WO2020186683A1 - Application de quercétine dans la préparation d'un médicament pour la prévention et le traitement d'une lésion hépatique induite par un médicament - Google Patents

Application de quercétine dans la préparation d'un médicament pour la prévention et le traitement d'une lésion hépatique induite par un médicament Download PDF

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WO2020186683A1
WO2020186683A1 PCT/CN2019/098902 CN2019098902W WO2020186683A1 WO 2020186683 A1 WO2020186683 A1 WO 2020186683A1 CN 2019098902 W CN2019098902 W CN 2019098902W WO 2020186683 A1 WO2020186683 A1 WO 2020186683A1
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quercetin
acetaminophen
drug
liver injury
preparation
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Chinese (zh)
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陈阿丽
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Guangdong Pharmaceutical University
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Guangdong Pharmaceutical University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics

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  • the invention belongs to the technical field of biomedicine, and relates to the medical use of quercetin in the protection and treatment of drug-induced acute liver injury, and in particular to the application of quercetin in the preparation of drugs for the protection and treatment of liver injury caused by acetaminophen.
  • Drug-induced liver injury refers to the direct toxicity of the drug itself or its metabolites to the liver after the human body is exposed to conventional or high-dose drugs, or the human body is allergic to the drug or its metabolites. Liver damage caused by metabolic idiosyncratic reactions.
  • Acetaminophen also known as paracetamol and N-acetaminophen, is a widely used clinical analgesic.
  • APAP can cause a transient increase in serum aminotransferase, especially in people with malnutrition, liver dysfunction, alcoholism, or taking certain CYP450-inducing drugs.
  • ALF acute liver failure
  • UDP-glucuronyl transferase UDP-glucuronyl transferase
  • SULT sulfotransferase
  • APAP undergoes liver metabolism through different pathways, namely cytochrome P450 enzymes (CYP450), mainly CYP2E1 and to a lesser extent CYP1A2, CYP2A6 and CYP3A4 metabolism, forming a highly active toxic intermediate
  • CYP450 cytochrome P450 enzymes
  • CYP2E1 mainly CYP2E1
  • CYP1A2A6 mainly CYP2A6
  • CYP3A4 cytochrome P450 enzymes
  • NAPQI N-acetyl-p-benzoquinone imine
  • GSH sulfhydryl group of glutathione
  • NAPQI mitochondrial oxidative stress and dysfunction
  • ETC mitochondrial electron transport chain
  • ROS Oxygen
  • N-acetylcysteine is the only detoxification drug approved by the FDA in 2011 for the treatment of intrinsic DILI caused by acetaminophen.
  • acetylcysteine has a short half-life and is only effective for early treatment.
  • excessive use of paracetamol and NAC within 8-12 hours have a good effect.
  • the main adverse reactions are skin rash, nausea, vomiting, and fever. Therefore, its therapeutic effect is not ideal.
  • Another main reason is that the mechanism of acetaminophen causing liver damage is very complicated. In view of this, it is very urgent and necessary to research and develop drug-induced liver injury drugs with good therapeutic effects.
  • Quercetin (quercetin, 3,3′,4′,5,7-pentahydroxyflavone) and its derivatives are the most widely distributed flavonoids in the plant kingdom. They are widely found in the flowers, leaves and fruits of plants. The most important bioflavonoid in the human diet has many functions such as dilating blood vessels, lowering blood pressure, preventing coronary heart disease, preventing myocardial ischemia/reperfusion injury, and anti-thrombosis. In addition, quercetin also has a powerful antioxidant The biological activity of the toxic free radicals can quench the toxic free radicals and form resonance stable phenoxy free radicals, which can protect and treat liver oxidative damage.
  • quercetin As a natural medicine that is non-toxic and non-triadic to the human body, quercetin has good antioxidant activity in vivo and in vitro and is expected to be used in clinical treatment of a series of diseases related to oxidation. In view of this, the inventor of the present application will provide the use of quercetin in the preparation of a drug for the protection and treatment of acetaminophen-induced drug-induced acute liver injury.
  • the purpose of the present invention is to overcome the shortcomings of the prior art and provide new medical uses of quercetin in the protection and treatment of drug-induced acute liver injury, and specifically relates to the preparation of quercetin in the protection and treatment of liver injury caused by acetaminophen Application in medicine.
  • quercetin in the preparation of drugs for protecting and treating drug-induced liver injury, and the structural formula of quercetin is:
  • the present invention adopts BABL/C mouse intraperitoneal injection of paracetamol to induce acute liver injury model, and its pathogenesis is similar to that of the clinic.
  • the experimental results show that quercetin can significantly weaken paracetamol-induced liver function related biochemical indicators Gu C
  • ALT aminotransferase
  • AST aspartate aminotransferase
  • Figure 2 The abnormal increase of aminotransferase (ALT) and aspartate aminotransferase (AST) (as shown in Figure 1), and the pathological results were significantly improved (as shown in Figure 2);
  • Quercetin can significantly improve the liver tissue lesions induced by acetaminophen ( As shown in Figure 3), and dose-dependent; at the same time, quercetin also significantly increased the liver antioxidant glutathione (GSH) content (as shown in Figure 4).
  • GSH liver antioxidant glutathione
  • quercetin in the preparation of acetaminophen-induced liver injury drugs, its protective and therapeutic mechanism is that quercetin can effectively resist the oxidative liver injury of acetaminophen, and reduce AST and ALT Activity, improve the liver's antioxidant capacity, protect liver cells from oxidative stress damage and fight against the powerful oxidation of acetaminophen intermediate metabolite N-acetyl-p-benzoquinone imine (NAPQI), mainly through oxidative stress Affect the liver toxicity of acetaminophen to exert its protective and therapeutic effects on liver injury.
  • NAPQI N-acetyl-p-benzoquinone imine
  • the quercetin is an oral preparation or an injection preparation.
  • the dosage of quercetin can be administered according to the patient's age, weight, intake of acetaminophen, and treatment schedule.
  • the recommended dosage for humans is 40 mg/kg/d.
  • the quercetin is administered orally or by injection, and oral administration is recommended.
  • the present invention provides a new use of quercetin in the preparation of drugs for protecting medicinal acute liver injury, especially the use of quercetin in preparing drugs for protecting paracetamol-induced medicinal liver injury; Quercetin It can effectively resist the liver damage caused by acetaminophen, and can be used to prepare therapeutic drugs for liver damage caused by acetaminophen, which provides patients with better choices;
  • Quercetin is derived from natural products, has simple preparation steps, low cost, low pollution, and is conducive to large-scale production. As a natural medicine that is non-toxic and has no triple effect on the human body, quercetin has a good body Internal and external antioxidant activity, it is expected to develop drugs for clinical treatment of liver injury caused by drugs;
  • the oral administration of the present invention can exert significant curative effect. On the one hand, safety is improved, and on the other hand, the pain caused by injection administration is reduced.
  • Figure 1 shows the abnormal biochemical indicators of liver function in BABL/C mice induced by acetaminophen.
  • BABL/C mice induced acute liver injury after intraperitoneal injection of 300 mg/kg acetaminophen.
  • the serum AST showed a significant increase trend after acetaminophen was given for 2 hours (*p ⁇ 0.05), while ALT showed a better and significant difference at 4 hours (**p ⁇ 0.01), and the subsequent AST and ALT continued to increase.
  • Figure 2 shows that quercetin protects the abnormalities of acetaminophen-induced liver function-related biochemical indicators in BABL/C mice.
  • NAC N-acetylcysteine
  • quercetin 100mg/kg, 200mg/kg, 400mg/kg
  • the AST and ALT of each treatment group are obvious Decrease, NAC, ***p ⁇ 0.001; Que (100mg/kg), ALT*p ⁇ 0.05, AST***p ⁇ 0.001; Que (200mg/kg, 400mg/kg), ***p ⁇ 0.001.
  • Figure 3 shows that the quercetin treatment group attenuated acetaminophen-induced liver damage, in which H&E staining is shown.
  • FIG. 4 shows that quercetin treatment significantly improved the content of glutathione GSH in the liver.
  • Acetaminophen in the following examples was purchased from Dalian Meilun Biological Technology Co., Ltd, with a purity greater than 98.5%, dissolved in sterile PBS, and dissolved in a 40 degree water bath; Quercetin and acetylcysteine were purchased from Sigma -Aldrich; The experimental animals were purchased from SPF male C57BL/6 mice weighing 18-22g from the Experimental Animal Center of Southern Medical University. The feeding conditions of the mice are temperature 23 ⁇ 2°C, humidity 55 ⁇ 5% and 12h sunshine, and they are given diet and water that meet rodent feeding standards.
  • mice 6-8 weeks adaptively fed for 3 days, divided into acetaminophen 0h group, acetaminophen 2h group, acetaminophen 4h group, and acetaminophen 6h group , Paracetamol group for 8 hours, fasting for 12 hours before the experiment, intraperitoneal injection of paracetamol 300mg/kg, from time 0, the mice of the corresponding group were killed every 2 hours, blood was taken, and left at room temperature for 1 hour. Centrifuge at 4500 rpm for 15 minutes, take the supernatant, the serum, and perform ALT and AST tests.
  • mice were fasted for 12 hours before the experiment and were divided into normal control group, model group (APAP, 300mg/kg), quercetin administration group (100mg/kg, 200mg/kg and 400mg/kg) and positive drugs
  • APAP 300mg/kg
  • quercetin administration group 100mg/kg, 200mg/kg and 400mg/kg
  • positive drugs In the treatment group (NAC, 300mg/kg), quercetin and positive drug NAC were given intraperitoneal injection of acetaminophen 300mg/kg 2-4 hours before intraperitoneal administration, and sacrificed 24 hours later.
  • ALT and AST test results show that quercetin can significantly reduce the abnormal rise of ALT and AST in mice serum induced by acetaminophen; compared with the positive drug NAC, 200mg/kg of quercetin is comparable to it Therapeutic effect.
  • the 400mg/kg quercetin treatment group showed significantly lower AST and ALT compared with positive NAC (##p ⁇ 0.01), showing a better effect than the positive drug (as shown in Figure 2).
  • liver tissues of mice were fixed overnight in 4% paraformaldehyde, sliced with paraffin embedded and then stained with H&E. The pathological structure was observed and photographed with a microscope. The experimental results showed that quercetin can significantly improve acetaminophen The induced liver tissue lesions are dose-dependent, and the therapeutic effect of 400 mg/kg quercetin is even better than that of the positive drug (as shown in Figure 3).
  • liver tissue of the mouse Weigh an appropriate 50 mg of liver tissue of the mouse, add physiological saline according to 1:9, homogenize, centrifuge at 10,000 rpm to take the supernatant, and determine the liver tissue GSH.
  • the results show that it is compared with the model group quercetin Supplement can significantly increase the content of GSH in the liver, thereby increasing the antioxidant capacity and achieving the detoxification effect (as shown in Figure 4).

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une utilisation médicale de la quercétine dans la prévention et le traitement d'une lésion hépatique aiguë induite par un médicament, et en particulier, une application de la quercétine dans la préparation d'un médicament pour la prévention et le traitement d'une lésion hépatique provoquée par l'acétaminophène. Des expériences menées sur des animaux prouvent que la quercétine régule une élévation anormale d'indicateurs biochimiques associés à des fonctions hépatiques induites par l'acétaminophène et des changements de structures pathologiques, et augmente la teneur en GSH antidote in vivo dans un tissu hépatique à lésion induite par l'acétaminophène ; la quercétine est une préparation orale ou une préparation pour injection, le dosage d'administration peut être changé en fonction de l'âge, du poids, de la quantité prise d'acétaminophène, de l'agencement d'un cours de traitement et similaire d'un patient ; un dosage d'administration recommandé pour une personne est de 40 mg/kg/j, et un mode d'administration orale est recommandé ; la quercétine peut résister efficacement à une lésion hépatique provoquée par l'acétaminophène, et peut être utilisée pour préparer un médicament pour traiter une lésion hépatique provoquée par l'acétaminophène.
PCT/CN2019/098902 2019-03-18 2019-08-01 Application de quercétine dans la préparation d'un médicament pour la prévention et le traitement d'une lésion hépatique induite par un médicament Ceased WO2020186683A1 (fr)

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CN201910204043.4 2019-03-18
CN201910204043.4A CN109864987A (zh) 2019-03-18 2019-03-18 槲皮素在制备保护和治疗药物性肝损伤的药物中的应用

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Publication number Priority date Publication date Assignee Title
CN118903101A (zh) * 2024-07-29 2024-11-08 哈尔滨医科大学 二氢槲皮素防治三氧化二砷诱导的心脏毒性的新用途

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CN109864987A (zh) * 2019-03-18 2019-06-11 广东药科大学 槲皮素在制备保护和治疗药物性肝损伤的药物中的应用
CN113209077A (zh) * 2021-05-15 2021-08-06 西北农林科技大学 槲皮素类化合物在保护丙烯酰胺引起的肝毒性中的应用
CN118662535B (zh) * 2024-05-17 2025-04-04 广东药科大学 青春双歧杆菌及其代谢物在制备改善肝损伤药物中的应用

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CN105998101A (zh) * 2016-06-22 2016-10-12 中央民族大学 维药斯米孜·欧提提取物在制备肝保护药物和保健品中的应用
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Publication number Priority date Publication date Assignee Title
CN118903101A (zh) * 2024-07-29 2024-11-08 哈尔滨医科大学 二氢槲皮素防治三氧化二砷诱导的心脏毒性的新用途

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