Use of glucose transporter 1 inhibitors for the preparation of medicaments for the treatment of diabetic neuropathy

Abstract

The application discloses application of a glucose transporter 1 inhibitor in preparation of a drug for treating diabetic neuropathy. The application verifies that the glucose transporter 1 inhibitor BAY-876 can be used as a drug for treating diabetic peripheral neuropathy and can be combined with mecobalamin to be used as a drug for treating diabetic peripheral neuropathy through pharmacodynamics experiments.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine, and particularly relates to application of a glucose transporter 1 inhibitor in preparation of a drug for treating diabetic neuropathy. BACKGROUND

[0002] Diabetic neuropathy is the most common complication of diabetes, affecting more than 50% of diabetic patients. According to the affected nerves, it can affect the sensory, motor and autonomic nerves and multiple organ systems. The clinical manifestations are leg, foot and hand pain and numbness; it can also cause digestive system, urinary tract, blood vessels and heart problems. The lesion most commonly damages the nerves of the legs and feet, and severe patients can be disabled, aggravating the public health burden.

[0003] Traditional treatment focuses on controlling high blood sugar and nerve repair drugs to slow down the disease progression or delay the onset, and methotrexate is often used as a nerve repair drug in clinical practice. In the current treatment method, there is a lack of effective overall therapy for peripheral neuropathy, which can only slow down the disease and cannot block the progress of the lesion, so there is an urgent need to find new anti-diabetic peripheral neuropathy drugs that can block the pathological process of diabetic peripheral neuropathy.

[0004] BAY-876 is a common glucose transporter 1 (GLUT1) inhibitor, which can effectively prevent glycolysis and the growth of ovarian cancer. There is no related report on the glucose transporter 1 inhibitor BAY-876 as a drug for treating diabetic neuropathy. SUMMARY

[0005] The purpose of the present application is to provide the application of a glucose transporter 1 inhibitor in the preparation of a drug for treating diabetic neuropathy.

[0006] The present application verifies through pharmacodynamic experiments that the glucose transporter 1 inhibitor BAY-876 can be used as a drug for treating diabetic peripheral neuropathy, and can also be used in combination with methotrexate as a drug for treating diabetic peripheral neuropathy.

[0007] The present application first discloses the application of the glucose transporter 1 inhibitor BAY-876 as a drug for treating diabetic peripheral neuropathy, which provides a new idea for the medication of diabetic neuropathy. BRIEF DESCRIPTION OF DRAWINGS

[0008] Figure 1 The results of the BAY-876 rat pharmacodynamic experiment in Example 1.

[0009] Figure 2 The results of the BAY-876 and methotrexate combined administration experiment in Example 2. DETAILED DESCRIPTION

[0010] The preferred embodiments of the present application will be described in detail below with reference to Examples. It should be understood that the following Examples are given to generally illustrate the application and should not be considered as limiting the scope of the application. Various modifications and alterations of the present application can be made by those skilled in the art without departing from the spirit and scope of the application.

[0011] The experimental methods used in the following examples are conventional methods unless otherwise specified.

[0012] The materials, reagents, etc. used in the following examples can be obtained commercially unless otherwise specified.

[0013] In the following examples, the method for establishing a diabetic rat animal model is as follows:

[0014] Prepare 0.1 mol / L sodium citrate buffer, pH 4.2 just before use; dissolve streptozotocin (STZ) in the sodium citrate buffer to make a 1% solution, filter sterilize with a 0.22 μm filter, and cool on ice.

[0015] SD rats, 4 weeks to 6 weeks old, weighing 180 to 200 g. Fasting for 12 h, intraperitoneal injection at a dose of 50 mg / kg, once a day, for 2 consecutive days.

[0016] One week later, blood glucose was measured by tail vein blood sampling, and the model was selected according to the standard of fasting blood glucose ≥ 16.7 mmol / L, and was included in the experiment.

[0017] Example 1

[0018] Glucose transporter 1 inhibitor BAY-876 rat pharmacodynamics experiment

[0019] 1. The selected rats were randomly divided into 4 groups, 8 rats in each group. Including ① model control group ② methylcobalamin treatment group ③ BAY-876 low dose treatment group ④ BAY-876 high dose treatment group; each group was given 10 mL / kg gavage, for 12 consecutive weeks. At the same time, 8 normal rats of the same age were fasted for 12 h, and an equal amount of 0.1 mol / L pH 4.2 citric acid buffer was injected intraperitoneally as a normal control group.

[0020] Model group: saline solution / DMSO solution (v / v 1000:1)

[0021] Methylcobalamin treatment group: the dose is 500 μg / kg

[0022] BAY-876 low dose group: the dose is 250 μg / kg

[0023] BAY-876 high dose group: the dose is 500 μg / kg.

[0024] 2. Preparation of drug solution:

[0025] Mecobalamin treatment group: 0.5mg mecobalamin tablets were crushed, added to distilled water to make a suspension, and then diluted to 10mL with physiological saline, which is a dose of 500μg / kg.

[0026] BAY-876 low-dose group: Weigh 0.5 mg BAY-876 and dissolve it in DMSO solution, then dilute to 20 mL with physiological saline, which is a dose of 250 μg / kg.

[0027] BAY-876 high-dose group: Weigh 0.5 mg BAY-876 and dissolve it in DMSO solution, then dilute to 10 mL with physiological saline, which is a dose of 500 μg / kg.

[0028] 3. Sciatic Nerve Conduction Velocity Detection: After 12 weeks of drug administration, rats were anesthetized by intraperitoneal injection of 0.4 mL / 100 g of 1% sodium pentobarbital. The proximal and distal ends of the rat's hind limbs were disinfected with alcohol. The skin between the semimembranosus and biceps femoris muscles was incised, and the two muscles were bluntly dissected to expose the main trunk of the sciatic nerve. The action potential of the sciatic nerve was recorded. The nerve stimulation electrode was placed 0.3 cm above the rat's lateral malleolus, and the recording electrode was placed at the proximal end of the sciatic nerve. The distance between the two electrodes was measured. Stimulation was performed at 1-minute intervals, repeated 3 times, and the average value was taken to calculate the conduction velocity. The test results are shown in Table 1 and [Table data missing]. Figure 1 .

[0029] Table 1 Comparison of sciatic nerve conduction velocities in rats (mean ± standard deviation)

[0030]

[0031] The results above show that the therapeutic effect of BAY-876 was comparable to that of the mecobalamin treatment group, but significantly different from the model group. This indicates that the glucose transporter 1 inhibitor BAY-876, administered orally, can effectively treat diabetic peripheral neuropathy at a lower dose than mecobalamin.

[0032] Example 2

[0033] Combined dosing experiment of glucose transporter 1 inhibitor BAY-876 and methylcobalamin

[0034] Rats that successfully developed the model were divided into three groups: the mecobalamin treatment group (dose of 250 μg / kg), the BAY-876 group (dose of 250 μg / kg), and the BAY-876 combined with mecobalamin group (125 μg / kg BAY-876 + 125 μg / kg mecobalamin).

[0035] The experimental periods were 8 weeks and 12 weeks, and the rest were carried out according to Example 1.

[0036] At the end of administration, the rat sciatic nerve conduction velocity was detected, and the data were statistically analyzed; through table 2 and Figure 2 It can be seen that the effect of BAY-876 combined with methylcobalamin is significantly better than that of BAY-876 or methylcobalamin alone, and the drug efficacy is four weeks earlier than that of single administration.

[0037] Table 2 Comparison of rat sciatic nerve conduction velocity (mean ± standard deviation)

[0038]

[0039] From the above results, it can be seen that the glucose transporter 1 inhibitor BAY-876 combined with methylcobalamin has better synergistic therapeutic effect. Through the experiment, it is also proved that the amount of methylcobalamin is reduced to 1 / 2 by combining the two drugs, and the onset time is fast, thereby greatly reducing the drug dosage and drug resistance problem, and achieving good therapeutic effect.

[0040] In summary, the application first discloses the application of glucose transporter 1 inhibitor BAY-876 in preparing a drug for treating diabetic peripheral neuropathy; the pharmacodynamic experimental data show that the glucose transporter 1 inhibitor BAY-876 is a kind of high-efficiency drug for diabetic peripheral neuropathy.

Claims

1. The application of glucose transporter 1 inhibitors in the preparation of therapeutic drugs for diabetic neuropathy, characterized in that, The glucose transporter 1 inhibitor is BAY-876.

2. Application of glucose transporter 1 inhibitor BAY-876 in combination with mecobalamin in the preparation of drugs for the treatment of diabetic neuropathy.

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