Use of forsythoside a in preparation of medicine for preventing edema caused by rosiglitazone

Abstract

The application discloses application of forsythoside in preparation of a medicine for preventing edema caused by rosiglitazone, and belongs to the technical field of biological medicine. In view of the problem that rosiglitazone can cause edema side effect when treating type 2 diabetes, the application uses forsythoside and rosiglitazone in combination, rosiglitazone can relieve type 2 diabetes, and forsythoside can effectively reduce edema caused by rosiglitazone, so that the side effect of rosiglitazone medicine can be obviously reduced, and the dosage of rosiglitazone can be reduced. The application provides a new safe and effective medicine combination for treating and preventing insulin resistance diseases, and provides a theoretical guidance for preventing and treating the edema side effect of rosiglitazone.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of biological medicine, in particular to the application of forsythoside in the preparation of a medicine for preventing edema caused by rosiglitazone. BACKGROUND

[0002] The incidence of type 2 diabetes mellitus is increasing year by year, which seriously threatens human life and health and quality of life. Insulin resistance is the main pathological feature of type 2 diabetes mellitus, and is the key factor causing metabolic disorders in type 2 diabetes mellitus. Rosiglitazone belongs to the class of thiazolidinediones, which is an agonist of nuclear receptor PPARγ. It mainly produces insulin sensitization effect by agonizing PPARγ in adipose tissue, and can delay the progression of type 2 diabetes mellitus. However, long-term use of rosiglitazone can cause adverse reactions such as edema. Therefore, there is an urgent need to develop a medicine that can effectively reduce the side effects of edema caused by rosiglitazone, reduce its dosage, and maximize its role in preventing and treating insulin resistance diseases.

[0003] Traditional Chinese medicine Forsythia has the effects of clearing heat and resolving toxins, and removing swelling and resolving nodes. Forsythoside is the main pharmacologically active component of traditional Chinese medicine Forsythia, and is also the index component for quality control of Forsythia stipularis as specified in the Chinese Pharmacopoeia. Studies have shown that forsythoside has the effect of improving insulin resistance. Based on the different mechanisms of rosiglitazone and forsythoside, and the complexity of the mechanism of insulin resistance diseases, it is not clear whether rosiglitazone combined with forsythoside can produce a coordinated effect in the treatment of insulin resistance and at the same time reduce the side effects of edema caused by rosiglitazone. SUMMARY

[0004] In view of the above problems, the present application aims to provide the application of forsythoside in the preparation of a medicine for preventing edema caused by rosiglitazone. Forsythoside and rosiglitazone are used together to treat insulin resistance, and the synergistic effect between the two can not only delay the progression of type 2 diabetes mellitus through rosiglitazone, but also effectively prevent edema caused by rosiglitazone.

[0005] To achieve the above-mentioned purpose, the technical scheme adopted by the present application is as follows:

[0006] In one aspect, the present application provides the application of forsythoside in the preparation of a medicine for preventing edema caused by rosiglitazone.

[0007] On the other hand, the present application also provides a pharmaceutical combination for preventing and / or treating insulin resistance, which comprises forsythoside and rosiglitazone.

[0008] Preferably, the mass ratio of forsythoside and rosiglitazone is 25:0.6~40.

[0009] Preferably, the mass ratio of forsythoside and rosiglitazone is 25:0.6~10.

[0010] Further, the pharmaceutical combination further comprises a pharmaceutically acceptable carrier.

[0011] Further, the dosage form of the pharmaceutical combination comprises tablets, capsules, dripping pills, granules, solutions or suspensions.

[0012] In another aspect, the present application also provides use of the pharmaceutical combination as described above in the preparation of a medicament for treating type 2 diabetes.

[0013] The beneficial effects of the present application are:

[0014] The present application is found through animal experiment research that, compared with single forsythoside or rosiglitazone, the combination of forsythoside and rosiglitazone has better protective effect on insulin resistance. By taking advantage of the synergistic effect between forsythoside and rosiglitazone, the disease course of type 2 diabetes can be delayed by rosiglitazone, and at the same time, the addition of forsythoside can effectively reduce the edema caused by rosiglitazone, that is, the side effects of rosiglitazone drug are significantly reduced, and the dosage is reduced. This also provides a new safe and effective drug combination for the treatment and prevention of insulin resistance diseases, and provides a theoretical guidance for preventing and treating the side effects of rosiglitazone edema. BRIEF DESCRIPTION OF DRAWINGS

[0015] Figure 1 The results of the influence of different treatment methods on the glucose tolerance of experimental mice in the present application.

[0016] Figure 2 The results of the influence of different treatment methods on the blood glucose level of experimental mice in the present application.

[0017] Figure 3 The results of the influence of different treatment methods on the serum insulin level of experimental mice in the present application.

[0018] Figure 4 The results of the influence of different treatment methods on the hematocrit of experimental mice in the present application. DETAILED DESCRIPTION

[0019] In order for those skilled in the art to better understand the technical solutions of the present application, the technical solutions of the present application are further described below in combination with the drawings and examples.

[0020] It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the present application. Additionally, for a range of values of, for example, concentrations, dosage amounts, and the like, it is to be understood that each intervening value, to the upper and lower limits of the ranges is also specifically included within the scope of the present application. The upper and lower limits of these intervening values will respec tively include every value there between (i.e., each number between the upper and lower limit, or each number between the upper and lower limit). These smaller ranges are thus each specifically included within the scope of the present application. The upper and lower limits of the smaller ranges can independently be included or excluded in the range. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present application pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, the preferred methods and materials are described herein. Other embodiments of the present application will be apparent to those skilled in the art from consideration of the specification and practice of the present application disclosed herein. Various modifications and variations of the present application will be apparent to those skilled in the art from consideration of the specification and practice of the present application disclosed herein. Additional embodiments of the present application will be apparent to those skilled in the art from consideration of the specification and practice of the present application disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope of the application being indicated by the following claims. The following terms are used in the present application and are intended to have the following meanings: "include," "includes" and "including" are open-ended terms that are intended to mean "comprising," "comprises" and "comprising," respectively, and thus are not intended to exclude additional, unrecited elements or method steps.

[0021] 1. Experimental materials and methods

[0022] 1.1 Research subjects and experimental reagents

[0023] Male C57BL / 6J mice, SPF level, purchased from Jiangsu Jizhu Pharmaceutical Biological Technology Co., Ltd., Experimental Animal Production License No.: SCXK (Su) 2018-0008. The experimental animal breeding environment is SPF level, and the breeding environment is well ventilated according to the requirements of the experimental animal breeding environment in China, the room temperature is maintained at 21-23℃, the relative humidity is maintained at 45%-55%, the indoor light and dark alternation is 12 hours each, the experimental mice are free to eat and drink, and 5 mice are raised per cage.

[0024] Forsythia suspensa was purchased from Chengdu Lemaitian Pharmaceutical Technology Co., Ltd., rosiglitazone was purchased from Shanghai Macklin Biochemical Technology Co., Ltd., D-glucose was purchased from Shanghai Sangon Biological Company, insulin enzyme-linked immunosorbent assay (ELISA) kit was purchased from Shanghai Sangon Biological Technology Co., Ltd., blood glucose test paper was purchased from Roche Company. Hirschmann heparinized capillary 60 μL was purchased from Germany Hirschmann Laboratory Instruments Company. High-fat feed with 60% fat content was purchased from Nanjing Coordination Biology. Insulin ELISA kit was purchased from Shanghai Sangon Biological.

[0025] 1.2 Experimental grouping and treatment of each group

[0026] Mice were acclimated for one week and then randomly divided into normal group, high-fat group (HFD group), Phil group (25 mg / kg), Rosi1 group (40 mg / kg), Rosi2 group (10 mg / kg), Rosi3 group (2.5 mg / kg), Rosi4 group (0.6 mg / kg), Phil + Rosi1 group (25 + 40 mg / kg), Phil + Rosi2 group (25 + 10 mg / kg), Phil + Rosi3 group (25 + 2.5 mg / kg), Phil + Rosi4 group (25 + 0.6 mg / kg), 10 mice in each group. The normal group of mice were fed with ordinary feed, and the rest of the mice were fed with high-fat feed with 60% fat content, and free water. Forsythiaside and rosiglitazone were suspended with 1% CMC-Na aqueous solution, and 3 days of use were prepared each time. Each group of mice was given corresponding liquid every day, and the normal group and high-fat group of mice were given the same volume of solvent control, for 17 consecutive weeks. Note: Phil: Forsythiaside; Rosi: Rosiglitazone.

[0027] 1.3 Oral glucose tolerance test

[0028] The mice were fasted for 6 h starting at 7 am, and the tail tip was taken for blood glucose determination as the fasting blood glucose value at 0 min. Then each group of mice was given 2 g / kg of glucose aqueous solution by gavage, and the blood glucose level of the mice was determined by blood glucose meter at 10, 20, 30, 60, 90, 120 min after gavage. The data were analyzed by GraphPad Prism software, and the area under the curve (AUC) was calculated.

[0029] 1.4 Non-fasting blood glucose and fasting blood glucose detection

[0030] The blood was taken from the orbital venous plexus of each group of mice, or the mice were fasted overnight, and the tail tip of the mice was taken for blood. The blood glucose was detected by blood glucose meter.

[0031] 1.5 Non-fasting and fasting serum insulin level detection

[0032] The blood was taken from the orbital venous plexus of each group of mice, or the mice were fasted overnight, and the blood was taken from the orbital venous plexus. The serum was separated by centrifugation at 4°C and 10,000 rpm for 10 min, and the non-fasting and fasting serum insulin levels were detected by ELISA method.

[0033] 1.6 Hematocrit detection

[0034] Packed Cell Volume (PCV) determination: Hescheim heparinized capillary orbital venous blood was taken, centrifuged, and the height of the blood cells was divided by the length of the whole blood column to represent the packed cell volume. Hemolyzed samples were excluded.

[0035] 1.7 Statistical methods

[0036] All data were expressed as mean ± SEM. The data were analyzed by GraphPad Prism 9.0 software or t test, and the difference was statistically significant when P < 0.05.

[0037] 2. Experimental results

[0038] 2.1 Effect of rosiglitazone combined with forsythoside on glucose tolerance of the body

[0039] The results of the effect of rosiglitazone combined with forsythoside on glucose tolerance of the body are shown in FIG. 1, wherein a is the oral glucose tolerance curve of each group of mice, and b is the area under the glucose tolerance curve. Figure 1 In FIG. 1, a is the oral glucose tolerance curve of each group of mice, and b is the area under the glucose tolerance curve. Figure 1 The results of the effect of rosiglitazone combined with forsythoside on glucose tolerance of the body are shown in FIG. 1, wherein a is the oral glucose tolerance curve of each group of mice, and b is the area under the glucose tolerance curve.

[0040] Figure 1 The results of the effect of rosiglitazone combined with forsythoside on glucose tolerance of the body are shown in FIG. 1, wherein a is the oral glucose tolerance curve of each group of mice, and b is the area under the glucose tolerance curve.

[0041] The results of the effect of rosiglitazone combined with forsythoside on glucose tolerance of the body are shown in FIG. 1, wherein a is the oral glucose tolerance curve of each group of mice, and b is the area under the glucose tolerance curve. p = 0.06). This shows that rosiglitazone combined with forsythoside has a synergistic effect in the treatment of obesity and insulin resistance, and has a better effect than the two single drugs.

[0042] 2.2 Effect of rosiglitazone combined with forsythoside on blood glucose

[0043] The results of the effect of rosiglitazone combined with forsythoside on blood glucose of mice are shown in FIG. 2, wherein a is the fasting blood glucose detection result, and b is the non-fasting blood glucose detection result. Figure 2 The results of the fasting blood glucose detection of the experimental mice are shown in FIG. 2, wherein a is the fasting blood glucose detection result, and b is the non-fasting blood glucose detection result.

[0044] Figure 2 ​​As shown in Fig. a, compared with normal mice, the fasting blood glucose of HFD mice was significantly increased; Rosi2.5, Rosi10 and Rosi40 mg / kg dose (Rosi3 group, Rosi2 group and Rosi1 group) alone could significantly reduce the fasting blood glucose level of HFD mice; and compared with single drug of Phil (Phil group) or Rosi10 mg / kg (Rosi2 group), Phil + Rosi10 mg / kg (Phil + Rosi2 group) could further reduce the fasting blood glucose level of HFD mice; and compared with Rosi0.6 mg / kg (Rosi4 group), Phil + Rosi0.6 mg / kg (Phil + Rosi4 group) had a further trend to reduce the fasting blood glucose of HFD mice. p =0.054).

[0045] The non-fasting blood glucose detection results of experimental mice are shown in Fig. b. Figure 2 As shown in Fig. b, compared with normal mice, the non-fasting blood glucose level of HFD mice was significantly increased; and compared with HFD mice, the non-fasting blood glucose levels of mice in Phil group and Rosi1 group, Rosi2 group, Rosi3 group and Rosi4 group had no significant difference; and compared with Rosi10 mg / kg (Rosi2 group), Phil + Rosi10 mg / kg (Phil + Rosi2 group) had a further trend to reduce the non-fasting blood glucose level of mice (P =0.058); and compared with HFD mice, the non-fasting blood glucose of mice in Phil + Rosi10 mg / kg group (Phil + Rosi2 group) and Phil + Rosi2.5 mg / kg group (Phil + Rosi3 group) was significantly reduced. p

[0046] The above results fully show that when treating obesity and insulin resistance, Rosi and Phil have a synergistic effect and a better effect than two single drugs.

[0047] 2.3 Effect of Rosi and Phil on serum insulin level

[0048] The effect of Rosi and Phil on serum insulin level of mice is shown in Fig. a. Figure 3 As shown in Fig. a, a is the fasting serum insulin detection result, and b is the non-fasting serum insulin detection result. Figure 3 The fasting serum insulin detection results of experimental mice are shown in Fig. a.

[0049] Figure 3 ​​As shown in Figure a, compared with normal mice, HFD mice showed a significant increase in serum fasted insulin levels, confirming insulin resistance in HFD mice. Both forsythoside (Phil group) and the 40 mg / kg rosiglitazone group (Rosi1 group) significantly reduced fasted serum insulin levels in HFD mice. The serum fasted insulin levels in the 10, 2.5, and 0.6 mg / kg rosiglitazone groups (Rosi2, Rosi3, and Rosi4 groups) showed no significant difference compared to the HFD group. However, the fasted serum insulin levels in the forsythoside combined with 40 mg / kg rosiglitazone group (Phil + Rosi1 group), the forsythoside combined with 10 mg / kg rosiglitazone group (Phil + Rosi 2 group), and the forsythoside combined with 2.5 mg / kg rosiglitazone group (Phil + Rosi 3 group) were significantly lower than those in the HFD group.

[0050] The results of serum insulin detection in experimental mice without fasting are attached. Figure 3 As shown in Figure b, serum non-fasting insulin levels in HFD mice were significantly increased, indicating insulin resistance in HFD mice. Both forsythoside and rosiglitazone, administered alone at various doses, significantly reduced serum non-fasting insulin levels in HFD mice. Compared to the 10 mg / kg rosiglitazone monotherapy group (Rosi2 group), the forsythoside combined with 10 mg / kg rosiglitazone group (Phil + Rosi 2 group) showed a further reduction in serum non-fasting insulin levels in mice. p =0.06), the combination of forsythoside and 0.6 mg / kg rosiglitazone (Phil + Rosi 4 group) showed a further decrease in serum non-fasting insulin levels in mice compared to the 0.6 mg / kg rosiglitazone monotherapy group (Rosi 4 group). p =0.06).

[0051] The above results indicate that rosiglitazone combined with forsythoside achieves a synergistic effect in the treatment of obese insulin resistance, and has better efficacy than either drug alone.

[0052] 2.4 Rosiglitazone combined with forsythoside significantly reduces edema side effects.

[0053] The results of the effect of rosiglitazone combined with forsythoside on edema are shown in the attached figure. Figure 4 As shown. From the appendix Figure 4As can be seen from the above table, compared with the normal group, the HFD group and the forsythoside A group (Phil group) had no significant effect on the hematocrit of the mice; the Rosi 1 group, Rosi 2 group and Rosi 3 group could significantly reduce the hematocrit of the HFD group mice, and the Rosi 4 group had no effect on the hematocrit of the HFD mice. The Phil + Rosi 1 group still significantly reduced the hematocrit of the HFD mice, and the Phil + Rosi 4 group had no effect on the hematocrit of the HFD mice; the Phil + Rosi 2 group and the Phil + Rosi 3 group had no effect on the hematocrit of the HFD mice.

[0054] The above results show that the application of rosiglitazone at a dose higher than (including) 2.5 mg / kg alone can significantly reduce the hematocrit of the mice, resulting in the side effect of edema; the combination of forsythoside A and rosiglitazone at a dose of 0.6-10 mg / kg does not produce the side effect of edema in the treatment of obesity and insulin resistance; and the combination of forsythoside A and rosiglitazone at a dose of 40 mg / kg reduces the side effect of edema in the treatment of obesity and insulin resistance.

[0055] The above shows and describes the basic principles, main features and advantages of the present application. It should be understood by those skilled in the art that the present application is not limited by the above examples, and the above examples and descriptions in the specification are only to illustrate the principles of the present application. Without departing from the spirit and scope of the present application, various changes and improvements can be made to the present application, and these changes and improvements all fall within the scope of the present application. The scope of protection of the present application is defined by the appended claims and their equivalents.

Claims

1. Use of a pharmaceutical combination for the manufacture of a medicament for preventing edema caused by rosiglitazone, characterized in that, The drug combination comprises forsythoside and rosiglitazone; and the mass ratio of forsythoside to rosiglitazone is 25:0.6-10.

2. Use according to claim 1, characterized in that: The drug combination further comprises a pharmaceutically acceptable carrier.

3. Use according to claim 1, characterized in that: The dosage form of the drug combination comprises tablets, capsules, dripping pills, granules, solutions or suspensions.

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