Application of gallic acid in preparation of medicine for preventing or treating peripheral neuropathy

Abstract

The invention relates to a medicine application technology, in particular to application of gallic acid in preparation of a medicine for preventing or treating peripheral neuropathy. The peripheral neuropathy disclosed by the invention is acute peripheral neuropathy caused by using a chemotherapeutic drug oxaliplatin. The gallic acid has a protective effect on oxaliplatin-induced acute peripheral neurotoxicity of mice. The gallic acid can be used as an adjuvant of a chemotherapeutic drug for cancer treatment, and has a remarkable relieving effect on neurotoxicity caused by chemotherapy.

Description

Technical Field

[0001] The invention relates to a pharmaceutical application technology, and in particular to an application of gallic acid in the preparation of a drug for preventing or treating peripheral neuropathy. Background Art

[0002] Chemotherapy-induced peripheral neuropathy (CIPN) is a serious clinical problem caused by cytotoxic drugs, including platinum, taxanes, proteasome inhibitors, vinca alkaloids, and immunomodulatory drugs, which cause different pathological damages to neurons and impair the progression of the peripheral and central nervous systems. [1] CIPN limits the improvement of chemotherapy drug dosage and efficacy to a certain extent and is the main dose-limiting toxicity of chemotherapy drugs. [2] In 2020, the American Society of Clinical Oncology (ASCO) updated its guidelines for the recommended prevention and treatment of chemotherapy-induced peripheral neuropathy (CIPN) in adult cancer survivors. The same neuropathy measurement tool was used in several clinical studies and found that oxaliplatin caused significant neurotoxicity. [3] .

[0003] Oxaliplatin-induced peripheral neurotoxicity (OIPN) is divided into acute OIPN and chronic OIPN based on clinical characteristics such as pathogenesis, symptoms, course, and incidence. Acute OIPN is characterized by sensitivity to cold, throat discomfort, discomfort when swallowing cold liquids, and muscle cramps. These symptoms may occur during drug infusion, but their severity usually peaks 2 to 3 days after each oxaliplatin dose. [3] 85-95% of patients develop acute OIPN after OXA therapy, which can be triggered by cold stimulation [4-6] The severity of acute neuropathy can predict the development of chronic neurotoxicity. The more severe the acute neuropathy in the first treatment cycle, the more severe the chronic neurotoxicity. [9] .

[0004] Chronic OIPN is cumulative. 10-15% of patients will develop chronic OIPN after receiving OXA treatment, with a cumulative dose of approximately 540-850 mg / m 2 Chronic OIPN can lead to sensory loss and altered proprioception, which can affect daily activities, including writing, taking medications, and other activities that require fine motor coordination. [8] .

[0005] Different drugs are selected for the prevention and treatment of acute OIPN and chronic OIPN in clinical practice. Calcium and magnesium salts are used to prevent acute OIPN, but large-scale randomized controlled clinical trials are needed in the colorectal cancer population to confirm the benefits of calcium and magnesium infusion for acute OIPN. Amifostine is used to treat acute OIPN, but intravenous administration of amifostine can cause significant adverse reactions, including hypotension, nausea, and vomiting. In some clinical trials, glutathione and duloxetine can prevent chronic OIPN, but further clinical trials are still needed to verify. There is still a lack of effective drugs for the prevention and treatment of acute OIPN.

[10] .

[0006] Gallic acid (GA) has a variety of pharmacological activities, such as anti-oxidation, inflammation, anti-tumor and antibacterial. GA still shows good safety when the oral dose reaches 5000 mg / kg in mice, and has good therapeutic effect and safety performance.

[11] .

[0007] References:

[0008] [1] Yang Y, Zhao B, Gao X, et al: Targeting strategies for oxaliplatin-induced peripheral neuropathy: clinical syndrome, molecular basis, and drug development. Journal of Experimental&Clinical Cancer Research 40, 2021

[0009] [2]Malacrida A, Meregalli C, Rodriguez-Menendez V, et al: Chemotherapy-Induced Peripheral Neuropathy and Changes in Cytoskeleton. International Journal of Molecular Sciences 20, 2019

[0010] [3]Loprinzi CL,Lacchetti C,Bleeker J,et al:Prevention and Managementof Chemotherapy-Induced Peripheral Neuropathy in Survivors of Adult Cancers:ASCO Guideline Update.Journal of Clinical Oncology 38:3325-3348,2020

[0011] [4]Han CH,Kilfoyle DH,Hill AG,et al:Preventing oxaliplatin-inducedneurotoxicity:rationale and design of phase Ib randomized,double-blind,placebo-controlled,cross-over trials for early clinical evaluation ofinvestigational therapeutics.Expert Opinion on Drug Metabolism&Toxicology 12:1479-1490,2016

[0012] [5]Brewer JR,Morrison G,Dolan ME,et al:Chemotherapy-inducedperipheral neuropathy:Current status and progress.Gynecologic Oncology 140:176-183,2016

[0013] [6]Sempere-Bigorra M,Julián-Rochina I,Cauli O:Chemotherapy-InducedNeuropathy and Diabetes:AScoping Review.Current Oncology 28:3124-3138,2021

[0014] [7]Grolleau F,Gamelin L,Boisdron-Celle M,et al:APossible Explanationfor a Neurotoxic Effect of the Anticancer Agent Oxaliplatin on NeuronalVoltage-Gated Sodium Channels.Journal of Neurophysiology 85:2293-2297,2001

[0015] [8]de Gramont A,Figer A,Seymour M,et al:Leucovorin and FluorouracilWith or Without Oxaliplatin as First-Line Treatment in Advanced ColorectalCancer.Journal of Clinical Oncology 18:2938-2947,2000

[0016] [9]Pachman DR,Qin R,Seisler DK,et al:Clinical Course of Oxaliplatin-Induced Neuropathy:Results From the Randomized Phase III Trial N08CB(Alliance).Journal of Clinical Oncology 33:3416-3422,2015

[0017]

[10] Kang L,Tian Y,Xu S,et al:Oxaliplatin-induced peripheralneuropathy:clinical features,mechanisms,prevention and treatment.Journal ofNeurology 268:3269-3282,2020

[0018]

[11] Harwansh RK, Deshmukh R, Shukla VP, et al. Recent Advancements in Gallic Acid-Based Drug Delivery: Applications, Clinical Trials, and Future Directions. Pharmaceutics. 2024; 16(9): 1202. Published 2024Sep 13. Summary of the invention

[0019] Purpose of the invention: The technical problem to be solved by the present invention is to provide an application of gallic acid in the preparation of a drug for preventing or treating peripheral neuropathy in view of the deficiencies in the prior art.

[0020] In order to solve the above technical problems, the present invention discloses an application of gallic acid in the preparation of a drug for preventing or treating peripheral neuropathy, in particular, an application of gallic acid in the preparation of a drug for preventing or treating acute peripheral neuropathy caused by oxaliplatin. The specific technical scheme is as follows:

[0021] The use of gallic acid in the preparation of a drug for preventing or treating peripheral neuropathy. Preferably, the gallic acid (Gallic acid), CAS No.: 149-91-7, has a structure as shown below:

[0022]

[0023] Wherein, the peripheral neuropathy is acute peripheral neuropathy.

[0024] Wherein, the acute peripheral neuropathy is acute peripheral neuropathy caused by the use of chemotherapy drugs. Preferably, the symptoms of the acute peripheral neuropathy include one or more of the following: numbness and pain in the skin of the extremities, glove and stocking-like sensation, cold skin, ants walking sensation, weakness in holding objects, cotton-like feeling when walking, or burning pain, flashing pain, and knife-like pain.

[0025] Wherein, the chemotherapy drug is the cancer chemotherapy drug oxaliplatin.

[0026] The acute peripheral neuropathy is caused by the use of oxaliplatin, and the clinical dosage of oxaliplatin is 85 mg / m 2 Repeat every two weeks and 130 mg / m 2 Repeat every three weeks.

[0027] Among them, gallic acid is used as an active ingredient and combined with one or more pharmaceutically acceptable solid or liquid adjuvants to prepare a drug for preventing or treating acute peripheral neuropathy in any dosage form.

[0028] Wherein, the liquid auxiliary agent includes physiological saline or ultrapure water.

[0029] Wherein, the dosage form includes any one of a solution, an emulsion, a suspension, an injection or a transdermal preparation.

[0030] The drug comprises a chemotherapy drug composition, wherein the chemotherapy drug composition comprises a cancer chemotherapy drug and gallic acid; the cancer chemotherapy drug is oxaliplatin. Gallic acid is used as a chemotherapy drug adjuvant to prevent or treat peripheral neuropathy caused by chemotherapy drugs.

[0031] The administration method of the drug includes any one of intraperitoneal, oral, sublingual, subcutaneous, intravenous or intramuscular.

[0032] Beneficial effects:

[0033] The present invention proposes the use of gallic acid in the preparation of a drug for preventing and treating acute peripheral neuropathy caused by oxaliplatin. In an animal model, gallic acid has a protective effect on acute peripheral neurotoxicity induced by oxaliplatin in mice. The drug gallic acid of the present invention can be used as an adjuvant of a chemotherapeutic drug for cancer treatment, and has a mitigating effect on neurotoxicity caused by chemotherapy. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] The present invention will be further described in detail below in conjunction with the accompanying drawings and specific embodiments, and the above and / or other advantages of the present invention will become more clear.

[0035] Figure 1 The effect of gallic acid on the body weight of mice in the acute OIPN model;

[0036] Figure 2 Effects of gallic acid on mechanical pain threshold in acute OIPN model mice;

[0037] Figure 3 This is the effect of gallic acid on the cold pain score of mice with acute OIPN model.

[0038] Note: Data are expressed as mean ± standard deviation (n = 11). Figure 1-3 Two-way ANOVA was performed, followed by Tukey's post hoc comparison. *P<0.05, **P<0.01 compared with the control group; #P<0.05, ##P<0.01 compared with the oxaliplatin group. DETAILED DESCRIPTION

[0039] The present invention is further described in detail below with reference to the accompanying drawings and specific embodiments.

[0040] In the following examples, the oxaliplatin (CAS No.: 61825-94-3) and the gallic acid (CAS No.: 149-91-7) were purchased from Taoshu Company.

[0041] Example 1 Gallic acid has a protective effect on oxaliplatin-induced acute peripheral neuropathy in mice

[0042] 1. Experimental materials:

[0043] Experimental drugs: Oxaliplatin was prepared with 5% glucose injection, and gallic acid was prepared with 0.9% normal saline.

[0044] Instruments: Electronic von Frey analgesia meter, Plantar Test (Hargreaves method) Glass stands, and Hot Cold Plate Analgesia Meter for Mice and Rats were all purchased from IITC (IITC Inc. Life Science, Woodland Hills, CA, USA).

[0045] Experimental animals: Male C57BL / 6 mice, weighing 18-22g, 6-8 weeks old, clean grade, purchased from Shanghai Slake Experimental Animal Center, and kept in the SPF-grade experimental animal room of Jiangsu Institute of Traditional Chinese Medicine. The experimental temperature was controlled at 25±1℃, and free access to drinking water and animal feed was provided. The experiment began after one week of feeding.

[0046] 2. Experimental methods:

[0047] (1) The experimental animals were randomly divided into four groups: blank control group (Control), oxaliplatin group (OXA), low-dose gallic acid group (OXA+GA-L) and high-dose gallic acid group (OXA+GA-H), as follows:

[0048] Blank control group (Control): intraperitoneal injection of 5% glucose injection on the first day;

[0049] Oxaliplatin group (OXA): All groups except the blank control group were intraperitoneally injected with 6 mg / kg oxaliplatin at a dosage volume of 0.05 mL / 10 g on day 1 to create an acute neurotoxic mouse model. The blank control group was intraperitoneally injected with an equal volume of 5% glucose injection.

[0050] Low-dose gallic acid group (OXA+GA-L): Gallic acid was first administered intragastrically, with the volume of gallic acid administered intragastrically being 0.2 mL / 10 g, and the dosage being 50 mg / kg; then 6 mg / kg of oxaliplatin 5% glucose injection was intraperitoneally injected at a dosage of 0.05 mL / 10 g. Gallic acid was administered for seven days, while oxaliplatin only needed to be administered on the first day.

[0051] Gallic acid high-dose group (OXA+GA-H): Gallic acid was first administered intragastrically, with the volume of gallic acid administered intragastrically being 0.2 mL / 10 g, and the dosage being 100 mg / kg; then 6 mg / kg of oxaliplatin 5% glucose solution was intraperitoneally injected at a dosage of 0.05 mL / 10 g. Gallic acid was administered for seven days, while oxaliplatin only needed to be administered on the first day.

[0052] (2) The first day of drug treatment was designated as Day 1, and the weight of mice was measured on Days 0, 3, and 6; behavioral tests of mice (mechanical pain test and cold pain test) were performed on Days 0, 1, 3, and 6.

[0053] (A) Body weight: The body weight of mice was measured at the same time point every day.

[0054] (B) Experimental determination of mechanical pain sensation in mice: Referring to the method of Meng Zhao et al. [KIMeng Zhao, et al. Acutecold hypersensitivity characteristically induced by oxaliplatin is caused by the enhanced responsiveness of TRPA1 in mice, Molecular Pain. 8 (2012) 55], the mechanical withdrawal threshold (von Frey test) was used to evaluate the mechanical hyperalgesia of mice. The mice were placed in a (20*17*13cm) plexiglass box, and the bottom contact surface of the mouse toes was a metal mesh. After the mice adapted to the measurement box environment for 5 minutes and were at rest, the soles of the mice were vertically stimulated with von Frey fiber filaments. After the mice showed a withdrawal reaction, the electronic display stress value was recorded.

[0055] (C) Mouse cold pain test: Before the measurement, the mice were placed in the measurement environment to adapt for 30 minutes. During the test, the mice were placed on a cold plate at 4°C and covered with a transparent plexiglass box. The measurement time was 60 seconds. During the measurement time, the escape behavior of the mice was recorded and scored: 0 points = no reaction; 1 point = mild cold escape reaction, such as lifting the hind legs or walking backwards; 2 points = strong cold escape reaction, such as jumping up, etc. The total score within the 60-second measurement time was recorded.

[0056] 3. Experimental results:

[0057] The results are as follows Figure 1 , Figure 2 , Figure 3 As shown, according to the diagram:

[0058] (A) Effects on the body weight of mice: Figure 1 As shown in the figure, the weight of mice in the blank control group increased over time, and mice in the oxaliplatin group showed a significant weight loss due to the stimulation of oxaliplatin (P<0.01). Compared with the oxaliplatin group, the high-dose gallic acid group was able to significantly alleviate the weight loss caused by oxaliplatin (P<0.05).

[0059] (B) Effects on mechanical pain perception in mice: Figure 2 As shown in the figure, during the measurement period, the mechanical paw withdrawal threshold of mice in the blank control group tended to be stable. On the sixth day after oxaliplatin administration, the mechanical paw withdrawal threshold of mice in the oxaliplatin group was significantly decreased compared with the blank control group (P<0.01); compared with the oxaliplatin group, gallic acid dose-dependently alleviated the decrease in mechanical pain threshold caused by oxaliplatin. The low-dose gallic acid group significantly inhibited the decrease in mechanical pain threshold of mice caused by oxaliplatin (P<0.05), and the high-dose gallic acid group significantly inhibited the decrease in mechanical pain threshold of mice caused by oxaliplatin (P<0.01). This indicates that gallic acid can reduce the mechanical pain sensitivity of mice caused by oxaliplatin.

[0060] (C) Effects on cold pain perception in mice: Before the experiment, mice in each group were insensitive to cold pain perception. Figure 3 As shown in the figure, on the sixth day after oxaliplatin administration, the cold pain scores of mice in the oxaliplatin group were significantly increased compared with the blank control group (P<0.01); compared with the oxaliplatin group, gallic acid alleviated the cold pain sensitivity caused by oxaliplatin in a dose-dependent manner. The low-dose gallic acid group significantly reduced the increase in the cold pain scores of mice caused by oxaliplatin (P<0.05), and the high-dose gallic acid group significantly reduced the increase in the cold pain scores of mice caused by oxaliplatin (P<0.01). This indicates that gallic acid can reduce the cold pain sensitivity of mice caused by oxaliplatin.

[0061] In summary, in the acute peripheral nerve injury model caused by oxaliplatin, mice were sensitive to mechanical pain and cold pain, and pre-administration of gallic acid reduced the sensitivity of mechanical pain and cold pain in mice. Gallic acid has a protective effect on peripheral nerve injury caused by oxaliplatin in mice. Two-way ANOVA was used, followed by Tukey's post hoc comparison. *P<0.05, **P<0.01 compared with the model group and the control group; #P<0.05, ##P<0.01 compared with the blank control group.

[0062] The present invention provides a method and idea for the use of gallic acid in the preparation of a drug for the prevention or treatment of peripheral neuropathy. There are many methods and approaches to implement the technical solution. The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention. All components not specified in this embodiment can be implemented using existing technologies.

Claims

1. Application of gallic acid in the preparation of drugs for preventing or treating peripheral neuropathy.

2. The use according to claim 1, characterized in that: The peripheral neuropathy is acute peripheral neuropathy.

3. The use according to claim 2, characterized in that: The acute peripheral neuropathy is acute peripheral neuropathy caused by the use of chemotherapy drugs.

4. The use according to claim 3, characterized in that: The chemotherapy drug is the cancer chemotherapy drug oxaliplatin.

5. The use according to claim 1, characterized in that: The medicine comprises a chemotherapy drug composition, which comprises a cancer chemotherapy drug and gallic acid; the cancer chemotherapy drug is oxaliplatin.

6. The use according to any one of claims 1 to 5, characterized in that: Gallic acid is used as an active ingredient and combined with one or more pharmaceutically acceptable solid or liquid adjuvants to prepare a drug for preventing or treating peripheral neuropathy in any dosage form.

7. The use according to claim 6, characterized in that: The liquid auxiliary agent includes physiological saline or ultrapure water.

8. The use according to claim 6, characterized in that: The dosage form includes any one of solution, emulsion, suspension, injection or transdermal preparation.

9. The use according to any one of claims 1 to 5, characterized in that: The administration of the drug includes any one of intraperitoneal, oral, sublingual, subcutaneous, intravenous or intramuscular administration.

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