Application of liquiritin in the preparation of drugs for preventing or treating chemotherapy-related atrial fibrillation

Abstract

The present invention discloses the use of liquiritin in the preparation of a drug for preventing or treating chemotherapy-related atrial fibrillation. The chemotherapy-related atrial fibrillation described in the present invention is atrial fibrillation induced by the chemotherapy drug oxaliplatin. Liquiritin has a protective effect against oxaliplatin-induced atrial fibrillation in rats. The drug liquiritin of the present invention can be used as an adjuvant for chemotherapy drugs in cancer treatment, exhibits a certain anti-cancer effect, and significantly improves chemotherapy-related atrial fibrillation.

Description

Technical Field

[0001] The present invention relates to pharmaceutical application technology, and in particular to the application of liquiritin in the preparation of a drug 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 a complex health dilemma: the threat of cancer remains, cardiovascular disease strikes, and the cardiac toxicity of chemotherapy drugs persists. [1,2] .

[0004] Under this background, the patient's heart may undergo structural remodeling. Compensatory hypertrophy of myocardial cells leads to necrosis and apoptosis; proliferation of myocardial fibrous connective tissue leads to fibrosis, which reduces myocardial compliance; myocardial blood supply is blocked and ischemia occurs, which weakens the pumping function; cardiac cavity expansion and inflammatory response 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; 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 who receive cancer chemotherapy and have structural heart disease to frequently experience arrhythmias several years after the end of chemotherapy, with atrial fibrillation 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 the risk of serious complications such as heart failure and thromboembolism is increased, making survival increasingly difficult. Faced with difficulties, modern medicine has limited treatment options. When traditional anti-arrhythmic 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 ideal therapeutic effects. [8] .

[0006] In comparison, traditional Chinese medicine, with its unique concepts and natural medicinal resources, has opened up new paths to solve arrhythmias caused by chemotherapy drugs. Many Chinese herbal ingredients have demonstrated cardioprotective effects. [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 treatment gap 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 address the deficiencies in the prior art and to provide an application of liquiritin in the preparation of a drug for preventing or treating atrial fibrillation associated with the chemotherapy drug oxaliplatin.

[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 structure of the liquiritin (CAS No: 551-15-5) is 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 associated with the chemotherapy drug oxaliplatin include increased incidence and duration of atrial fibrillation, accompanied by palpitations, chest tightness, dizziness, fatigue, and in severe cases, dyspnea, chest pain, and even serious consequences such as heart failure and thrombosis. In some embodiments, the clinical use dose 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 comprise: (i) liquiritin; and (ii) a cancer chemotherapy drug. Liquiritin is used as a chemotherapy drug adjuvant to prevent or treat atrial fibrillation induced 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] The administration of the drug includes intraperitoneal injection, oral administration, sublingual administration, subcutaneous injection, intravenous injection or intramuscular injection.

[0032] The dosage of liquiritin in the pharmaceutical composition is 316.3-632.6 mg / kg for humans and 20-40 mg / kg for rats, such as 25, 30, or 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 any of the aforementioned cancers while also preventing and / or treating atrial fibrillation caused by cancer chemotherapy drugs.

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

[0039] The dosage of liquiritin in the pharmaceutical composition is 316.3-632.6 mg / kg for humans and 20-40 mg / kg for rats, such as 25, 30, or 35 mg / kg.

[0040] Beneficial effects:

[0041] This 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 relevant research model, liquiritin has demonstrated an ameliorative effect on symptoms associated with oxaliplatin-induced atrial fibrillation. The drug, liquiritin, can be used as an adjuvant for chemotherapy drugs in 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 below in conjunction with the accompanying drawings and specific embodiments, and the above and / or other advantages of the present invention will become more apparent.

[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 The effects 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 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 Liquiritin has a protective effect on oxaliplatin-induced atrial fibrillation in rats

[0050] 1. Experimental Materials

[0051] Test 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.), pathology slicer (Shanghai Leica Instrument Co., Ltd.), tissue spreader (Jinhua Kedi Instrument Equipment Co., Ltd., Zhejiang Province).

[0053] Experimental animals: Male Sprague-Dawley rats, weighing 220-250 g, aged 6-8 weeks, SPF grade, were purchased from Sibeifu (Suzhou) Biotechnology Co., Ltd. and housed in the SPF-grade experimental animal room of the Jiangsu Institute of Traditional Chinese Medicine. The experimental temperature was controlled at 25 ± 1°C, with free access to water and animal feed. Experiments were conducted 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), respectively as follows:

[0056] Vehicle group: daily gavage of equal volume of corn oil for 5 weeks; intraperitoneal injection of equal volume of 5% glucose twice a week starting from the second week for 4 weeks;

[0057] OXA group: daily gavage of an equal volume of corn oil for 5 weeks; starting from the second week, intraperitoneal injection of OXA solution (4 mg OXA / kg) was given 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 4 mg OXA / kg of OXA solution twice a week starting from the second week for 4 weeks;

[0059] LIQ H +OXA group: mice were gavaged with 40 mg liquiritin / kg of liquiritin solution daily for 5 weeks; and 4 mg OXA / kg of OXA solution was intraperitoneally injected twice a week from the second week onwards for 4 weeks.

[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 esophageal pacing to observe the susceptibility to atrial fibrillation in rats. After anesthetizing the rats with isoflurane, the rats were fixed on the operating table, and their lead II electrocardiograms were recorded through electrodes and a biosignal 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 the catheter 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 stimulations, each lasting 30 seconds. The criteria for determining whether atrial fibrillation occurred 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 calculated.

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

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

[0064] 3. Experimental Results

[0065] The results are as follows Figure 1 、 Figure 2 、 Figure 3 As shown in the figure, we can see that:

[0066] (A) Effects on rat body weight: Figure 1 As shown, the weight of the rats in the control group increased over time. However, the rats in the oxaliplatin group showed a significant weight loss one week after oxaliplatin administration due to the stimulation of oxaliplatin, and this weight loss persisted until the end of the drug administration (**P<0.01). After four weeks of liquiritin administration, the high-dose liquiritin group significantly alleviated the weight loss caused by oxaliplatin compared to the oxaliplatin group, and this effect persisted until the end of the drug 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-treated group showed irregular arrangement, swelling, ruptured interstitial hemorrhage, and extensive inflammatory cell infiltration. Atrial fibrosis and collagen deposition increased, with the relative fibrosis area increasing to 196.32% (**P<0.01) and the relative collagen area increasing to 172.60% (**P<0.01). After liquiritin administration, myocardial cell damage, atrial fibrosis, and collagen deposition were significantly improved, with the relative fibrosis area decreasing 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 decreasing to 125.05% of the low-dose liquiritin group and even 90.6% of the high-dose liquiritin group (##P<0.01). This suggests that liquiritin can ameliorate oxaliplatin-induced atrial pathological remodeling in rats.

[0068] (C) Effects on susceptibility to atrial fibrillation in rats: Figure 3 The above figure is a typical example of the atrial fibrillation susceptibility test of rats in each group after four weeks of oxaliplatin administration and at the end of the experiment by induced atrial fibrillation through esophageal pacing. Figure 3 As can be seen, AF was not induced in the control rats, while 54.55% of the rats developed AF after oxaliplatin administration. After 5 weeks of liquiritin administration, the AF induction rate in rats was significantly reduced. Low-dose liquiritin reduced the AF induction rate to 45.45%, while high-dose liquiritin reduced the AF induction rate to 27.27%. Compared with the control rats, the average duration of AF in the oxaliplatin-treated rats was 40.64 seconds (**P < 0.01). After liquiritin administration, the average duration of AF was reduced to 12.18 seconds in the low-dose liquiritin group and even to 1.91 seconds in the high-dose liquiritin group (#P < 0.05). These results indicate that liquiritin can reduce the increased susceptibility to AF induced by oxaliplatin in rats.

[0069] In summary, in the oxaliplatin-induced rat atrial fibrillation model, atrial fibrosis and collagen deposition were significant, and the inducibility and duration of atrial fibrillation were significantly increased. However, pre-administration of liquiritin alleviated atrial fibrosis and collagen deposition in rats, significantly reducing atrial fibrillation susceptibility. In other words, liquiritin reduced the increased susceptibility to atrial fibrillation induced by oxaliplatin in rats.

[0070] The present invention provides a method and concept for the use of liquiritin in the preparation of a drug for preventing or treating chemotherapy-related atrial fibrillation. There are numerous methods and approaches for implementing this technical solution. The foregoing description is merely a preferred embodiment of the present invention. It should be noted that those skilled in the art may make various improvements and modifications without departing from the principles of the present invention, and such improvements and modifications are also within the scope of protection of the present invention. Any components not specified in this embodiment may be implemented using existing technologies.

Claims

1. The use of liquiritin in the preparation of a drug for preventing and treating atrial fibrillation caused by chemotherapy drugs, characterized in that: The chemotherapy drug is the cancer chemotherapy drug oxaliplatin; the mass ratio of the liquiritin to oxaliplatin is 21.9-43.8:1.

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