Use of gallic acid in the preparation of a medicament for preventing or treating peripheral neuropathy

Abstract

The application relates to a pharmaceutical application technology, in particular to application of gallic acid in preparation of a medicine for preventing or treating peripheral neuropathy. The peripheral neuropathy is acute peripheral neuropathy caused by using a chemotherapy drug, oxaliplatin. The gallic acid has a protective effect on acute peripheral nerve toxicity of mice induced by oxaliplatin. The medicine, gallic acid, can be used as an adjuvant of a chemotherapy drug for cancer treatment, and has a significant alleviating effect on nerve toxicity caused by chemotherapy.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical medicine, in particular to the application of gallic acid in the preparation of drugs for preventing or treating peripheral neuropathy. BACKGROUND

[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 damage to neurons, and damage the progress of peripheral and central nervous system [1] . CIPN limits the dose and efficacy of chemotherapy drugs to some extent, which is the main dose-limiting toxicity of chemotherapy drugs [2] . In 2020, the American Society of Clinical Oncology (ASCO) updated the guidelines for the prevention and treatment of chemotherapy-induced peripheral neuropathy (CIPN) management in adult cancer survivors. In several clinical studies, the same neuropathy measurement tool was used, and it was found that oxaliplatin caused significant neurotoxicity [3] .

[0003] Oxaliplatin (OXA) induced peripheral neuropathy (OIPN) is divided into acute OIPN and chronic OIPN according to the clinical characteristics of pathogenesis, symptoms, course and incidence. The characteristics of acute OIPN are sensitivity to cold, throat discomfort, discomfort when swallowing cold liquid and muscle spasm. These symptoms can 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 treatment, which can be triggered by cold stimulation [4-6] . The degree of acute neuropathy can predict the development of chronic neurotoxicity. In the first treatment cycle, the more severe the acute neuropathy of the patient, the more severe the chronic neurotoxicity [9] .

[0004] Chronic OIPN is cumulative, and 10-15% of patients will develop chronic OIPN after receiving OXA treatment, with a cumulative dose of about 540-850 mg / m 2 , and cannot be relieved. Chronic OIPN can further cause sensory loss and changes in proprioception, which can affect daily activities, including writing, taking medication and other activities that require fine motor coordination [8] .

[0005] Different drugs are selected for the prevention and treatment of acute and chronic OIPN in clinic. Calcium and magnesium salts are used for the prevention of acute OIPN, but large-scale randomized controlled clinical trials need to be conducted in colorectal cancer population to confirm the benefits of calcium and magnesium infusion on acute OIPN. Amifostine is used for the treatment of 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 various pharmacological activities, such as antioxidant, anti-inflammatory, anti-tumor and antibacterial activities, etc. GA still has good safety at an oral dose of 5000 mg / kg in mice, and has good therapeutic effect and safety performance

[11] .

[0007] Reference:

[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 Management of 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-induced neurotoxicity: rationale and design of phase Ib randomized, double-blind, placebo-controlled, cross-over trials for early clinical evaluation of investigational therapeutics. Expert Opinion on Drug Metabolism & Toxicology 12:1479-1490, 2016

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

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

[0014] [7] Grolleau F, Gamelin L, Boisdron-Celle M, et al: A Possible Explanation for a Neurotoxic Effect of the Anticancer Agent Oxaliplatin on Neuronal Voltage-Gated Sodium Channels. Journal of Neurophysiology 85:2293-2297, 2001

[0015] [8] de Gramont A, Figer A, Seymour M, et al: Leucovorin and Fluorouracil With or Without Oxaliplatin as First-Line Treatment in Advanced Colorectal Cancer. 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 peripheral neuropathy: clinical features, mechanisms, prevention and treatment. Journal of Neurology 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 2024 Sep 13. SUMMARY

[0019] The technical problem solved by the present application is to provide an application of gallic acid in the preparation of a drug for preventing or treating peripheral neuropathy.

[0020] To solve the above technical problems, the present application 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 induced by oxaliplatin. The specific technical solutions are as follows:

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

[0022]

[0023] The peripheral neuropathy is acute peripheral neuropathy.

[0024] The acute peripheral neuropathy is acute peripheral neuropathy induced by a chemotherapy drug. Preferably, the symptoms of the acute peripheral neuropathy include one or more of the following: numbness and pain in the skin at the end of the limbs, a glove and sock-like sensation, cold skin, an ant-like sensation, weakness in holding objects, a cotton-like sensation or burning, shooting, and knife-like pain when walking.

[0025] The chemotherapy drug is the cancer chemotherapy drug oxaliplatin.

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

[0027] The gallic acid is used as an active ingredient in combination 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] The liquid adjuvant comprises physiological saline or ultrapure water.

[0029] The dosage form comprises any one of solution, emulsion, suspension, injection or transdermal preparation.

[0030] The medicine comprises a chemotherapy medicine composition, the chemotherapy medicine composition comprises a cancer chemotherapy medicine and gallic acid, the cancer chemotherapy medicine is oxaliplatin, and the gallic acid is used as an adjuvant of the chemotherapy medicine to prevent or treat chemotherapy medicine-induced peripheral neuropathy.

[0031] The medicine is administered in any one of intraperitoneal, oral, sublingual, subcutaneous, intravenous or intramuscular modes.

[0032] Beneficial effects:

[0033] The application of gallic acid in preparing a medicine for preventing and treating acute oxaliplatin-induced peripheral neuropathy is provided, and gallic acid has a protective effect on acute peripheral nerve toxicity induced by oxaliplatin in an animal model. The medicine gallic acid can be used as an adjuvant of a chemotherapy medicine for cancer treatment, and has an alleviating effect on chemotherapy-induced neurotoxicity. BRIEF DESCRIPTION OF DRAWINGS

[0034] The above and / or other aspects of the present application will become apparent and more readily appreciated from the following description, taken in conjunction with the accompanying drawings, in which:

[0035] Figure 1 Effect of gallic acid on body weight of acute OIPN model mice;

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

[0037] Figure 3 Effect of gallic acid on cold pain score of acute OIPN model mice.

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

[0039] The application will be further described below in conjunction with the drawings and specific examples.

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

[0041] Example 1 Protective effect of gallic acid 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 pain meter, Plantar Test (Hargreaves method) Glass stands, Hot Cold Plate Analgesia Meter for Mice and Rats were purchased from IITC (IITC Inc. Life Science, Woodland Hills, CA, USA).

[0045] Experimental animals: male C57BL / 6 mice, weighing 18-22 g, 6-8 weeks old, clean grade, purchased from Shanghai Slek Experimental Animal Center, and raised in the SPF level experimental animal room of Jiangsu Province Institute of Traditional Chinese Medicine. The experimental temperature was controlled at 25±1℃, and the animals were allowed to drink water and eat animal feed freely. The experiment started after one week of feeding.

[0046] 2. Experimental methods:

[0047] (1) The experimental animals were randomly divided into four groups: 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] Control group (Control): intraperitoneal injection of 5% glucose injection on the first day;

[0049] Oxaliplatin group (OXA): intraperitoneal injection of 6mg / kg oxaliplatin to induce acute neurotoxicity in mice on the first day, except for the control group, which was intraperitoneally injected with the same volume of 5% glucose injection.

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

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

[0052] (2) The first day of drug treatment was defined as Day 1, and the mouse body weight was measured on days 0, 3, and 6; the mouse behavior was measured on days 0, 1, 3, and 6 (mouse mechanical pain test and mouse cold pain test).

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

[0054] (B) Mouse mechanical pain test: referring to the method of Meng Zhao et al. [K.I. Meng Zhao, et al. Acute cold hypersensitivity characteristically induced by oxaliplatin is caused by the enhanced responsiveness of TRPA1 in mice, Molecular Pain. 8 (2012) 55], the mechanical paw withdrawal threshold (von Frey test) was used to evaluate the mechanical pain hypersensitivity of the mice. The mice were placed in a (20*17*13 cm) organic glass box, and the bottom of the mouse toe contact surface was a metal mesh. After the mice adapted to the measurement box environment for 5 minutes, the mouse foot center was stimulated vertically with a von Frey fiber filament, and the electronic display stress value was recorded after the mouse showed a withdrawal reaction.

[0055] (C) Mouse cold pain test: before measurement, the mice were placed in the measurement environment for 30 minutes, and during detection, the mice were placed on a cold plate at 4°C in a transparent organic glass box. The measurement time was 60 s, and the escape behavior of the mice was recorded and scored during the measurement time: 0 points = no reaction; 1 point = mild cold escape reaction, such as lifting the hind foot or walking backward; 2 points = strong cold escape reaction, such as jumping up, etc. The total score within 60 s of measurement time was recorded.

[0056] 3. Experimental results:

[0057] Results are shown in Figure 1 , Figure 2 , Figure 3 According to the figures, it can be seen that:

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

[0059] (B) Effect on the mechanical pain sensation of mice: As shown in Figure 2 , the mechanical withdrawal threshold of mice in the blank control group tended to be stable during the measurement. On the sixth day after administration of oxaliplatin, the mechanical 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 showed a dose-dependent alleviation of the decrease in mechanical pain threshold caused by oxaliplatin, and 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) Effect on the cold pain sensation of mice: Before the experiment, the mice in each group were not sensitive to cold pain. As shown in Figure 3 , on the sixth day after administration of oxaliplatin, the cold pain score of mice in the oxaliplatin group was significantly increased compared with the blank control group (P < 0.01); compared with the oxaliplatin group, gallic acid showed a dose-dependent alleviation of the cold pain sensation caused by oxaliplatin, and the low-dose gallic acid group significantly reduced the increase in cold pain score of mice caused by oxaliplatin (P < 0.05), and the high-dose gallic acid group significantly reduced the increase in cold pain score of mice caused by oxaliplatin (P < 0.01). This indicates that gallic acid can reduce the cold pain sensation 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 mechanical pain and cold pain sensitivity of mice, and gallic acid had a protective effect on the peripheral nerve injury of mice caused by oxaliplatin. Two-way ANOVA was used for analysis, 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 blank control group.

[0062] The application provides a thought and a method for application of gallic acid in preparation of a medicine for preventing or treating peripheral neuropathy. The method and approach for specifically realizing the technical scheme are various, and the above description is only a preferred embodiment of the application. It should be noted that, for ordinary skilled in the art, several improvements and refinements can be made without departing from the principle of the application, and the improvements and refinements should also be regarded as the protection scope of the application. The components not explicitly described in the embodiment can be realized by using the prior art.

Claims

1. Use of gallic acid in the preparation of a medicament for preventing or treating peripheral neuropathy, wherein the peripheral neuropathy is acute peripheral neuropathy; the acute peripheral neuropathy is acute peripheral neuropathy induced by a chemotherapeutic drug; and the chemotherapeutic drug is cancer chemotherapeutic drug oxaliplatin.

2. Use according to claim 1, characterized in that, The medicament comprises a chemotherapeutic drug composition, wherein the chemotherapeutic drug composition comprises a cancer chemotherapeutic drug and gallic acid; and the cancer chemotherapeutic drug is oxaliplatin.

3. Use according to any one of claims 1-2, characterized in that, The medicament is prepared by combining gallic acid as an active ingredient with one or more pharmaceutically acceptable solid or liquid adjuvants into any dosage form.

4. Use according to claim 3, characterized in that, The liquid adjuvant is normal saline or ultrapure water.

5. Use according to claim 3, characterized in that, The dosage form is any one of emulsion, suspension, injection or transdermal preparation.

6. Use according to any one of claims 1 to 2, characterized in that, The medicament is administered by any one of intraperitoneal, oral, sublingual, subcutaneous, intravenous or intramuscular administration.

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