WO2018053807A1 - Utilisation de sel d'éthanolamine du niclosamide dans la préparation d'un médicament pour le diabète de type 1 - Google Patents

Utilisation de sel d'éthanolamine du niclosamide dans la préparation d'un médicament pour le diabète de type 1 Download PDF

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WO2018053807A1
WO2018053807A1 PCT/CN2016/099876 CN2016099876W WO2018053807A1 WO 2018053807 A1 WO2018053807 A1 WO 2018053807A1 CN 2016099876 W CN2016099876 W CN 2016099876W WO 2018053807 A1 WO2018053807 A1 WO 2018053807A1
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effect
mice
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PCT/CN2016/099876
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Chinese (zh)
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孙惠力
杜蘅
韩鹏勋
邵牧民
郭岚
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深圳市中医院
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Priority to PCT/CN2016/099876 priority Critical patent/WO2018053807A1/fr
Priority to CN201611166593.4A priority patent/CN106727472B/zh
Priority to PCT/CN2016/110319 priority patent/WO2018053954A1/fr
Publication of WO2018053807A1 publication Critical patent/WO2018053807A1/fr

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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol

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  • the present invention relates to a novel application of Niclosamide ethanolamine salt (NEN) and, more particularly, to the use of NEN for the preparation of a medicament for the prevention and treatment of type 1 diabetes and its complications.
  • NEN Niclosamide ethanolamine salt
  • Type 1 diabetes also known as insulin-dependent diabetes, is a type of metabolic disease caused by the destruction of islet beta cells leading to an absolute deficiency of insulin, which in turn causes an increase in blood sugar.
  • the typical type 1 diabetes is mainly characterized by "three more and one less" symptoms, that is, polydipsia, polyphagia, polyuria, weight loss, often spontaneous ketosis tendency, serious complications, high disability and mortality, currently In addition to insulin therapy, there is no effective oral hypoglycemic agent.
  • Niclosamide and its ethanolamine salt are recommended by WHO for snail-killing and anthelmintic drugs. In recent years, studies have shown that these drugs have obvious anti-tumor effects.
  • the invention relates to a new application of NEN, and finds that NEN has a strong preventive effect on type 1 diabetes and its complications. It is an object of the present invention to provide a use of NEN for the preparation of a medicament for the prevention and treatment of type 1 diabetes and its complications.
  • the present invention provides the following technical solutions:
  • the present invention has the following beneficial effects: the present invention aims to investigate the protective effect of NEN on type 1 diabetes and its complications and the mechanism of action of NEN.
  • the results show that NEN can improve the polydipsia, polyphagia, and more of type 1 diabetic mice.
  • Urinary symptoms lower blood sugar, glycosylated hemoglobin, urine sugar levels, increase serum insulin levels, and improve pancreatic pathological damage.
  • it can reduce urinary albumin excretion rate, reduce glomerular filtration rate, reduce glomerular vasospasm area, reduce urine NAG, NGAL excretion, and inhibit Akt/mTOR/ in renal cortex.
  • Activation of the 4E-BP1 signaling pathway Activation of the 4E-BP1 signaling pathway.
  • NEN also has obvious protection for the liver, which has a significant improvement on muscle function. According to the above studies, it can be concluded that NEN has a significant protective effect on type 1 diabetes and its complications, and its protective mechanism of renal target organs is related to the inhibition of Akt/mTOR/4E-BP1 signaling pathway.
  • NEN is prepared into an oral administration form, an injection administration form, a mucosal administration form or a transdermal administration form using an existing preparation process, or a tablet, a capsule, a granule, an oral solution, a patch or a coagulant.
  • Glue medications can be used to prevent and treat type 1 diabetes and its complications.
  • Figure 1 shows the effect of NEN on the physiological indexes of type 1 diabetic mice.
  • Figure 1 (a) shows the effect of NEN on the water consumption of mice
  • Figure 1 (b) shows the effect of NEN on the food intake of mice.
  • (c) the effect of NEN on the urine volume of mice.
  • Figure 1 (d) shows the effect of NEN on the body weight of mice; among them, compared with the control group, ***P ⁇ 0.001; compared with the STZ group, ## P ⁇ 0.01, ### P ⁇ 0.001;
  • Figure 2 shows the effect of NEN on metabolic markers and pancreatic pathology in type 1 diabetic mice.
  • Figure 2(a) shows the effect of NEN on fasting blood glucose in mice
  • Figure 2(b) shows the effect of NEN on glycosylated hemoglobin in mice.
  • Figure 2(c) shows the effect of NEN on serum insulin in mice
  • Figure 2(d) shows the effect of NEN on urine glucose in mice
  • Figure 2(e) shows the effect of NEN on islet area in mice.
  • 2(f) showed the effect of NEN on the islet area of mice by HE staining
  • Fig. 2(g) showed the effect of NEN on islet cells by immunofluorescence staining; among them, compared with the control group, ***P ⁇ 0.001; Comparison of STZ group, ## P ⁇ 0.01, ### P ⁇ 0.001;
  • Figure 3 shows the effect of NEN on urinary albumin excretion rate and creatinine clearance rate in type 1 diabetic mice;
  • Fig. 3(a) shows the effect of NEN on urinary albumin excretion rate in mice, and
  • Fig. 3(b) shows NEN pair. results Effect of creatinine clearance in mice; wherein, compared with the control group, *** P ⁇ 0.001; compared with STZ group, # P ⁇ 0.05, ## P ⁇ 0.01;
  • Figure 4 shows the effect of NEN on kidney weight/body weight and glomerular vasospasm in type 1 diabetic mice;
  • Figure 4(a) shows the effect of NEN on kidney weight/body weight in mice, and
  • Figure 4(b) shows NEN.
  • Figure 4(c) shows the effect of NEN on mouse glomeruli by PAS staining; *P ⁇ 0.05, ***P ⁇ compared with control group 0.001; compared with STZ group, # P ⁇ 0.05, ### P ⁇ 0.001;
  • Figure 5 shows the effect of NEN on renal tubular injury in type 1 diabetic mice.
  • Figure 5 (a) shows the effect of NEN on urine NAG in mice
  • Figure 5 (b) shows the effect of NEN on urine NGAL in mice.
  • Figure 6 shows the effect of NEN on Akt/mTOR/4E-BP1 signaling pathway in renal cortex of type 1 diabetic mice;
  • Figure 6(a) shows the effect of NEN on Akt/mTOR/4E-BP1 signaling pathway protein by immunoblotting
  • Fig. 6(b) shows the effect of NEN on the expression of p-Akt (Ser473) protein in mouse renal cortex
  • Fig. 6(c) shows the effect of NEN on the expression of p-mTOR (Ser2448) protein in mouse renal cortex.
  • 6(d) is the effect of NEN on the expression of p-4E-BP1 (Thr37/46) protein in mouse renal cortex
  • Figure 6(e) shows the expression of p-4E-BP1 (Thr70) protein in mouse renal cortex by NEN.
  • Figure 6 (f) is the effect of NEN on the expression of 4E-BP1 total protein in mouse renal cortex; *P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001 compared with control group; compared with STZ group, # P ⁇ 0.05, ## P ⁇ 0.01, ### P ⁇ 0.001;
  • Figure 7 shows the effect of NEN on liver function in type 1 diabetic mice.
  • Figure 7 (a) shows the effect of NEN on serum alanine aminotransferase (ALT)
  • Figure 7 (b) shows NEN on mouse serum aspartate aminotransferase (AST).
  • Figure 7 (c) is the effect of NEN on serum total protein (TP)
  • Figure 7 (d) is the effect of NEN on mouse serum albumin (ALB); among them, compared with the control group, ** P ⁇ 0.01, *** P ⁇ 0.001; compared with STZ group, # P ⁇ 0.05, ## P ⁇ 0.01, ### P ⁇ 0.001;
  • Figure 8 shows the effect of NEN on the muscle function of type 1 diabetic mice.
  • Figure 8 (a) shows the effect of NEN on the grip of mice, and
  • Figure 8 (b) shows the number of shocks per minute by NEN on the treadmill. The results were affected; among them, ***P ⁇ 0.001 compared with the control group; ## P ⁇ 0.01 compared with the STZ group.
  • Type 1 diabetes mainly causes insulin deficiency due to destruction of islet ⁇ cells, which leads to high blood sugar, serious complications, high disability and high mortality.
  • the current pathogenesis is still unclear.
  • Sugar drugs There is no effective oral drop in addition to insulin treatment.
  • the present invention aims to observe the preventive and therapeutic effects of NEN on type 1 diabetes and its complications.
  • Animal model 8 week old male C57BL/6 mice (body weight 18-22g) were purchased from Guangdong Medical Laboratory Animal Center. Animal experiments were carried out in strict accordance with the relevant guidelines and regulations for animal ethics at Guangzhou University of Traditional Chinese Medicine. The experimental animals were controlled to freely ingest and drink at a constant room temperature of 20 ⁇ 1 ° C, 12 hours light and 12 hours dark cycle. The mouse model of type 1 diabetes was induced by a single intraperitoneal injection of 200 mg/kg streptozotocin (STZ, purchased from Sigma, USA). The fasting blood glucose ⁇ 16.7 mmol/L after 7 days of STZ injection confirmed the successful modeling.
  • STZ streptozotocin
  • mice were randomly assigned to the following groups (8-10 per group): the normal control group (ie, the control group in the chart of the present invention), the type 1 diabetic mouse model group (ie, the STZ group), and the NEN treatment group (ie, In the STZ+NEN group, the control group and the STZ group were fed with regular food, and the STZ+NEN group was fed with NEN-added food.
  • NEN was purchased from Hubei Shengtian Hengchuang Biotechnology Co., Ltd., and was added to the food of mice at a standard rate of 10g/kg. The above experimental treatment lasted for 8 weeks.
  • mice At 8 weeks of treatment, the body weight of the mice was weighed, and urine was collected using a mouse metabolic cage (Tenibus, Italy), urine volume was recorded, and water intake and food intake were recorded.
  • the blood glucose of each group of mice was measured using a blood glucose meter (Roche, Switzerland), and after 8 weeks of administration, the mice were sacrificed and blood samples, pancreas and kidney tissue samples were collected.
  • the glycated hemoglobin (HbA 1C ) content was measured using an Ultra2 glycated hemoglobin analyzer (Primus, USA).
  • Tissue preparation Immediately after the mice were sacrificed, the pancreas was removed and fixed with 10% formalin. The kidneys were then removed, weighed, rinsed in phosphate buffer, and a certain amount of kidney tissue was cut along the longitudinal section and fixed with 10% formalin. The remaining kidney tissue was immediately frozen in liquid nitrogen and stored at -80 °C. Subsequent experimental studies.
  • pancreatic paraffin section (3 ⁇ m thick) and kidney paraffin section (2 ⁇ m thick)
  • HE staining and PAS staining were used to evaluate the pathological damage of islets and glomeruli. Areas of islet area and glomerular vasospasm were counted using the 4.10 version of NIS-Elements image processing software (Nikon, Japan) for image processing analysis. Each pancreatic tissue section measures 4-10 islet area, and each kidney tissue section is measured. 40-50 glomerular vasospasm area, the length of the scale in the picture is 50 ⁇ m.
  • pancreatic immunofluorescence staining pancreatic tissue paraffin section (3 ⁇ m thick), dewaxing, hydration, the slice was placed in boiling sodium citrate buffer (pH 6) for 20 minutes for antigen retrieval, and then cooled to room temperature, PBS Wash 3 times, each time 5 min, then add mouse glucagon primary antibody (Abcam, UK) and rabbit-derived insulin primary antibody (CST, USA) overnight at 4 ° C, wash PBS 3 times, each time Anti-mouse fluorescent secondary antibody (Abcam, UK) and anti-rabbit fluorescent secondary antibody (Jackson ImmunoResearch, USA) were added at intervals of 5 min, respectively, and incubated at 37 ° C for 1 hour, followed by water-soluble sealing tablets containing DAPI (Southern Biotech, The United States) covers (blue, representing the nucleus), and finally uses laser confocal microscopy (Zeiss, Germany) to observe the content of alpha cells (glucagon, green) and beta cells (insulin, red).
  • ELISA ELISA kits for detecting serum insulin, urinary albumin and urinary NGAL in mice were purchased from Merck, Germany, Bethyl, USA and R&D systems. ELISA experiments were performed according to the manufacturer's instructions to detect serum insulin, urinary albumin, and urinary NGAL levels in each group of mice.
  • p-Akt Ser473
  • p-mTOR Ser2448
  • p-4E-BP1 Thr37/46
  • p-4E-BP1 Thr70
  • 4E-BP1 antibody was purchased from CST Company of the United States; ⁇ -actin antibody was purchased. In the United States sigma company.
  • Measurement data are expressed as mean ⁇ standard deviation. Statistical differences between the two groups of samples were analyzed by independent sample t-test. Comparisons between groups of samples were analyzed by one-way analysis of variance, and statistical analysis was performed using SPSS16.0 statistical software. A statistical difference was considered to be significant at P ⁇ 0.05.
  • NEN can improve the symptoms of polydipsia, polyphagia, and polyuria in type 1 diabetic mice.
  • Figure 1 shows the effect of NEN on the physiological indexes of mice.
  • Figure 1 (a) shows the effect of NEN on the 24-hour water consumption of mice
  • Figure 1 (b) shows the effect of NEN on the 24-hour intake of mice.
  • 1(c) is the effect of NEN on the 24-hour urine volume of mice.
  • the group showed symptoms of polydipsia, polyphagia, polyuria and weight loss (Fig. 1a, b, c, d); compared with the STZ group, the symptoms of polydipsia, polyphagia, and polyuria were significantly improved in the STZ+NEN group (Fig. 1a). , b, c).
  • NEN can reduce blood sugar, glycosylated hemoglobin, urine sugar in type 1 diabetic mice, increase serum insulin levels, and improve pancreatic pathological damage.
  • Figure 2 shows the effect of NEN on metabolic parameters and pancreatic pathology in mice.
  • Figure 2(a) shows the effect of NEN on blood glucose in mice
  • Figure 2(b) shows the effect of NEN on glycosylated hemoglobin in mice.
  • Figure 2(c) shows the effect of NEN on serum insulin in mice
  • Figure 2(d) shows the effect of NEN on urine glucose in mice
  • Figure 2(e) shows the effect of NEN on islet area in mice
  • Figure 2 (f) The results of HE staining showed the effect of NEN on mouse islet area
  • Figure 2 (g) shows the effect of NEN on mouse islet cells by confocal imaging
  • n 6-8 per group, 8 weeks, with Compared with the control group, the blood glucose, glycated hemoglobin, and urine sugar of the STZ group increased significantly (Fig.
  • NEN can reduce the excretion rate of albuminuria and reduce the creatinine clearance rate in type 1 diabetic mice.
  • Figure 3 shows the effect of NEN on urinary albumin excretion rate and creatinine clearance in mice
  • NEN can reduce the kidney weight/body weight ratio and glomerular vasospasm area in type 1 diabetic mice.
  • Figure 4 shows the effect of NEN on kidney weight/body weight and glomerular vasospasm in mice
  • Figure 4(c) shows the effect of NEN on the glomerulus of mice by PAS staining; compared with control group In the STZ group, the kidney weight/body weight and glomerular vasospasm area increased significantly (Fig. 4a, b, c). After 8 weeks of NEN treatment, the kidney weight/body weight and glomerular vasospasm area were significantly smaller (Fig. 4a, b, c).
  • NEN can improve renal tubular damage in type 1 diabetic mice.
  • Figure 5 shows the effect of NEN on renal tubular injury in mice.
  • Figure 5(a) shows the effect of NEN on urine NAG in mice
  • Figure 5(b) shows the effect of NEN on urine NGAL in mice
  • n In each group of 6-8, compared with the control group, the urine NAG and NGAL excretion of the STZ group were significantly increased (Fig. 5a, b), and the NAG and NGAL excretion rates were significantly reduced after 8 weeks of NEN treatment (Fig. 5a, b).
  • NEN can inhibit the overactivation of Akt/mTOR/4E-BP1 signaling pathway in the renal cortex of type 1 diabetic mice.
  • Figure 6 shows the effect of NEN on the renal cortex Akt/mTOR/4E-BP1 signaling pathway in mice;
  • Figure 6(a) shows the effect of NEN on the Akt/mTOR/4E-BP1 signaling pathway protein by immunoblotting.
  • 6(b) is the statistical result of the effect of NEN on mouse renal cortex p-Akt (Ser473) protein
  • Figure 6 (c) is the statistical result of the effect of NEN on mouse renal cortex p-mTOR (Ser2448) protein
  • Figure 6 ( d) is the statistical result of the effect of NEN on mouse renal cortex p-4E-BP1 (Thr37/46) protein
  • Figure 6(e) is the statistical result of the effect of NEN on mouse renal cortex p-4E-BP1 (Thr70) protein.
  • -mTOR(Ser2448), p-4E-BP1 (Thr37/46), p-4E-BP1 (Thr70) and 4E-BP1 protein were significantly increased, and NEN treatment significantly reduced its expression.
  • NEN has obvious liver protection effect on type 1 diabetic mice.
  • Figure 7 shows the effect of NEN on liver function in mice.
  • Figure 7(a) shows the effect of NEN on serum alanine aminotransferase (ALT)
  • Figure 7(b) shows the effect of NEN on serum aspartate aminotransferase (AST) in mice.
  • Fig. 7(c) shows the effect of NEN on serum total protein (TP)
  • serum ALT and AST in the STZ group were significantly increased (Fig. 7a, b), serum TP, ALB decreased significantly (Fig. 7c, d), NEN treatment can significantly reduce ALT, AST ( Figure 7a, b), TP, ALB increased significantly (Fig. 7c, d).
  • NEN has a significant improvement in muscle function in type 1 diabetic mice.
  • Figure 8 shows the effect of NEN on muscle function in mice.
  • Figure 8(a) shows the effect of NEN on the grip of mice
  • Figure 8(b) shows the effect of NEN on the number of shocks per 30 minutes on the treadmill.
  • n 6-8 in each group, at 8 weeks, compared with the control group, the grip strength of the STZ group was significantly reduced (Fig. 8a), and the number of shocks was significantly increased (Fig. 8b).
  • the NEN treatment significantly increased the grip of the mice. (Fig. 8a), reduce the number of shocks (Fig. 8b).
  • NEN as an anthelmintic and anti-tumor drug, can improve the symptoms of polydipsia, polyphagia and polyuria in type 1 diabetic mice, and lower blood sugar, glycated hemoglobin and urine sugar levels.
  • High serum insulin levels improve pathological damage in the pancreas. It has obvious protective effects on kidney, liver and muscle damage complicated by type 1 diabetes.
  • NEN has a significant preventive effect on type 1 diabetes and its complications.

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Abstract

L'invention concerne une utilisation de sel d'éthanolamine du niclosamide dans la préparation d'un médicament permettant de prévenir et de traiter le diabète de type 1 et ses complications. Le sel d'éthanolamine du niclosamide peut atténuer les symptômes de la polydipsie, de la polyphagie et de la polyurie chez des souris diabétiques de type I, réduire la glycémie, le taux d'hémoglobine glyquée et de glucose dans l'urine, augmenter le taux d'insuline sérique, atténuer une lésion pathologique du pancréas, réduire le taux d'excrétion urinaire d'albumine, la clairance de la créatinine, la surface des glomérules et l'excrétion urinaire de NAG et de NGAL, et inhiber l'activation de la voie de signalisation Akt/mTOR/4E-BP1 dans les tissus rénaux, ce qui permet de protéger le foie et d'améliorer la fonction musculaire.
PCT/CN2016/099876 2016-09-23 2016-09-23 Utilisation de sel d'éthanolamine du niclosamide dans la préparation d'un médicament pour le diabète de type 1 WO2018053807A1 (fr)

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CN201611166593.4A CN106727472B (zh) 2016-09-23 2016-12-16 氯硝柳胺乙醇胺盐在预防和治疗2型糖尿病肾病中的应用
PCT/CN2016/110319 WO2018053954A1 (fr) 2016-09-23 2016-12-16 Utilisation de sel d'éthanolamine du niclosamide dans la préparation d'un médicament pour le diabète de type 2

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WO2018053807A1 (fr) * 2016-09-23 2018-03-29 深圳市中医院 Utilisation de sel d'éthanolamine du niclosamide dans la préparation d'un médicament pour le diabète de type 1
WO2019165622A1 (fr) * 2018-03-01 2019-09-06 深圳市中医院 Utilisation d'un sel d'éthanolamine de niclosamide et d'une composition pharmaceutique de celui-ci
CN112316150B (zh) * 2020-12-04 2023-04-28 深圳市中医院 一种用于预防或治疗代谢或损伤相关疾病的药物组合物
CN112426531B (zh) * 2020-12-04 2023-04-07 深圳市中医院 一种药物组合物在制备治疗肾脏疾病药物中的用途

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WO2018053807A1 (fr) * 2016-09-23 2018-03-29 深圳市中医院 Utilisation de sel d'éthanolamine du niclosamide dans la préparation d'un médicament pour le diabète de type 1

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CN103415287A (zh) * 2010-11-16 2013-11-27 新泽西医科和牙科大学 以安全的线粒体解偶联化学剂治疗ii型糖尿病和糖尿病相关疾病
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