宿主对多种细菌、寄生 虫和病毒产生防御反应。M2型巨噬细胞抑制炎症反应，清除碎片和凋亡细胞，促进组织修复和伤口愈合，改善免疫调节，并具有促血管生成和促纤维化特性。巨噬细胞M1/M2极化的平衡影响了免疫应答中Th1/Th2平衡，M1/M2极化失衡会造成AP病情的恶化。
发明内容
发明前期通过16S rDNA测序-代谢组学联用技术对急性胰腺炎大鼠粪便微生物及其代谢物进行了探究。微生物测序结果发现，与假手术组相比，急性胰腺炎组乳杆菌属(Lactobacillus)的相对丰度显著降低。乳杆菌属广泛参与色氨酸的代谢调控。体外实验中，采用不同浓度的色氨酸预处理3种乳酸杆菌，并通过非靶向代谢物检测方法检测3种乳酸杆菌对色氨酸代谢物的影响，共筛选出7种差异显著的代谢物。通过分别观察其对巨噬细胞极化的影响，发现Norharman(H-吡啶并[3，4-b]吲哚，CAS 244-63-3)作为新的化合物对巨噬细胞极化的影响具有研究价值。
基于以上问题，本发明提供Norharman改善急性胰腺炎的机制及应用，本发明揭示Norharman对急性胰腺炎具有明显的改善作用，本发明表明Norharman在改善急性胰腺炎方面具有深入研究和开发的价值，为创新药研发提供实验资料。
为解决以上技术问题，本发明提供了Norharman在制备用于预防或治疗急性胰腺炎药物中的应用。
进一步地，上述技术方案中，将Norharman制备成单一化学成分的药物制剂，或与其他药物合用制备成复方药物制剂。
进一步地，上述技术方案中，所述用于预防或治疗急性胰腺炎药物的剂量为小鼠不超过100mg/kg，人类(70kg)不超过11.08mg/kg。小鼠剂量和人类剂量根据《中药药理研究方法学》((第3版)，陈奇主编，人民卫生出版社，2011年，第1261-1263页)所述的方法进行换算。
进一步地，上述技术方案中，所述用于预防或治疗急性胰腺炎药物的剂型包括片剂、丸剂、散剂、胶囊。
进一步地，上述技术方案中，Norharman使血清淀粉酶、脂肪酶水平降低，改善胰腺和肠组织损伤。
进一步地，上述技术方案中，Norharman通过调控巨噬细胞M1型极化改善急性胰腺炎。
与现有技术相比，本发明的有益效果是：本发明揭示Norharman对急性胰腺炎具有明显的改善作用，这种作用是通过调控巨噬细胞M1型极化改善急性胰腺炎。本发明的成果表明Norharman在急性胰腺炎方面具有深入研究和开发的价值，本发明的成果为加强Norharman对急性胰腺炎的改善作用提供了新的方向和思路，为急性胰腺炎方面的创新药研发提供了实验资料和新的研发方向。
附图说明
图1为本发明的实施例1中的Norharman对急性胰腺炎小鼠血清淀粉酶和脂肪酶的影响结果图。n＝6，与对照组相比，**P<0.01，与模型组相比， ##P<0.01。
图2为本发明的实施例1中的Norharman对急性胰腺炎小鼠胰腺和肠组织病理的影响结果图。
图3为本发明的实施例1中的Norharman对急性胰腺炎小鼠脾脏巨噬细胞M1型极化的影响结果图。n＝3，与对照组相比，**P<0.01，与模型组相比， ##P<0.01。
图4为本发明的实施例1中的Norharman对急性胰腺炎小鼠胰腺中巨噬细胞M1型极化的影响结果图。
图5为本发明的实施例1中的Norharman对急性胰腺炎小鼠肠道和胰腺组织促炎因子释放的影响结果图。n＝4，与对照组相比，*P<0.05，**P<0.01，与模型组相比， #P<0.05， ##P<0.01。
具体实施方式
下述非限定性实施例可以使本领域的普通技术人员更全面地理解本发明，但不以任何方式限制本发明。
为使本发明的目的、技术方案和优点更加清楚明白，下面结合实施例和附图，对本发明作进一步的详细说明，本发明的示意性实施方式及其说明仅用于解释本发明，并不作为对本发明的限定。
实施例1
本实施例在体内实验中，采用腹腔注射雨蛙素联合LPS(脂多糖)诱导急性胰腺炎小鼠模型。将15只C57BL/6小鼠随机分为对照组、模型组、Norharman给药组，每组6只小鼠。具体操作为：实验前禁食不禁水12小时，用胰岛素针抽取雨蛙素(100μg/kg)进行腹腔注射，间隔1小时一次，连续注射7次，最后一次需要联合LPS(10mg/kg)共同用药。对照组则用生理盐水替代造模药物进行腹腔注射。将Norharman(100mg/kg)通过灌胃方式给药，间隔8小时一次。最后一次腹腔注射后24小时，经戊巴比妥钠麻醉小鼠，采取仰卧位用胶布固定四肢。腹壁消毒后用1mL注射器在心尖搏动处进针取血约0.8-1mL，将采集的全血轻柔注射于2mL无菌离心管中，4℃放置2小时，可见部分血清析出。于4℃离心机中3000rpm离心10min，取上清液放置于新的无菌离心管，-80℃保存以便ELISA检测。沿腹部正中线切开腹部，在右后方沿胃部走向找到十二指肠、充分暴露胰腺和脾脏。取脾脏放于PBS液中，留待脾脏细胞的提取。取胰腺组织、部分肠道组织分别放于多聚甲醛组织固定液中，以便进行HE染色观察组织病理变化。取胰腺和肠组织，低温PBS冰上彻底冲洗肠腔粪便后，快速放进冻存管、置入液氮罐中保存，以备后续qRT-PCR实验。(注意一定要用低温PBS，且动作迅速，避免肠道组织的降解)。
ELISA检测血清淀粉酶和脂肪酶水平，HE染色观察胰腺和肠组织病理损伤情况。
分子机制研究中，体内实验采用流式细胞术检测小鼠脾脏巨噬细胞M1极化，免疫荧光染色观察胰腺中M1型巨噬细胞比例。
体内实验结果显示，与对照组相比，模型组小鼠血清淀粉酶和脂肪酶水平显著升高；与模型组相比，Norharman给药组小鼠血清淀粉酶、脂肪酶水平显著下降。与对照组相比，模型组小鼠胰腺组织水肿，坏死，炎性细胞浸润，与对照组相比，模型组小鼠肠组织肠上皮下间隙增大，绒毛明显稀疏或缺失，绒毛顶端破损、脱落。与模型组相比，Norharman给药组小鼠胰腺和肠组织损伤得到明显改善。
见附图1，结果显示，Norharman可以降低急性胰腺炎小鼠血清淀粉酶和脂肪酶水平；见附图2，结果显示，Norharman可以改善急性胰腺炎小鼠胰腺和肠组织损伤，提示Norharman对急性胰腺炎小鼠具有明显的改善作用。
分子机制研究表明，与对照组相比，模型组小鼠脾脏M1型巨噬细胞比例显著升高；与模型组相比，Norharman给药组小鼠脾脏M1型巨噬细胞比例显著降低。与对照组相比，模型组小鼠胰腺中M1型巨噬细胞数量增多；与模型组相比，Norharman给药组小胰腺中M1型巨噬细胞数量减少。
见附图3，结果显示，Norharman可以降低急性胰腺炎小鼠脾脏M1型巨噬细胞的比例；见附图4，结果显示，这些结果表明，Norharman减轻急性胰腺炎可能是通过调节巨噬细胞M1型极化。
为进一步明确Norharman在调控急性胰腺炎巨噬细胞极化的作用，体内采用qRT-PCR分别检测小鼠胰腺和肠组织中炎性因子IL-1β和TNF-α基因表达。与对照组相比，模型组小鼠胰腺和肠组织中炎性因子IL-1β和TNF-α基因表达显著上调，与模型组相比，Norharman给药组小胰腺和肠组织炎性因子IL-1β和TNF-α基因表达显著下调。
见附图5，结果显示，Norharman可以抑制急性胰腺炎小鼠胰腺和肠组织中炎性因 子IL-1β和TNF-α基因表达。
如上即为本发明的实施例。上述实施例以及实施例中的具体参数仅是为了清楚表述发明验证过程，并非用以限制本发明的专利保护范围，本发明的专利保护范围仍然以其权利要求书为准，凡是运用本发明的说明书及附图内容所作的等同结构变化，同理均应包含在本发明的保护范围内。

Claims (8)

  1. Norharman在制备用于预防或治疗急性胰腺炎药物中的应用。
  2. 根据权利要求1所述的应用，其特征在于：将Norharman制备成单一化学成分的药物制剂，或与其他药物合用制备成复方药物制剂。
  3. 根据权利要求1所述的应用，其特征在于，所述急性胰腺炎为哺乳动物患有的急性胰腺炎。
  4. 根据权利要求3所述的应用，其特征在于，所述哺乳动物为人类。
  5. 根据权利要求1所述的应用，其特征在于，所述用于预防或治疗急性胰腺炎药物的剂量为不超过11.08mg/kg。
  6. 根据权利要求1所述的应用，其特征在于，所述用于预防或治疗急性胰腺炎药物的剂型包括片剂、丸剂、散剂、胶囊。
  7. 根据权利要求1所述的应用，其特征在于，Norharman使血清淀粉酶、脂肪酶水平降低，改善胰腺和肠组织损伤。
  8. 根据权利要求1所述的应用，其特征在于，Norharman通过调控巨噬细胞M1型极化改善急性胰腺炎。
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