Application of liquiritin in preparation of medicine for preventing or treating chemotherapy medicine related atrial fibrillation

Abstract

The invention discloses an application of liquiritin in preparation of a medicine for preventing or treating atrial fibrillation related to chemotherapeutics. The chemotherapeutic drug related atrial fibrillation disclosed by the invention is atrial fibrillation caused by using a chemotherapeutic drug oxaliplatin. The liquiritin has a protection effect on oxaliplatin-induced atrial fibrillation of rats. The medicine liquiritin disclosed by the invention can be used as an adjuvant of a chemotherapy medicine for cancer treatment, has a certain cancer inhibition effect, and has a remarkable improvement effect on atrial fibrillation related to chemotherapy.

Description

Technical Field

[0001] The present invention relates to pharmaceutical application technology, and in particular to the application of liquiritin in the preparation of drugs for preventing and / or treating atrial fibrillation associated with chemotherapy drugs. Background Art

[0002] This section merely provides background information related to the present disclosure and is not necessarily prior art.

[0003] In the modern tumor treatment system, traditional chemotherapy drugs are an important means of fighting cancer and are widely used in the clinical treatment of various types of cancer, bringing hope of survival to patients. However, the adverse reactions caused by them, especially cardiovascular adverse reactions, have become a key problem that restricts the effectiveness of chemotherapy and affects the prognosis of patients, and have attracted much attention from the international medical community. At present, the aging population has increased the incidence of cancer, and the modern lifestyle has given rise to cardiovascular risk factors such as hypertension and hyperlipidemia. In addition, advances in cancer treatment technology have improved the survival rate of patients. Recovered cancer patients often fall into complex health dilemmas: the threat of cancer remains, cardiovascular disease strikes, and the cardiac toxicity of chemotherapy drugs persists. [1,2] .

[0004] In this context, the patient's heart may undergo structural remodeling. Compensatory hypertrophy of myocardial cells leads to necrosis and apoptosis; hyperplasia of myocardial fiber connective tissue leads to fibrosis, which reduces myocardial compliance; myocardial blood supply is blocked and ischemia occurs, weakening the pumping function; cardiac chambers expand and inflammatory reactions are rampant. [3] These changes work together to form a permanent arrhythmogenic substrate, like a "time bomb" hidden in the heart. Once the substrate is formed, the electrophysiological conduction of the heart is disrupted. Intracardiac conduction is blocked, the transmission of ECG signals slows down, and it is difficult for different parts of the heart to coordinate; the myocardial repolarization is uneven, and the recovery of the resting potential of myocardial cells in different regions is different, resulting in disordered cardiac electrical activity. [4] The combination of these two factors causes patients with structural heart disease who receive cancer chemotherapy to suffer from frequent arrhythmias several years after the end of chemotherapy, with atrial fibrillation (AF) being the most prominent. [5-7] .

[0005] At present, most of the commonly used anti-cancer drugs in clinical practice and the emerging preparations under development are difficult to avoid cardiac risks. Among the adverse cardiac reactions of chemotherapy drugs, arrhythmias, led by atrial fibrillation, are significant. Patients suffer from palpitations, chest tightness and other problems, and also increase the risk of serious complications such as heart failure and thromboembolism, making survival increasingly difficult. Faced with difficulties, modern medicine has limited treatment options. When traditional antiarrhythmic drugs are used in chemotherapy patients, because patients have to fight cancer and tolerate the toxic side effects of chemotherapy, they have poor tolerance and many adverse reactions, making it difficult to achieve the ideal therapeutic effect. [8] .

[0006] In comparison, traditional Chinese medicine, with its unique concepts and natural drug resources, has opened up new paths to solve arrhythmias caused by chemotherapy drugs. Many Chinese herbal medicine ingredients have demonstrated effects such as heart protection. [5,9,10] The present invention focuses on liquiritin, a natural flavonoid compound extracted from licorice. Previous studies have revealed its anti-inflammatory, antioxidant, and immunomodulatory biological activities. It has great potential in overcoming the problem of atrial fibrillation associated with chemotherapy drugs, and is expected to fill the gap in treatment and benefit chemotherapy patients. [11,12] .

[0007] References:

[0008] 1.Thompson R, Davis L, Wilson M. The impact of chemotherapy on cardiac function in cancer patients. Journal of Clinical Oncology. 2016.

[0009] 2.Abdul-Rahman T,Dunham A,Huang H,Bukhari SMA,Mehta A,Awuah WA,etal.Chemotherapy induced cardiotoxicity: a state of the art review on generalmechanisms,prevention,treatment and recent advances in noveltherapeutics.Current Problems in Cardiology.2023;48(4):101591.

[0010] 3.Aldhoon B, Melenovsky V, Peichl P, Kautzner J. New insights into intomechanisms of atrial fibrillation. Physiological Research. 2010; 59(1).

[0011] 4. Nattel S, Burstein B, Dobrev D. Atrial remodeling and atrial fibrillation: mechanisms and implications. Circulation: Arrhythmia and Electrophysiology. 2008; 1 (1): 62-73.

[0012] 5.Li W,Cheng X,Zhu G.A review of chemotherapeutic drugs-inducedarrhythmia and potential intervention with traditional Chinesemedicines.Frontiers in Pharmacology.2024.6.Pansa A,Riva P,Da RoitA.471Potential Role Of Neoadjuvant Radio-Chemotherapy On New-Onset AtrialFibrillation After Hybrid Ivor-Lewis Esophagectomy For Cancer.Diseases of theEsophagus.2020.

[0013] 7.Xu QQ,Han SJ,Wei XH,You LZ,Sun LC,Shang HC.Risk factors forarrhythmias occurred in cancer patients after chemotherapy:An evidence-basedsystematic review and meta-analysis.Heliyon.2024.

[0014] 8.Al-Hasnawi Z,Hasan HM,Azeez JMA,Kadhim N,Shimal AA,Sadeq MH,etal.Cardioprotective strategies in the management of chemotherapy-inducedcardiotoxicity:current approaches and future directions.Annals of Medicineand Surgery.2024;86(12):7212-7220.

[0015] 9.Zhou M,Wang W,Weng J,Lai Z.A Review on Probable Causes ofCardiotoxicity Caused by Common Cancer Drugs and the Role of TraditionalChinese Medicine in Prevention and Treatment.Pharmacogenomics andPersonalized Medicine.2023;1067-1077.

[0016] 10.Najiha Othman SN,Lum PT,Gan SH,Mani S,Sekar M.Protective effect ofnatural products against chemotherapy-induced cardiotoxicity:areview.Pharmacognosy Journal.2020;12(5):1180-1189.

[0017] 11.Mou SQ,Zhou ZY,Feng H,Zhang N,Lin Z,Aiyasiding X,et al.Liquiritinattenuates lipopolysaccharides-induced cardiomyocyte injury via an AMP-activated protein kinase-dependent signaling pathway.Frontiers inPharmacology.2021;12:648688.

[0018] 12.Chen Z,Liu YJ,Yu B,Li W,Zhang M,Wu X,et al.Liquiritin attenuatespathological cardiac hypertrophy by activating the PKA / LKB1 / AMPKpathway.Frontiers in Pharmacology.2024;13:870699.

[0019] 13.Han Summary of the invention

[0020] Purpose of the invention: The technical problem to be solved by the present invention is to provide an application of liquiritin in the preparation of a drug for preventing or treating atrial fibrillation associated with the chemotherapy drug oxaliplatin in view of the deficiencies in the prior art.

[0021] In order to solve the above technical problems, the present invention discloses the following technical solutions:

[0022] In a first aspect, the present invention discloses the use of liquiritin in the preparation of a drug for preventing and / or treating atrial fibrillation induced by chemotherapy drugs.

[0023] In the present invention, the liquiritin (CAS No: 551-15-5) has a structure as shown below:

[0024]

[0025] In the present invention, the atrial fibrillation is related atrial fibrillation caused during the use of chemotherapy drugs. In some embodiments, the chemotherapy drug is oxaliplatin (OXA), and the symptoms of atrial fibrillation related to the chemotherapy drug oxaliplatin include increased incidence and duration of atrial fibrillation, accompanied by palpitations, chest tightness, dizziness, fatigue, and in severe cases, dyspnea and chest pain may occur, and even lead to serious consequences such as heart failure and thrombosis. In some embodiments, the clinical dosage of the chemotherapy drug oxaliplatin is 85mg OXA / m 2 Repeat every 2 weeks or 130 mg OXA / m2 of body surface area 2 BSA was repeated every three weeks.

[0026] In a second aspect, the present invention discloses a pharmaceutical composition for preventing and / or treating cancer.

[0027] The pharmaceutical compositions all include: (i) liquiritin; and (ii) cancer chemotherapy drugs. Liquiritin is used as a chemotherapy drug adjuvant to prevent or treat atrial fibrillation caused by the chemotherapy drug oxaliplatin.

[0028] In some embodiments, the cancer chemotherapy drug is oxaliplatin.

[0029] In some embodiments, the mass ratio of liquiritin to oxaliplatin is 21.9-43.8:1.

[0030] The dosage form of the pharmaceutical composition includes any one of a solution, an emulsion, a suspension, an injection or a transdermal preparation.

[0031] Wherein, the administration method of the drug includes intraperitoneal injection, oral administration, sublingual administration, subcutaneous injection, intravenous injection or intramuscular injection.

[0032] Wherein, the dosage of liquiritin in the pharmaceutical composition is 316.3-632.6 mg / kg for human; 20-40 mg / kg for rat, such as 25, 30, 35 mg / kg.

[0033] Among them, the prevention and / or treatment of cancer specifically refers to the prevention and / or treatment of colorectal cancer, gastric cancer, breast cancer, ovarian cancer, pancreatic cancer or liver cancer, etc.; further, the pharmaceutical composition can prevent and / or treat atrial fibrillation caused by cancer chemotherapy drugs while preventing and / or treating any of the aforementioned cancers.

[0034] In a third aspect, the present invention discloses a pharmaceutical composition for preventing and / or treating atrial fibrillation, which uses glycyrrhizin as an active ingredient and is combined with one or more pharmaceutically acceptable solid or liquid adjuvants to prepare a drug in any dosage form for preventing or treating atrial fibrillation associated with the chemotherapy drug oxaliplatin.

[0035] In some embodiments, liquiritin is used as the sole active ingredient in combination with one or more pharmaceutically acceptable solid or liquid adjuvants to prepare a drug for preventing or treating atrial fibrillation associated with the chemotherapy drug oxaliplatin in any dosage form.

[0036] Wherein, the liquid auxiliary agent includes physiological saline or ultrapure water.

[0037] The dosage form of the pharmaceutical composition includes any one of a solution, an emulsion, a suspension, an injection or a transdermal preparation.

[0038] Wherein, the administration method of the drug includes intraperitoneal injection, oral administration, sublingual administration, subcutaneous injection, intravenous injection or intramuscular injection.

[0039] Wherein, the dosage of liquiritin in the pharmaceutical composition is 316.3-632.6 mg / kg for human; 20-40 mg / kg for rat, such as 25, 30, 35 mg / kg.

[0040] Beneficial effects:

[0041] The present invention proposes the use of liquiritin in the preparation of a drug for preventing and treating atrial fibrillation associated with the chemotherapy drug oxaliplatin. In a related research model, liquiritin shows an improvement effect on the symptoms associated with atrial fibrillation induced by oxaliplatin. The drug liquiritin of the present invention can be used as an adjuvant of chemotherapy drugs for cancer treatment, and has an alleviating effect on adverse reactions associated with atrial fibrillation caused by the chemotherapy drug oxaliplatin. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] 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.

[0043] Figure 1 The effect of liquiritin on body weight of rats with OXA-induced atrial fibrillation.

[0044] Figure 2 The effect of liquiritin on the pathological structure of atrial tissue in OXA rats.

[0045] Figure 3 This is the effect of liquiritin on the inducibility rate and duration of atrial fibrillation in OXA rats and representative figures of each group. DETAILED DESCRIPTION

[0046] The present invention can be better understood according to the following examples. However, it is easy for those skilled in the art to understand that the contents described in the examples are only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the claims.

[0047] The experimental methods described in the following examples are conventional methods unless otherwise specified; the reagents and materials described are commercially available unless otherwise specified.

[0048] In the following examples, the oxaliplatin (CAS No.: 61825-94-3) and the liquiritin (CAS No.: 515-15-5) were purchased from Taoshu Company.

[0049] Example 1 Licorice glycosides have a protective effect on oxaliplatin-induced atrial fibrillation in rats

[0050] 1. Experimental Materials

[0051] Experimental drugs: Oxaliplatin solution: Oxaliplatin was prepared with 5% glucose solution (final concentration was 2 mg / mL); Liquiritin solution: Liquiritin was prepared with corn oil (final concentration was 2.5 mg / mL).

[0052] Instruments: Powerlab multichannel physiological recorder (ADInstruments, Australia), gas anesthesia machine (MSS, UK), dehydrator (DIPATH, Italy), embedding machine (Wuhan Junjie Electronics Co., Ltd.), pathological slicer (Shanghai Leica Instrument Co., Ltd.), tissue spreader (Keddy Instrument Equipment Co., Ltd., Jinhua City, Zhejiang Province).

[0053] Experimental animals: Male SD rats, weighing 220-250g, 6-8 weeks old, SPF grade, purchased from Sibeifu (Suzhou) Biotechnology Co., Ltd., 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 they were free to drink water and eat animal feed. The experiment was carried out after one week of adaptive feeding.

[0054] 2. Experimental methods:

[0055] (1) The experimental animals were randomly divided into four groups: control group (Vehicle), oxaliplatin group (OXA), low-dose liquiritin group (LIQ L +OXA and high-dose liquiritin group (LIQ H +OXA), as follows:

[0056] Vehicle group: daily intragastric administration of an equal volume of corn oil for 5 weeks; from the second week onwards, intraperitoneal injection of an equal volume of 5% glucose twice a week for 4 weeks;

[0057] OXA group: daily intragastric administration of an equal volume of corn oil for 5 weeks; from the second week onwards, intraperitoneal injection of OXA solution 4 mg OXA / kg twice a week for 4 weeks;

[0058] LIQ L +OXA group: daily gavage of 20 mg liquiritin / kg of liquiritin solution for 5 weeks; intraperitoneal injection of OXA solution 4 mg OXA / kg twice a week from the second week onwards for 4 weeks;

[0059] LIQ H +OXA group: daily gavage of 40 mg of liquiritin / kg of liquiritin solution for 5 weeks; intraperitoneal injection of OXA solution 4 mg of OXA / kg twice a week for 4 weeks starting from the second week.

[0060] (2) Body weight: The body weight of rats was recorded at the same time point every 7 days.

[0061] (3) Determination of susceptibility to atrial fibrillation in rats: On the second day after the last oral administration, atrial fibrillation was induced in rats by transesophageal pacing to observe the susceptibility to atrial fibrillation in rats. After the rats were anesthetized with isoflurane, they were fixed on the operating table, and their lead II electrocardiograms were recorded through electrodes and a biological signal acquisition and processing system under the skin of the rats' limbs. A medical 5F10-grade coronary sinus electrode catheter was inserted into the atrium through the rat's esophagus. After it captured the atrial electrocardiogram, the stimulator parameters were set to 50Hz. After the rats recovered sinus rhythm, the next stimulation was performed, for a total of 5 times, each for 30 seconds. The criteria for determining whether atrial fibrillation occurred or not were as follows: ① The P wave disappeared and was replaced by an irregular f wave; ② The R-R interval was absolutely unequal. The induction rate and duration of atrial fibrillation were counted.

[0062] (4) Histopathological section staining: The heart tissue was fixed with 4% paraformaldehyde for 72 h and then dehydrated. The wax-soaked tissue was embedded in an embedding machine at 20°C. The paraffin block was cut into 4 μm-thick slices by a paraffin slicer, then unfolded and placed on a glass slide and baked in an oven. HE, Masson and Sirius red staining were used to observe the pathological changes of rat myocardial tissue.

[0063] (5) Data were analyzed using Graphpad Prism 8 and one-way ANOVA. *P<0.05, **P<0.01 for comparison between model group and control group; #P<0.05, ##P<0.01 for comparison between liquiritin group and model group.

[0064] 3. Experimental results

[0065] The results are as follows Figure 1 , Figure 2 , Figure 3 As shown, according to the diagram:

[0066] (A) Effects on rat body weight: Figure 1 As shown in the figure, the weight of the rats in the control group increased over time, and the rats in the oxaliplatin group showed a significant weight loss after one week of oxaliplatin administration due to the stimulation of oxaliplatin, and this phenomenon lasted until the end of the administration (**P<0.01). After four weeks of liquiritin administration, compared with the oxaliplatin group, the high-dose liquiritin group was able to significantly alleviate the weight loss caused by oxaliplatin, and this effect lasted until the end of the administration (#P<0.05 or ##P<0.01).

[0067] (B) Effects on the pathological structure of rat atrial tissue: After staining of longitudinal heart tissue sections, Figure 2As shown, compared with the control group, the atrial myocytes in the oxaliplatin group were irregularly arranged, the myocardial cells were swollen, the interstitial hemorrhage was broken, and a large number of inflammatory cells infiltrated. The atrial tissue fibrosis and collagen deposition increased, and the relative fibrosis area increased to 196.32% (**P<0.01), and the relative collagen area increased to 172.60% (**P<0.01); after the administration of liquiritin, the myocardial cell damage, atrial fibrosis and collagen deposition were significantly improved, and the relative fibrosis area could be reduced to 127.70% of the low-dose liquiritin group and even 82.11% of the high-dose liquiritin group (##P<0.01), and the relative collagen area could be reduced to 125.05% of the low-dose liquiritin group (##P<0.01) and even 90.6% of the high-dose liquiritin group (##P<0.01). This shows that liquiritin can improve the pathological remodeling of the atrial tissue in rats caused by oxaliplatin.

[0068] (C) Effects on susceptibility to atrial fibrillation in rats: Figure 3 The above figure is a typical example of the susceptibility of rats in each group to atrial fibrillation induced by transesophageal pacing after four weeks of oxaliplatin administration and at the end of the experiment. Figure 3 It can be seen that the rats in the control group failed to induce atrial fibrillation, while 54.55% of the rats induced atrial fibrillation after oxaliplatin administration. After 5 weeks of liquiritin administration, the atrial fibrillation induction rate of rats was significantly reduced. Low-dose liquiritin can reduce the atrial fibrillation induction rate of rats to 45.45%, while high-dose liquiritin can reduce the atrial fibrillation induction rate to 27.27%. Compared with the rats in the control group, the average duration of atrial fibrillation in the rats in the oxaliplatin group was 40.64s (**P<0.01). After liquiritin administration, the average duration of atrial fibrillation can be reduced to 12.18s in the low-dose liquiritin group and even 1.91s in the high-dose liquiritin group (#P<0.05). The above results show that liquiritin can reduce the increased susceptibility to atrial fibrillation in rats induced by oxaliplatin.

[0069] In summary, in the oxaliplatin-induced rat atrial fibrillation model, rat atrial fibrosis and collagen deposition were significant, and the induction rate and duration of atrial fibrillation were significantly increased, while pre-administration of liquiritin alleviated the atrial fibrosis and collagen deposition in rats, and the susceptibility to atrial fibrillation was significantly reduced. That is, liquiritin reduced the increased susceptibility to atrial fibrillation induced by oxaliplatin in rats.

[0070] The present invention provides a method and idea for the application of liquiritin in the preparation of drugs for preventing or treating atrial fibrillation related to chemotherapy drugs. 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 principles 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 by existing technologies.

Claims

1. Use of liquiritin in the preparation of a drug for preventing and / or treating atrial fibrillation induced by chemotherapy drugs, characterized in that: The chemotherapy drug is the cancer chemotherapy drug oxaliplatin.

2. A pharmaceutical composition for preventing and / or treating cancer, characterized in that: include: (i) Liquorice glycoside; (ii) a chemotherapeutic drug, wherein the chemotherapeutic drug is oxaliplatin.

3. The pharmaceutical composition according to claim 2, characterized in that: The dosage form of the pharmaceutical composition includes solution, emulsion, suspension, injection or transdermal preparation.

4. The pharmaceutical composition according to claim 2, characterized in that: The administration methods of the pharmaceutical composition include intraperitoneal injection, oral administration, sublingual administration, subcutaneous injection, intravenous injection or intramuscular injection.

5. The pharmaceutical composition according to claim 2, characterized in that: The dosage of liquiritin in the pharmaceutical composition is 316.3-632.6 mg / kg.

6. A pharmaceutical composition for preventing and / or treating atrial fibrillation, characterized in that: Licorice glycoside is used as an active ingredient and is combined with one or more pharmaceutically acceptable solid or liquid adjuvants.

7. The pharmaceutical composition according to claim 6, characterized in that: The dosage form of the pharmaceutical composition includes solution, emulsion, suspension, injection or transdermal preparation.

8. The pharmaceutical composition according to claim 6, characterized in that: The administration method of the pharmaceutical composition includes any one of intraperitoneal injection, oral administration, sublingual injection, subcutaneous injection, intravenous injection or intramuscular injection.

9. The pharmaceutical composition according to claim 6, characterized in that: The dosage of liquiritin in the pharmaceutical composition is 316.3-632.6 mg / kg.

Images