CN110420204A - A kind of composition and its application containing resveratrol - Google Patents
A kind of composition and its application containing resveratrol Download PDFInfo
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Abstract
本发明提供了一种含白藜芦醇的组合物及其应用，属于医学和生物学技术领域，包括托吡酯和白藜芦醇，所述托吡酯和白藜芦醇的质量比为1～5:1。采用本发明提供的组合物能够降低肝脏甘油三酯、降低肝脏胆固醇、降低丙酮酸转氨酶、降低天冬氨酸转氨酶和降低甘油三酯，进而来治疗非酒精性脂肪肝。
The invention provides a composition containing resveratrol and its application, belonging to the technical field of medicine and biology, comprising topiramate and resveratrol, and the mass ratio of topiramate and resveratrol is 1 to 5: 1. The composition provided by the invention can reduce liver triglyceride, liver cholesterol, pyruvate transaminase, aspartate transaminase and triglyceride, and then treat non-alcoholic fatty liver.
Description
技术领域technical field
本发明属于医学和生物学技术领域，尤其涉及一种含白藜芦醇的组合物及其应用。The invention belongs to the technical field of medicine and biology, and in particular relates to a composition containing resveratrol and its application.
背景技术Background technique
在世界诸多国家中，超重和肥胖给健康带来巨大挑战。肥胖的主要特征为内脏脂肪增多，因此又称为腹型肥胖或中心型肥胖。肥胖常伴随“三高”，即高血糖、高血压、高血脂，人们将其定义为代谢综合症。多项研究发现，肥胖可引2型糖尿病、高脂血症、非酒精性脂肪肝病、动脉粥样硬化、冠心病、阻塞性睡眠呼吸暂停低通气综合征等并发症。Overweight and obesity pose major health challenges in many countries around the world. The main feature of obesity is increased visceral fat, so it is also called abdominal obesity or central obesity. Obesity is often accompanied by "three highs", namely hyperglycemia, hypertension, and hyperlipidemia, which are defined as metabolic syndrome. Many studies have found that obesity can lead to complications such as type 2 diabetes, hyperlipidemia, non-alcoholic fatty liver disease, atherosclerosis, coronary heart disease, and obstructive sleep apnea-hypopnea syndrome.
非酒精性脂肪肝病(Nonalcohonic fatty liver disease,NAFLD)是一种肝细胞脂质代谢异常疾病，其主要病理表现为肝细胞脂肪变性，严重时可发生气球样变。NAFLD早期表现为肝细胞脂质沉积，并伴随肝细胞炎症，进而发展为非酒精性脂肪肝炎(non-alcoholic steatohepatitis,NASH)。NASH患者肝组织内往往伴随炎症细胞浸润以及肝细胞坏死，部分患者甚至进展为肝细胞纤维化或肝细胞肝癌。Nonalcoholic fatty liver disease (NAFLD) is a disease of abnormal lipid metabolism in liver cells. Early NAFLD manifests as lipid deposition in hepatocytes, accompanied by inflammation of hepatocytes, and then develops into non-alcoholic steatohepatitis (NASH). The liver tissue of NASH patients is often accompanied by inflammatory cell infiltration and liver cell necrosis, and some patients even progress to hepatic fibrosis or hepatocellular carcinoma.
在过去的二十年中，非酒精性脂肪肝(NAFLD)在全球的患病率不断上升。近十年，我国NAFLD患病率也正以惊人速度上升。流行病学调查显示，我国NAFLD患病率高达26％-45％，已经取代慢性病毒性肝炎，成为第一大慢性肝病。NAFLD与多种疾病存在发病关联，包括二型糖尿病、高血压、脑卒中、冠心病、慢性肾脏病、多囊卵巢综合征、中枢性睡眠呼吸暂停、以及癌症。目前，NAFLD造成的疾病负担已成为世界性难题。Over the past two decades, the prevalence of nonalcoholic fatty liver disease (NAFLD) has increased worldwide. In the past ten years, the prevalence of NAFLD in my country has also been increasing at an alarming rate. Epidemiological surveys show that the prevalence of NAFLD in my country is as high as 26%-45%, and it has replaced chronic viral hepatitis as the number one chronic liver disease. NAFLD is associated with a variety of diseases, including type 2 diabetes, hypertension, stroke, coronary heart disease, chronic kidney disease, polycystic ovary syndrome, central sleep apnea, and cancer. Currently, the disease burden caused by NAFLD has become a worldwide problem.
托吡酯(TPM)又名妥泰，是自然态单糖右旋果糖的硫化物，极易溶于有机溶剂；能够被生物很好利用，利用率可达到80％，经胃肠道能够迅速吸收。进食食物对其药效无明显影响，其血药浓度可很快达到峰值，具有线性药物动力学特征，血药浓度与剂量呈正相关，且个体间差异极小。TPM在肝脏代谢有限，无肝酶诱导时给药的80％以分子原形经肾脏排出，其血浆清除率较稳定。2011年发表在《Lancet》上的研究显示，托吡酯可作为饮食辅助，用于治疗肥胖。TPM具有显著降低体重的功效，肥胖小鼠在给予TPM治疗后，体重降低17.80％±1.26％，脂肪量降低37.5％。TPM可有效降低血液中甘油三酯含量。研究表明，TPM可通过增加下丘脑GABA能受体表达，增强外周交感神经活性，促进甘油三酯水解。此外，TPM亦可直接作用于脂肪细胞，增强甘油三酯水解水平。一系列研究表明其在治疗肥胖方面的巨大优势。但由于托吡酯可引起交感神经过度激活，产生一系列副作用，从而限制其应用。因而只有降低其使用剂量才能降低其毒副作用，但是降低剂量最直接造成的后果就是药效的降低，因此需要找到一种既能降低其毒副作用，又可以不影响其疗效，甚至起到更好的效果的方法。Topiramate (TPM), also known as Topiramate, is the sulfide of the natural monosaccharide dextrose, which is easily soluble in organic solvents; it can be well utilized by organisms, and the utilization rate can reach 80%, and it can be quickly absorbed through the gastrointestinal tract. Eating food has no obvious effect on its efficacy, and its blood concentration can quickly reach the peak, with linear pharmacokinetic characteristics, and the blood concentration is positively correlated with the dose, and the inter-individual differences are very small. TPM has limited metabolism in the liver, and 80% of the administered dose is excreted through the kidneys in the form of the molecule when there is no liver enzyme induction, and its plasma clearance rate is relatively stable. Research published in The Lancet in 2011 showed that topiramate could be used as a dietary aid in the treatment of obesity. TPM has the effect of significantly reducing body weight. After being treated with TPM, the body weight of obese mice was reduced by 17.80%±1.26%, and the fat mass was reduced by 37.5%. TPM can effectively reduce the triglyceride content in the blood. Studies have shown that TPM can enhance the activity of peripheral sympathetic nerves and promote the hydrolysis of triglycerides by increasing the expression of GABAergic receptors in the hypothalamus. In addition, TPM can also directly act on fat cells to enhance the hydrolysis level of triglycerides. A series of studies have shown its great advantages in the treatment of obesity. However, topiramate can cause excessive activation of sympathetic nerves and produce a series of side effects, thus limiting its application. Thereby only reducing its dosage can reduce its toxic and side effects, but the most direct consequence of reducing the dosage is the reduction of drug efficacy, so it is necessary to find a method that can not only reduce its toxic and side effects, but also not affect its curative effect, or even play a better role. method of effect.
白藜芦醇(resveratrol，RSV)是葡萄、浆果、花生和葡萄酒中发现的一种非黄酮类多酚类植物抗毒素，具有抗氧化应激、抗炎症、抗凋亡和抗癌活性。研究显示，白藜芦醇可降低心血管疾病发病率。除了在心血管系统中引起有益作用外，白藜芦醇在神经保护方面也显示出较好的改善作用。此外，白藜芦醇还可通过调节线粒体功能来减轻糖尿病大鼠的心脏损伤，线粒体部分功能通过SIRT1激活和增加PGC-1a脱乙酰化来介导。现已证实，白藜芦醇具有多种促进健康的作用，通过介导抗氧化、抗炎等机制来预防许多疾病，如心血管疾病，糖尿病，衰老，神经变性和癌症。白藜芦醇可通过激活sirt1，有效降低肝细胞甘油三酯含量。这表明白藜芦醇具有成为NAFLD药物的潜力。但是，白藜芦醇不能有效降低患者体重和血清甘油三酯含量，无法从根本上缓解胰岛素抵抗和肝细胞炎症。Resveratrol (RSV), a non-flavonoid polyphenolic phytoalexin found in grapes, berries, peanuts, and wine, has anti-oxidative stress, anti-inflammatory, anti-apoptotic, and anticancer activities. Studies have shown that resveratrol can reduce the incidence of cardiovascular disease. In addition to causing beneficial effects in the cardiovascular system, resveratrol has also been shown to improve neuroprotection. In addition, resveratrol can also attenuate cardiac injury in diabetic rats by regulating mitochondrial function, which is partially mediated through SIRT1 activation and increased PGC-1a deacetylation. It has been confirmed that resveratrol has multiple health-promoting effects and can prevent many diseases such as cardiovascular disease, diabetes, aging, neurodegeneration and cancer by mediating antioxidant, anti-inflammatory and other mechanisms. Resveratrol can effectively reduce the triglyceride content of liver cells by activating SIRT1. This suggests that resveratrol has potential as a NAFLD drug. However, resveratrol cannot effectively reduce the patient's body weight and serum triglyceride levels, and cannot fundamentally alleviate insulin resistance and liver cell inflammation.
发明内容Contents of the invention
有鉴于此，本发明的目的在于提供一种含白藜芦醇的组合物及其应用，采用本发明提供的组合物能够治疗非酒精性脂肪肝。In view of this, the object of the present invention is to provide a composition containing resveratrol and its application, and the composition provided by the present invention can be used to treat non-alcoholic fatty liver.
为了实现上述发明目的，本发明提供了以下技术方案：In order to realize the above-mentioned purpose of the invention, the present invention provides the following technical solutions:
本发明提供了一种含白藜芦醇的组合物，包括托吡酯和白藜芦醇，所述托吡酯和白藜芦醇的质量比为1～5:1。The invention provides a composition containing resveratrol, which comprises topiramate and resveratrol, and the mass ratio of the topiramate and resveratrol is 1-5:1.
本发明还提供了上述技术方案所述的组合物在制备治疗非酒精性脂肪肝的药物中的应用。The present invention also provides the application of the composition described in the above technical solution in the preparation of a medicament for treating non-alcoholic fatty liver.
本发明还提供了上述技术方案所述的组合物在制备降低肝脏甘油三酯的药物中的应用。The present invention also provides the application of the composition described in the above technical solution in the preparation of a medicine for lowering liver triglyceride.
本发明还提供了上述技术方案所述的组合物在制备降低肝脏胆固醇的药物中的应用。The present invention also provides the application of the composition described in the above technical solution in the preparation of a medicament for lowering liver cholesterol.
本发明还提供了上述技术方案所述的组合物在制备降低丙酮酸转氨酶的药物中的应用。The present invention also provides the application of the composition described in the above technical solution in the preparation of a drug for reducing pyruvate transaminase.
本发明还提供了上述技术方案所述的组合物在制备降低天冬氨酸转氨酶的药物中的应用。The present invention also provides the application of the composition described in the above technical solution in the preparation of a drug for reducing aspartate aminotransferase.
本发明还提供了上述技术方案所述的组合物在制备降低甘油三酯的药物中的应用。The present invention also provides the application of the composition described in the above technical solution in the preparation of a medicine for lowering triglycerides.
本发明还提供了上述技术方案所述的组合物在制备降低体重的药物中的应用。The present invention also provides the application of the composition described in the above technical solution in the preparation of a medicine for reducing body weight.
本发明还提供了上述技术方案所述的组合物在制备降低血糖的药物中的应用。The present invention also provides the application of the composition described in the above technical solution in the preparation of a drug for lowering blood sugar.
优选的，所述药物的剂型包括片剂、粉剂、颗粒剂、胶囊、口服液或缓释剂。Preferably, the dosage forms of the medicine include tablets, powders, granules, capsules, oral liquids or sustained-release preparations.
本发明提供了一种含白藜芦醇的组合物及其应用，包括托吡酯和白藜芦醇，所述托吡酯和白藜芦醇的质量比为1～5:1。采用本发明提供的组合物能够降低肝脏甘油三酯、降低肝脏胆固醇、降低丙酮酸转氨酶、降低天冬氨酸转氨酶和降低甘油三酯，进而来治疗非酒精性脂肪肝。The invention provides a resveratrol-containing composition and application thereof, comprising topiramate and resveratrol, and the mass ratio of the topiramate and resveratrol is 1-5:1. The composition provided by the invention can reduce liver triglyceride, liver cholesterol, pyruvate transaminase, aspartate transaminase and triglyceride, thereby treating non-alcoholic fatty liver.
附图说明Description of drawings
图1是托吡酯干预组、白藜芦醇干预组、托吡酯联合白藜芦醇剂量减半组对小鼠体重的影响；其中，ND代表正常饮食给予空白溶剂，HFD代表高脂饮食给予空白溶剂；HFD+TPM代表高脂饮食给予托吡酯；HFD+RSV代表高脂饮食给予白藜芦醇；HFD+T+R代表高脂饮食给予剂量减半托吡酯和白藜芦醇；Figure 1 shows the effects of topiramate intervention group, resveratrol intervention group, and topiramate combined with half-dose resveratrol group on the body weight of mice; where, ND represents a normal diet given a blank solvent, and HFD represents a high-fat diet given a blank solvent; HFD+TPM means high-fat diet with topiramate; HFD+RSV means high-fat diet with resveratrol; HFD+T+R means high-fat diet with half the dose of topiramate and resveratrol;
图2是各组对小鼠随机血糖的影响；Fig. 2 is the influence of each group on random blood glucose of mice;
图3是各组对小鼠肝脏甘油三酯的影响；Figure 3 is the effect of each group on mouse liver triglycerides;
图4是各组对小鼠肝脏胆固醇的影响；Figure 4 is the effect of each group on mouse liver cholesterol;
图5是各组对小鼠天冬氨酸转氨酶的影响；Fig. 5 is the impact of each group on mouse aspartate aminotransferase;
图6是各组对小鼠丙氨酸转氨酶的影响；Figure 6 is the impact of each group on mouse alanine aminotransferase;
图7是各组对小鼠血清甘油三脂的影响。Figure 7 is the effect of each group on serum triglycerides in mice.
具体实施方式Detailed ways
本发明提供了一种含白藜芦醇的组合物，包括托吡酯和白藜芦醇，所述托吡酯和白藜芦醇的质量比为1～5:1。本发明对所述白藜芦醇和托吡酯的来源没有特殊限定，采用常规市售产品即可。The invention provides a composition containing resveratrol, which comprises topiramate and resveratrol, and the mass ratio of the topiramate and resveratrol is 1-5:1. In the present invention, the sources of the resveratrol and topiramate are not particularly limited, and conventional commercially available products can be used.
本发明还提供了上述技术方案所述的组合物在制备治疗非酒精性脂肪肝的药物中的应用。在本发明中，所述药物优选以组合物为唯一活性成分，还包括药学上可接受的辅料或辅助性成分。在本发明中，所述药物的剂型优选包括片剂、粉剂、颗粒剂、胶囊、口服液或缓释剂。本发明对所述组合物在上述剂型中的用量没有特殊限定，采用常规剂型中药物的用量即可。本发明对所述上述剂型使用的辅料或者辅助性成分的种类和含量没有特殊限定，采用常规即可。The present invention also provides the application of the composition described in the above technical solution in the preparation of a medicament for treating non-alcoholic fatty liver. In the present invention, the medicament preferably uses the composition as the only active ingredient, and also includes pharmaceutically acceptable adjuvants or auxiliary ingredients. In the present invention, the dosage form of the drug preferably includes tablets, powders, granules, capsules, oral liquids or sustained-release preparations. In the present invention, there is no special limitation on the dosage of the composition in the above-mentioned dosage form, and the dosage of the medicine in the conventional dosage form can be used. The present invention has no special limitation on the types and contents of the adjuvants or auxiliary components used in the above-mentioned dosage forms, and conventional methods can be used.
本发明还提供了上述技术方案所述的组合物在制备降低肝脏甘油三酯的药物中的应用。在本发明中，所述药物优选以组合物为唯一活性成分，还包括药学上可接受的辅料或辅助性成分。在本发明中，所述药物的剂型优选包括片剂、粉剂、颗粒剂、胶囊、口服液或缓释剂。本发明对所述组合物在上述剂型中的用量没有特殊限定，采用常规剂型中药物的用量即可。本发明对所述上述剂型使用的辅料或者辅助性成分的种类和含量没有特殊限定，采用常规即可。The present invention also provides the application of the composition described in the above technical solution in the preparation of a medicine for lowering liver triglyceride. In the present invention, the medicament preferably uses the composition as the only active ingredient, and also includes pharmaceutically acceptable adjuvants or auxiliary ingredients. In the present invention, the dosage form of the drug preferably includes tablets, powders, granules, capsules, oral liquids or sustained-release preparations. In the present invention, there is no special limitation on the dosage of the composition in the above-mentioned dosage form, and the dosage of the medicine in the conventional dosage form can be used. The present invention has no special limitation on the types and contents of the adjuvants or auxiliary components used in the above-mentioned dosage forms, and conventional methods can be used.
本发明还提供了上述技术方案所述的组合物在制备降低肝脏胆固醇的药物中的应用。在本发明中，所述药物优选以组合物为唯一活性成分，还包括药学上可接受的辅料或辅助性成分。在本发明中，所述药物的剂型优选包括片剂、粉剂、颗粒剂、胶囊、口服液或缓释剂。本发明对所述组合物在上述剂型中的用量没有特殊限定，采用常规剂型中药物的用量即可。本发明对所述上述剂型使用的辅料或者辅助性成分的种类和含量没有特殊限定，采用常规即可。The present invention also provides the application of the composition described in the above technical solution in the preparation of a medicament for lowering liver cholesterol. In the present invention, the medicament preferably uses the composition as the only active ingredient, and also includes pharmaceutically acceptable adjuvants or auxiliary ingredients. In the present invention, the dosage form of the drug preferably includes tablets, powders, granules, capsules, oral liquids or sustained-release preparations. In the present invention, there is no special limitation on the dosage of the composition in the above-mentioned dosage form, and the dosage of the medicine in the conventional dosage form can be used. The present invention has no special limitation on the types and contents of the adjuvants or auxiliary components used in the above-mentioned dosage forms, and conventional methods can be used.
本发明还提供了上述技术方案所述的组合物在制备降低丙酮酸转氨酶的药物中的应用。在本发明中，所述药物优选以组合物为唯一活性成分，还包括药学上可接受的辅料或辅助性成分。在本发明中，所述药物的剂型优选包括片剂、粉剂、颗粒剂、胶囊、口服液或缓释剂。本发明对所述组合物在上述剂型中的用量没有特殊限定，采用常规剂型中药物的用量即可。本发明对所述上述剂型使用的辅料或者辅助性成分的种类和含量没有特殊限定，采用常规即可。The present invention also provides the application of the composition described in the above technical solution in the preparation of a drug for reducing pyruvate transaminase. In the present invention, the medicament preferably uses the composition as the only active ingredient, and also includes pharmaceutically acceptable adjuvants or auxiliary ingredients. In the present invention, the dosage form of the drug preferably includes tablets, powders, granules, capsules, oral liquids or sustained-release preparations. In the present invention, there is no special limitation on the dosage of the composition in the above-mentioned dosage form, and the dosage of the medicine in the conventional dosage form can be used. The present invention has no special limitation on the types and contents of the adjuvants or auxiliary components used in the above-mentioned dosage forms, and conventional methods can be used.
本发明还提供了上述技术方案所述的组合物在制备降低天冬氨酸转氨酶的药物中的应用。在本发明中，所述药物优选以组合物为唯一活性成分，还包括药学上可接受的辅料或辅助性成分。在本发明中，所述药物的剂型优选包括片剂、粉剂、颗粒剂、胶囊、口服液或缓释剂。本发明对所述组合物在上述剂型中的用量没有特殊限定，采用常规剂型中药物的用量即可。本发明对所述上述剂型使用的辅料或者辅助性成分的种类和含量没有特殊限定，采用常规即可。The present invention also provides the application of the composition described in the above technical solution in the preparation of a drug for reducing aspartate aminotransferase. In the present invention, the medicament preferably uses the composition as the only active ingredient, and also includes pharmaceutically acceptable adjuvants or auxiliary ingredients. In the present invention, the dosage form of the drug preferably includes tablets, powders, granules, capsules, oral liquids or sustained-release preparations. In the present invention, there is no special limitation on the dosage of the composition in the above-mentioned dosage form, and the dosage of the medicine in the conventional dosage form can be used. The present invention has no special limitation on the types and contents of the adjuvants or auxiliary components used in the above-mentioned dosage forms, and conventional methods can be used.
本发明还提供了上述技术方案所述的组合物在制备降低甘油三酯的药物中的应用。在本发明中，所述药物优选以组合物为唯一活性成分，还包括药学上可接受的辅料或辅助性成分。在本发明中，所述药物的剂型优选包括片剂、粉剂、颗粒剂、胶囊、口服液或缓释剂。本发明对所述组合物在上述剂型中的用量没有特殊限定，采用常规剂型中药物的用量即可。本发明对所述上述剂型使用的辅料或者辅助性成分的种类和含量没有特殊限定，采用常规即可。The present invention also provides the application of the composition described in the above technical solution in the preparation of a medicine for lowering triglycerides. In the present invention, the medicament preferably uses the composition as the only active ingredient, and also includes pharmaceutically acceptable adjuvants or auxiliary ingredients. In the present invention, the dosage form of the drug preferably includes tablets, powders, granules, capsules, oral liquids or sustained-release preparations. In the present invention, there is no special limitation on the dosage of the composition in the above-mentioned dosage form, and the dosage of the medicine in the conventional dosage form can be used. The present invention has no special limitation on the types and contents of the adjuvants or auxiliary components used in the above-mentioned dosage forms, and conventional methods can be used.
本发明还提供了上述技术方案所述的组合物在制备降低体重的药物中的应用。在本发明中，所述药物优选以组合物为唯一活性成分，还包括药学上可接受的辅料或辅助性成分。在本发明中，所述药物的剂型优选包括片剂、粉剂、颗粒剂、胶囊、口服液或缓释剂。本发明对所述组合物在上述剂型中的用量没有特殊限定，采用常规剂型中药物的用量即可。本发明对所述上述剂型使用的辅料或者辅助性成分的种类和含量没有特殊限定，采用常规即可。The present invention also provides the application of the composition described in the above technical solution in the preparation of a medicine for reducing body weight. In the present invention, the medicament preferably uses the composition as the only active ingredient, and also includes pharmaceutically acceptable adjuvants or auxiliary ingredients. In the present invention, the dosage form of the drug preferably includes tablets, powders, granules, capsules, oral liquids or sustained-release preparations. In the present invention, there is no special limitation on the dosage of the composition in the above-mentioned dosage form, and the dosage of the medicine in the conventional dosage form can be used. The present invention has no special limitation on the types and contents of the adjuvants or auxiliary components used in the above-mentioned dosage forms, and conventional methods can be used.
本发明还提供了上述技术方案所述的组合物在制备降低血糖的药物中的应用。在本发明中，所述药物优选以组合物为唯一活性成分，还包括药学上可接受的辅料或辅助性成分。在本发明中，所述药物的剂型优选包括片剂、粉剂、颗粒剂、胶囊、口服液或缓释剂。本发明对所述组合物在上述剂型中的用量没有特殊限定，采用常规剂型中药物的用量即可。本发明对所述上述剂型使用的辅料或者辅助性成分的种类和含量没有特殊限定，采用常规即可。The present invention also provides the application of the composition described in the above technical solution in the preparation of a drug for lowering blood sugar. In the present invention, the medicament preferably uses the composition as the only active ingredient, and also includes pharmaceutically acceptable adjuvants or auxiliary ingredients. In the present invention, the dosage form of the drug preferably includes tablets, powders, granules, capsules, oral liquids or sustained-release preparations. In the present invention, there is no special limitation on the dosage of the composition in the above-mentioned dosage form, and the dosage of the medicine in the conventional dosage form can be used. The present invention has no special limitation on the types and contents of the adjuvants or auxiliary components used in the above-mentioned dosage forms, and conventional methods can be used.
下面结合实施例对本发明提供的技术方案进行详细的说明，但是不能把它们理解为对本发明保护范围的限定。The technical solutions provided by the present invention will be described in detail below in conjunction with the examples, but they should not be interpreted as limiting the protection scope of the present invention.
实施例1Example 1
所使用的小鼠为：8周龄雄性、健康SPF级C57小鼠，购于北京维通利华公司。The mice used were: 8-week-old male, healthy SPF grade C57 mice, purchased from Beijing Weitong Lihua Company.
C57小鼠饲养条件：环境温度为22±0.5℃，12小时/12小时明暗交替。实验数据用均数±标准误表示，托吡酯联合白藜芦醇各剂量减半组和高脂饮食，空白溶剂对照做对比，*P＜0.05，**p＜0.01，***p＜0.001，n＝6。Raising conditions for C57 mice: ambient temperature 22±0.5°C, 12 hours/12 hours alternating light and dark. The experimental data are expressed as mean ± standard error. The topiramate combined with resveratrol half-dose group was compared with the high-fat diet and blank solvent control, *P<0.05, **p<0.01, ***p<0.001, n=6.
托吡酯联合白藜芦醇对高脂饮食导致肥胖小鼠体重的影响：Effects of topiramate combined with resveratrol on the body weight of obese mice induced by high-fat diet:
经普通饲料适应性培养一周后，将老鼠分为两组，一组继续普通饲料喂养，另一组改为高脂饲料(脂肪提供的能量占总能量的60％)喂养8周，此时高脂饮食小鼠平均体重为26.84g，正常饮食小鼠体重为25.92g；之后将高脂饮食小鼠随机分为托吡酯干预组、白藜芦醇干预组、托吡酯联合白藜芦醇剂量减半组和空白溶剂对照组，开始分组腹腔注射：A组给予托吡酯50mg/kg/d，B组给予白藜芦醇20mg/kg/d，C组给予托吡酯25mg/kg/d和白藜芦醇10mg/kg/d，D组给予空白溶剂对照；同时给予普通饲料喂养小鼠空白溶剂对照。After a week of adaptive training with common feed, the mice were divided into two groups, one group continued to be fed with common feed, and the other group was fed with high-fat feed (the energy provided by fat accounted for 60% of the total energy) for 8 weeks. The average body weight of the fat-fed mice was 26.84 g, and the body weight of the normal-fed mice was 25.92 g; then the high-fat fed mice were randomly divided into a topiramate intervention group, a resveratrol intervention group, and a topiramate combined resveratrol half-dose group And blank solvent control group, began to group intraperitoneal injection: A group was given topiramate 50mg/kg/d, B group was given resveratrol 20mg/kg/d, C group was given topiramate 25mg/kg/d and resveratrol 10mg/d kg/d, group D was given a blank solvent control; at the same time, mice were fed with normal feed and fed with a blank solvent control.
溶剂采用DMSO，将各组药物溶在上述溶剂中。The solvent is DMSO, and each group of drugs is dissolved in the above solvent.
实验过程中，从开始给药第一天起，每天称量小鼠的体重。两组小鼠给药前体重无明显差异，给药第7天时托吡酯联合白藜芦醇剂量减半组和空白溶剂对照组小鼠的体重开始出现差异，并随时间变化差异逐渐加大，结果如图1所示。实验结果显示，托吡酯联合白藜芦醇能够明显抑制高脂饮食小鼠的体重增长。During the experiment, the mice were weighed every day from the first day of drug administration. There was no significant difference in body weight between the two groups of mice before administration. On the 7th day of administration, the body weight of mice in the topiramate combined with half-dose resveratrol group and the blank solvent control group began to differ, and the difference gradually increased with time. The results As shown in Figure 1. The experimental results showed that topiramate combined with resveratrol could significantly inhibit the weight gain of mice fed a high-fat diet.
给药前四组小鼠随机血糖无明显差异，随着腹腔注射给药，托吡酯联合白藜芦醇剂量减半组和空白溶剂对照组小鼠的血糖开始出现差异，结果如图2所示。实验结果显示，托吡酯联合白藜芦醇能够明显降低高脂饮食小鼠的血糖。Before administration, there was no significant difference in the random blood glucose of the mice in the four groups. Following the intraperitoneal injection, the blood glucose of the mice in the topiramate combined with half-dose resveratrol group and the blank solvent control group began to differ. The results are shown in Figure 2. Experimental results show that topiramate combined with resveratrol can significantly reduce blood sugar in mice fed a high-fat diet.
腹腔注射给药结束后，分别监测小鼠肝脏甘油三脂、胆固醇、丙酮酸转氨酶、天冬氨酸转氨酶，以及血清甘油三脂的值，结果显示：托吡酯联合白藜芦醇能明显降低小鼠的肝脏甘油三脂(p＜0.01)，同时降脂效果是优于各自单独使用的(如图3)；托吡酯联合白藜芦醇能明显降低小鼠的肝脏胆固醇(p＜0.01)，胆固醇降低效果也是明显优于两种药单独使用的(如图4)，托吡酯联合白藜芦醇能明显降低小鼠的丙酮酸转氨酶和天冬氨酸转氨酶(p＜0.01)(如图5、6)，托吡酯联合白藜芦醇能明显降低小鼠的血清甘油三脂(p＜0.001)(如图7)，表明托吡酯联合白藜芦醇具有改善胰岛素抵抗、非酒精性脂肪肝的作用，并且这些疗效都是明显优于单独使用其中任何一种药物的。After intraperitoneal injection, the values of liver triglyceride, cholesterol, pyruvate transaminase, aspartate transaminase, and serum triglyceride were monitored respectively. The results showed that topiramate combined with resveratrol could significantly reduce the liver triglyceride (p<0.01), and the lipid-lowering effect is better than that of each alone (as shown in Figure 3); topiramate combined with resveratrol can significantly reduce the liver cholesterol of mice (p<0.01), and cholesterol The effect is also significantly better than that of the two drugs used alone (as shown in Figure 4). Topiramate combined with resveratrol can significantly reduce the pyruvate aminotransferase and aspartate aminotransferase in mice (p<0.01) (as shown in Figures 5 and 6) , topiramate combined with resveratrol can significantly reduce serum triglycerides in mice (p<0.001) (as shown in Figure 7), indicating that topiramate combined with resveratrol has the effect of improving insulin resistance and non-alcoholic fatty liver, and these The curative effect is obviously better than that of using any one of them alone.
上述结果表明托吡酯联合白藜芦醇可以明显降低各自使用剂量，仍能达到优于单独使用的效果，是一项具有巨大临床前景的联合应用发现。The above results show that topiramate combined with resveratrol can significantly reduce the respective doses, and still achieve better results than those used alone, which is a discovery of combined application with great clinical prospects.
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。The above is only a preferred embodiment of the present invention, it should be pointed out that, for those of ordinary skill in the art, without departing from the principle of the present invention, some improvements and modifications can also be made, and these improvements and modifications can also be made. It should be regarded as the protection scope of the present invention.
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