WO2023155327A1 - 降低脑内铁含量的药物在制备治疗和/或预防神经精神疾病药物中的应用 - Google Patents

降低脑内铁含量的药物在制备治疗和/或预防神经精神疾病药物中的应用 Download PDF

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WO2023155327A1
WO2023155327A1 PCT/CN2022/095270 CN2022095270W WO2023155327A1 WO 2023155327 A1 WO2023155327 A1 WO 2023155327A1 CN 2022095270 W CN2022095270 W CN 2022095270W WO 2023155327 A1 WO2023155327 A1 WO 2023155327A1
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drug
mice
medicine
iron
morphine
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French (fr)
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镇学初
颜鹏举
李宁宁
高树柳
史智峰
高瑞辰
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苏州大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse

Definitions

  • the invention belongs to the technical field of new uses of medicines, and in particular refers to the application of a medicine for reducing iron content in the brain in the preparation of medicines for treating and/or preventing neuropsychiatric diseases.
  • Drugs refer to natural, semi-synthetic or synthetic substances that can cause dependence, excite or inhibit the central nervous system, cause hallucinations, or damage motor functions, thoughts, behaviors, feelings, and emotions. Including opium, morphine, heroin, cocaine, amphetamine, methamphetamine (ice), etc.
  • Drug addiction also known as drug dependence, drug abuse, or substance use disorder, is a chronic relapsing brain disorder characterized by compulsive seeking and use of drugs.
  • Drug addiction also known as drug dependence, drug abuse, or substance use disorder, is a chronic relapsing brain disorder characterized by compulsive seeking and use of drugs.
  • the number of people who use drugs in the world is more than 300 million, of which more than 35 million are drug addicts. Drug-related deaths have increased by 17.5% over the past decade.
  • Vadadustat is a novel oral hypoxia-inducible factor prolyl hydroxylase inhibitor.
  • valdurestat can significantly improve renal anemia and increase the levels of erythropoietin and hemoglobin in patients with chronic kidney disease. At the same time, it can regulate iron metabolism by reducing hepcidin and increasing transferrin without serious adverse reactions, but its effect on drug or drug addiction or dependence has not been reported.
  • Deferiprone (Deferiprone/CP20/3-hydroxy-1,2-dimethyl-4-(1H)-pyridone) is an iron chelating agent that can remove iron ions in ferritin and hemosiderin for Treatment of acute iron poisoning and diseases caused by chronic iron accumulation. Deferiprone is mainly used clinically for the treatment of iron overloaded thalassemia patients who tolerate or are unwilling to accept the existing chelation therapy. Many studies have reported that it can alleviate iron deposition-related Parkinson's disease, Alzheimer's disease and oxidative stress damage caused by iron overload by complexing excess iron, but its effect on drug or drug addiction or dependence has not been seen. reports.
  • the present invention provides an application of a drug for reducing iron content in the brain in the preparation of drugs for the treatment and prevention of neuropsychiatric diseases.
  • the drug for reducing iron content in the brain is selected from valdustat and desferri Ketones, pointing the way to the provision of drugs for the prevention and/or treatment of drug or drug addiction.
  • the purpose of the present invention is to provide a strategy for preventing and treating drug or drug addiction by reducing the iron content in the brain through drugs or diet.
  • the present invention provides a new application of drugs or diets for reducing iron content in the brain in the prevention and treatment of drug or drug addiction or dependence.
  • the present invention provides the application of valdurestat, deferiprone and low-iron diet in the preparation of drugs for preventing and treating drug or drug addiction or dependence.
  • the medicine has preventive and therapeutic effects on drug or drug addiction or dependence by reducing the iron content in the brain.
  • the mental illness is a mental illness caused by drugs, drug addiction, or dependence.
  • the drug is morphine or methamphetamine.
  • the drug is a hypoxia-inducible factor prolyl hydroxylase inhibitor drug or an iron chelator drug.
  • hypoxia-inducible factor prolyl hydroxylase inhibitor drug is a compound represented by formula I or a pharmaceutically acceptable salt thereof, wherein the structure of formula I is:
  • the iron chelator drug is a compound represented by formula II or a pharmaceutically acceptable salt thereof, wherein the structure of formula II is:
  • the pharmaceutically acceptable salt includes one or more of inorganic acid salts, organic acid salts, alkylsulfonates and arylsulfonates.
  • the medicament for preventing and/or treating mental diseases further includes a pharmaceutically acceptable carrier.
  • the carrier is selected from one or more of disintegrating agents, diluents, lubricants, binders, wetting agents, flavoring agents, suspending agents, surfactants and preservatives Various.
  • the dosage form of the drug for preventing or/and treating mental diseases is tablet, capsule, soft capsule, granule, pill, oral liquid, emulsion, dry suspension, dry infusion ointment or injection.
  • the disintegrant is selected from corn starch, potato starch, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked carmellose sodium, carboxymethyl One or more of base cellulose, carboxymethyl cellulose calcium and alginic acid.
  • the lubricant is selected from one or more of micropowder silica gel, magnesium stearate, calcium stearate, stearic acid, talcum powder and anhydrous silica gel.
  • the binder is selected from one or more of gum arabic, gelatin, dextrin, hydroxypropylcellulose, methylcellulose and polyvinylpyrrolidone; the wetting agent selected from sodium lauryl sulfate; the flavoring agent can be one or more of aspartame, stevioside, sucrose, maltitol and citric acid.
  • the suspending agent is selected from one or more of gum arabic, gelatin, methylcellulose, sodium carboxymethylcellulose, hydroxymethylcellulose and aluminum stearate gel. multiple; the surfactant is selected from one or more of lecithin, sorbitan monooleate and glyceryl monostearate; the preservative is selected from methyl p-hydroxybenzoate or/ and propylparaben.
  • the present invention establishes the mouse brain iron deficiency model by continuously feeding mice with low-iron feed for 3-4 weeks, and then gives the mice intraperitoneal injection of methamphetamine (2mg/kg/day) to carry out the methamphetamine condition for mice for 4 days Place preference training was used to build a drug addiction model. After the training, the preference scores of the mice staying on the methamphetamine-drug side were detected. Significantly lower in the control group.
  • the invention establishes a mouse brain iron deficiency model by continuously feeding mice with low-iron feed for 3-4 weeks, and then gives mice an intraperitoneal injection of morphine (20mg/kg/day) to carry out 7-day morphine conditional place preference training on mice
  • morphine (20mg/kg/day)
  • mice an intraperitoneal injection of morphine (20mg/kg/day) to carry out 7-day morphine conditional place preference training on mice
  • the preference score of the mice staying on the morphine-drug side was detected, and it was found that the preference score of the mice in the low-iron diet-fed group to the morphine-drug side was significantly lower than that of the normal diet control group.
  • the present invention gives mice valdurestat (10mg/kg/day) by intraperitoneal injection every day, and gives mice morphine (20mg/kg/day) by intraperitoneal injection after 6 hours to carry out 7-day morphine condition place preference training for mice
  • mice valdurestat (10mg/kg/day) by intraperitoneal injection every day
  • mice morphine (20mg/kg/day) by intraperitoneal injection after 6 hours to carry out 7-day morphine condition place preference training for mice
  • a drug addiction model was constructed, and the preference score of the mice staying on the morphine-drug side was detected after the training. It was found that the administration of valdurestat could significantly reduce the preference score of the mice on the morphine-drug side.
  • the present invention gives mice 1 ⁇ L of 13 mg/mL deferiprone through a brain stereotaxic catheter (dorsal hippocampus), and then intraperitoneally injects mice with morphine (20 mg/kg/day) after 6 hours to carry out 7-day morphine treatment on mice.
  • morphine 20 mg/kg/day
  • Conditional place preference training was used to build a drug addiction model. After the training, the preference score of the mice staying on the morphine-drug side was detected. The results showed that administration of deferiprone could significantly reduce the preference score of the mice to the morphine-drug side.
  • a low-iron diet, deferiprone, and valdurestat all reduced brain iron levels and decreased morphine- and methamphetamine-induced conditioned place preference scores. Therefore, a drug or dietary formulation that lowers the iron content in the brain has a significant effect in the prevention and treatment of drug or drug addiction or dependence.
  • the existing drugs such as valdurestat and deferiprone that reduce the iron content in the brain can prevent the formation of addictive behaviors of morphine and methamphetamine after administration (eg, a low-iron diet, valdurestat 10 mg/kg/day, and deferiprone significantly reduced morphine- and methamphetamine-induced conditioned place preference scores).
  • opioids represented by methadone are addictive in the treatment of opioid addiction (such as: morphine, etc.), and improper use will lead to drug dependence.
  • opioid addiction such as: morphine, etc.
  • drugs that reduce iron content in the brain are not addictive in themselves during the treatment of drug addiction.
  • non-opioid addiction treatment drugs represented by clonidine may cause serious adverse reactions after long-term use.
  • the existing iron-lowering drugs (valdurestat and deferiprone, etc.) have good clinical tolerance and few adverse reactions, and no serious adverse events have been reported under reasonable dosages.
  • Fig. 1 is the effect diagram of the effect of the low-iron diet of the present invention on the iron content in the mouse brain;
  • Fig. 2 is the effect diagram of the effect of low-iron diet of the present invention on mouse methamphetamine addiction
  • Fig. 3 is the effect diagram of the effect of low-iron diet of the present invention on mouse morphine addiction
  • Fig. 4 is the effect diagram of the effect of valdurestat of the present invention on morphine addiction
  • Fig. 5 is a graph showing the effect of deferiprone of the present invention on morphine addiction.
  • the C57BL/6J mice used in the present invention were purchased from Shanghai Slack Experimental Animal Co., Ltd., and the low-iron feed used in the present invention was purchased from Jiangsu Synergy Biotechnology Co., Ltd.
  • mice Thirty-six male C57BL/6J mice (8 weeks old, weighing 22-25g) were fed in an SPF animal room, and after one week of adaptive feeding, they were randomly divided into a normal diet control group (3 mice) and a low-iron diet control group (3 mice). Only). The mice in the low-iron diet group were continuously fed with low-iron diet for 3-4 weeks, and the mice in the normal diet group were fed with normal diet.
  • the brain tissue of the mice was taken.
  • the tissue samples were placed in a polytetrafluoroethylene nitrification inner tank, and soaked overnight with 5 mL of nitric acid. Cover the inner cover, tighten the stainless steel jacket, put it into a constant temperature drying oven, continue at 80°C for 2h, 120°C for 2h, and 160°C for 4h, naturally cool to room temperature in the box, open and heat until the acid solution is nearly dry, and nitrate Aspirate the liquid into a 25mL volumetric flask, wash the inner tank and inner cover with a small amount of nitric acid solution (1%) for 3 times, combine the washing liquid into the volumetric flask and dilute to the mark with 1% nitric acid.
  • Iron content was determined by inductively coupled plasma mass spectrometry (ICP-MS).
  • the C57BL/6J mice used in the present invention were purchased from Shanghai Slack Experimental Animal Co., Ltd., and the low-iron feed used in the present invention was purchased from Jiangsu Synergy Biotechnology Co., Ltd.
  • mice Thirty-six male C57BL/6J mice (8 weeks old, weighing 22-25g) were raised in an SPF grade animal room, and after adaptive feeding for 1 week, they were randomly divided into normal diet + normal saline control group (11 mice), normal diet + A methamphetamine group (13 rats), low iron diet + normal saline control group (13 rats), low iron diet + methamphetamine group (12 rats).
  • the mice in the low-iron diet group were continuously fed with low-iron diet for 3-4 weeks, and the mice in the normal diet group were fed with normal diet.
  • the mice in the control group were injected with normal saline intraperitoneally, and the mice in the methamphetamine group were injected with methamphetamine (2 mg/kg/day) for 4 consecutive days.
  • the conditional place preference box (experimental instrument) of Shanghai Jiliang Software Technology Co., Ltd. was used as the behavioral training and testing instrument.
  • the experimental instrument is divided into two boxes with medicine box (black box) and non-medicine box (white box) (the two boxes can be closed and connected).
  • medicine box black box
  • non-medicine box white box
  • the mice were put into the experimental apparatus (connected state) to move freely for 900 seconds, and the activity time of the mice in the medicine box was recorded and analyzed as the baseline value.
  • Drug addiction training was carried out on the second day, and mice were restricted in a drug box (closed state) for training for 60 minutes/day after administration according to grouping requirements, for a total of four days of training.
  • mice were put into the experimental apparatus to move freely (connected state) for 900 seconds, and the activity time of the mice in the medicine box was recorded and analyzed.
  • the activity time of the mice in the medicine box on the sixth day was subtracted from the activity time (baseline) of the mice in the medicine box on the first day to obtain a difference, and this difference was the preference score.
  • the C57BL/6J mice used in the present invention were purchased from Shanghai Slack Experimental Animal Co., Ltd., and the low-iron feed used in the present invention was purchased from Jiangsu Synergy Biotechnology Co., Ltd.
  • mice 36 male C57BL/6J mice (8 weeks old, weighing 22-25g) were raised in an SPF animal room, and after one week of adaptive feeding, they were randomly divided into normal diet + normal saline control group (10 mice), normal diet + morphine group (10 rats), low-iron diet+normal saline control group (8 rats), and low-iron diet+morphine group (9 rats).
  • the mice in the low-iron diet group were continuously fed with low-iron diet for 3-4 weeks, and the mice in the normal diet group were fed with normal diet.
  • the mice in the control group were injected with normal saline intraperitoneally, and the mice in the morphine group were injected with morphine (20 mg/kg/day) for 7 consecutive days.
  • the conditional place preference box (experimental instrument) of Shanghai Jiliang Software Technology Co., Ltd. was used as the behavioral training and testing instrument.
  • the experimental instrument is divided into two boxes with medicine box (black box) and non-medicine box (white box) (the two boxes can be closed and connected).
  • medicine box black box
  • non-medicine box white box
  • the mice were put into the experimental apparatus (connected state) to move freely for 900 seconds, and the activity time of the mice in the medicine box was recorded and analyzed as the baseline value.
  • Drug addiction training was carried out on the second day, and mice were restricted in a drug box (closed state) for training for 30 minutes/day after administration according to the grouping requirements, for a total of seven days of training.
  • mice were put into the experimental apparatus for free activities (communication state) for 900 seconds and recorded and analyzed the activity time of the mice in the medicine box.
  • the activity time of the mice in the medicine box on the ninth day minus the activity time of the mice in the medicine box on the first day (baseline) was used to obtain a difference, and this difference was the preference score.
  • the C57BL/6J mice used in the present invention were purchased from Shanghai Slack Experimental Animal Co., Ltd., and the valdurestat used in the present invention was purchased from Selleck Company.
  • mice Thirty-six male C57BL/6J mice (8 weeks old, weighing 22-25g) were fed in an SPF animal room, and after one week of adaptive feeding, they were randomly divided into normal saline control group (10 mice), morphine group (11 mice), Valdurestat group (10 rats) and morphine+valdurestat group (11 rats).
  • the mice in the normal saline control group were injected with normal saline intraperitoneally
  • the mice in the morphine group were injected with morphine (20 mg/kg/day) intraperitoneally
  • the mice in the morphine+valdurestat group were injected with valdurestat (10 mg/kg/day) intraperitoneally.
  • morphine (20 mg/kg/day) was injected intraperitoneally for 7 consecutive days.
  • the conditional place preference box (experimental instrument) of Shanghai Jiliang Software Technology Co., Ltd. was used as the behavioral training and testing instrument.
  • the experimental instrument is divided into two boxes with medicine box (black box) and non-medicine box (white box) (the two boxes can be closed and connected).
  • medicine box black box
  • non-medicine box white box
  • the mice were put into the experimental apparatus (connected state) to move freely for 900 seconds, and the activity time of the mice in the medicine box was recorded and analyzed as the baseline value.
  • Drug addiction training was carried out on the second day, and mice were restricted in a drug box (closed state) for training for 30 minutes/day after administration according to the grouping requirements, for a total of seven days of training.
  • mice were put into the experimental apparatus for free movement (communication state) for 900 seconds and recorded and analyzed the activity time of the mice in the medicine box.
  • the activity time of the mice in the medicine box on the ninth day minus the activity time of the mice in the medicine box on the first day (baseline) was used to obtain a difference, and this difference was the preference score.
  • the C57BL/6J mice used in the present invention were purchased from Shanghai Slack Experimental Animal Co., Ltd., and the deferiprone used in the present invention was purchased from Sigma-Aldrich, USA.
  • mice Thirty-six male C57BL/6J mice (8 weeks old, weighing 22-25g) were fed in an SPF animal room, and after one week of adaptive feeding, they were randomly divided into normal saline control group (8 mice), morphine group (7 mice), deferiprone group (9 rats) and morphine + deferiprone group (8 rats).
  • mice in the normal saline control group were intraperitoneally injected with normal saline, the mice in the morphine group were injected intraperitoneally with morphine (20 mg/kg/day), and the mice in the morphine+deferiprone group were first given deferiprone (13 mg/mL, 1 ⁇ L) for 6 hours Morphine (20mg/kg/day) was injected intraperitoneally again for 7 consecutive days.
  • the conditional place preference box (experimental instrument) of Shanghai Jiliang Software Technology Co., Ltd. was used as the behavioral training and testing instrument.
  • the experimental instrument is divided into two boxes with medicine box (black box) and non-medicine box (white box) (the two boxes can be closed and connected).
  • medicine box black box
  • non-medicine box white box
  • the mice were put into the experimental apparatus (connected state) to move freely for 900 seconds, and the activity time of the mice in the medicine box was recorded and analyzed as the baseline value.
  • Drug addiction training was carried out on the second day, and mice were restricted in a drug box (closed state) for training for 30 minutes/day after administration according to the grouping requirements, for a total of seven days of training.
  • mice were put into the experimental apparatus for free movement (communication state) for 900 seconds and recorded and analyzed the activity time of the mice in the medicine box.
  • the activity time of the mice in the medicine box on the ninth day minus the activity time of the mice in the medicine box on the first day (baseline) was used to obtain a difference, and this difference was the preference score.

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Abstract

本发明提供了一种降低脑内铁含量的药物在制备治疗和/或预防神经精神疾病药物中的应用，属于药物新用途技术领域。本发明提供了降低铁含量的饮食/药物在施用后可预防毒品或药物成瘾行为的形成，从而实现对毒品或药物成瘾或依赖的预防和治疗，所述药物为缺氧诱导因子脯氨酰羟化酶抑制剂或铁螯合剂。

Description

降低脑内铁含量的药物在制备治疗和/或预防神经精神疾病药物中的应用 技术领域
本发明属于药物新用途技术领域，尤其是指一种降低脑内铁含量的药物在制备治疗和/或预防神经精神疾病药物中的应用。
背景技术
毒品是指能引起依赖性，使中枢神经系统产生兴奋或抑制，以致造成幻觉，或对动作机能、思想、行为、感觉、情绪损害的天然、半合成或合成的物质。包括鸦片、吗啡、海洛因、可卡因、苯丙胺、甲基苯丙胺(冰毒)等。毒品成瘾又称为毒品依赖、药物滥用或物质使用障碍，是一种以强迫性地寻求和使用毒品为特征的慢性复发性脑疾病。目前，全球有170多个国家和地区存在毒品贩运问题，130多个国家和地区存在毒品消费问题。全球使用毒品的人数更是超过了3亿，其中药物成瘾的患者超过了3500万。与毒品有关的死亡人数在过去的十年间增加了17.5％。在我国，截止2020年底共有吸毒人员180.1万人，2020年缴获毒品55.49吨。毒品成瘾已经成为了一个严重的社会问题，给我们的生活造成了沉重的医疗和经济负担。目前临床上戒毒药物主要是以美沙酮为代表的阿片类药物和可乐定为代表的非阿片类药物。阿片类药物控制症状较好，但是本身具有成瘾性；非阿片类药物虽不具成瘾性，但是戒断症状明显且副作用较大。临床上对药物/毒品(尤其是新型合成毒品)成瘾暂无特别有效的治疗药物和明确的治疗方案。因此，临床上迫切需要开发能够预防毒品成瘾、有效控制戒断症状、防止复吸且副作用小的新型药物。
伐度司他(AKB-6548/Vadadustat)是一种新型口服缺氧诱导因子脯氨酰羟化酶抑制剂。多项临床研究证实，伐度司他可以明显改善肾性贫血，提高 慢性肾病患者促红细胞生成素和血红蛋白水平。同时，可以通过降低铁调素和增加转铁蛋白以调节铁代谢，且无严重不良反应，但是其对毒品或药物成瘾或依赖的作用并未见报道。
去铁酮(Deferiprone/CP20/3-羟基-1,2-二甲基-4-(1H)-吡啶酮)是一种铁螯合剂，能清除铁蛋白和含铁血黄素中的铁离子，用于治疗药急性铁中毒和慢性铁蓄积引起的疾病。去铁酮临床上主要用于治疗耐受或不愿意接受现有螯合剂治疗的铁负荷过多的地中海贫血患者。有很多的研究报道其可通过络合过量的铁从而缓解铁沉积相关的帕金森、老年痴呆疾病以及铁过载导致的氧化应激损伤，但是其对毒品或药物成瘾或依赖的作用并未见报道。
发明内容
为解决上述技术问题，本发明提供一种降低脑内铁含量的药物在制备治疗和或预防神经精神疾病药物中的应用，所述降低脑内铁含量的药物选自伐度司他和去铁酮，为提供预防和/或治疗毒品或药物成瘾的药物指明了方向。本发明的目的在于提供一种通过药物或饮食降低脑内铁含量来预防和治疗毒品或药物成瘾的策略。
针对目前临床上防治毒品成瘾的药物缺乏的现状，本发明提供了降低脑内铁含量的药物或饮食在预防和治疗药物或毒品成瘾或依赖的一种新应用。具体地，本发明提供了伐度司他、去铁酮以及低铁饮食在制备用于预防和治疗毒品或药物成瘾或依赖的药物方面的应用。目前，尚无通过调控脑内铁含量预防和治疗毒品或药物成瘾或依赖的相关报道。
一种降低脑内铁含量的药物在制备预防或/和治疗精神疾病的药物中的应用。所述药物通过降低脑内铁含量从而对毒品或药物成瘾或依赖的预防和治疗作用。
在本发明的一个实施例中，所述精神疾病是由毒品、药物成瘾、依赖引起的精神疾病。
在本发明的一个实施例中，所述毒品为吗啡或甲基苯丙胺。
在本发明的一个实施例中，所述药物为缺氧诱导因子脯氨酰羟化酶抑制剂类药物或铁螯合剂类药物。
在本发明的一个实施例中，所述缺氧诱导因子脯氨酰羟化酶抑制剂类药物为式I所示的化合物或其药学上可接受的盐，其中，式I结构为：
Figure PCTCN2022095270-appb-000001
在本发明的一个实施例中，所述铁螯合剂类药物为式II所示的化合物或其药学上可接受的盐，其中，式II结构为：
Figure PCTCN2022095270-appb-000002
在本发明的一个实施例中，所述药学上可接受的盐包括无机酸盐、有机酸盐、烷基磺酸盐和芳基磺酸盐中的一种或多种。
在本发明的一个实施例中，所述预防或/和治疗精神疾病的药物还包括药学上可接受的载体。
在本发明的一个实施例中，所述载体选自崩解剂、稀释剂、润滑剂、粘合剂、湿润剂、矫味剂、助悬剂、表面活性剂和防腐剂中的一种或多种。
在本发明的一个实施例中，所述预防或/和治疗精神疾病的药物的剂型为片剂、胶囊剂、软胶囊剂、颗粒剂、丸剂、口服液、乳剂、干混悬剂、干浸膏剂或注射剂。
在本发明的一个实施例中，崩解剂选自玉米淀粉、马铃薯淀粉、交联聚乙烯吡咯烷酮、羧甲基淀粉钠、低取代羟丙基纤维素、交联羧甲纤维素钠、羧甲基纤维素、羧甲基纤维素钙和藻酸中的一种或多种。
在本发明的一个实施例中，所述润滑剂选自微粉硅胶、硬脂酸镁、硬脂酸钙、硬脂酸、滑石粉和无水硅胶中的一种或多种。
在本发明的一个实施例中，所述粘合剂选自阿拉伯胶、明胶、糊精、羟丙基纤维素、甲基纤维素和聚乙烯吡咯烷酮中的一种或多种；所述湿润剂选自十二烷基硫酸钠；所述矫味剂可以为阿斯巴甜、甜菊甙、蔗糖、麦芽糖醇和柠檬酸中的一种或多种。
在本发明的一个实施例中，所述助悬剂选自阿拉伯胶、明胶、甲基纤维素、羧甲基纤维素钠、羟甲基纤维素和硬脂酸铝凝胶中的一种或多种；所述表面活性剂选自卵磷脂、山梨糖醇酐单油酸酯和单硬脂酸甘油酯中的一种或多种；所述防腐剂选自对羟苯甲酸甲酯或/和对羟苯甲酸丙酯。
本发明通过用低铁饲料连续喂养小鼠3-4周建立小鼠脑缺铁模型，再给予小鼠腹腔注射甲基苯丙胺(2mg/kg/天)对小鼠进行4天的甲基苯丙胺条件位置偏爱训练构建毒品成瘾模型，训练结束后检测小鼠停留在甲基苯丙胺伴药侧的偏爱评分，结果发现低铁饲料喂养组小鼠对甲基苯丙胺伴药侧的偏爱评分相对于正常饲料对照组显著降低。
本发明通过用低铁饲料连续喂养小鼠3-4周建立小鼠脑缺铁模型，再给予小鼠腹腔注射吗啡(20mg/kg/天)对小鼠进行7天的吗啡条件位置偏爱训练构建毒品成瘾模型，训练结束后检测小鼠停留在吗啡伴药侧的偏爱评分，结果发现低铁饲料喂养组小鼠对吗啡伴药侧的偏爱评分相对于正常饲料对照组显著降低。
本发明通过每天腹腔注射给予小鼠伐度司他(10mg/kg/天)，6小时后再腹腔注射给予小鼠吗啡(20mg/kg/天)对小鼠进行7天的吗啡条件位置偏爱训练构建毒品成瘾模型，训练结束后检测小鼠停留在吗啡伴药侧的偏爱评分，结果发现伐度司他给药可以显著降低小鼠对吗啡伴药侧的偏爱评分。
本发明通过脑立体定位埋管(背侧海马)给予小鼠13mg/mL的去铁酮1μL，6小时后再腹腔注射给予小鼠吗啡(20mg/kg/天)对小鼠进行7天的吗啡条件位置偏爱训练构建毒品成瘾模型，训练结束后检测小鼠停留在吗啡 伴药侧的偏爱评分，结果发现去铁酮给药可以显著降低小鼠对吗啡伴药侧的偏爱评分。
低铁饮食、去铁酮和伐度司他都能够降低脑内铁含量并且降低吗啡及甲基苯丙胺诱导的条件位置偏爱评分。因此，降低脑内铁含量的药物或饮食配方在用于毒品或药物成瘾或依赖的预防和治疗中具有显著效果。
本发明的上述技术方案相比现有技术具有以下优点：
(1)针对目前临床上防治毒品成瘾的药物缺乏的现状，现有伐度司他、去铁酮等降低脑内铁含量的药物能够在施用后预防吗啡和甲基苯丙胺成瘾行为的形成(如：低铁饮食，10mg/kg/天的伐度司他和去铁酮能够显著降低吗啡和甲基苯丙胺诱导的条件位置偏爱评分)。
(2)临床上暂无预防或治疗新型毒品或药物成瘾(如：甲基苯丙胺等)或依赖的药物，现有降低脑内铁含量的药物(伐度司他和去铁酮等)对甲基苯丙胺的成瘾或依赖具有作用。
(3)临床上以美沙酮为代表的阿片类药物在治疗阿片类药物成瘾(如：吗啡等)时自身具有成瘾性，使用不当会导致药物使用依赖，现有降低脑内铁含量的药物(伐度司他和去铁酮等)在治疗毒品成瘾过程中自身不具有成瘾性。
(4)临床上以可乐定为代表的非阿片类成瘾治疗药物长期使用后会出现严重不良反应。现有降低铁含量的药物(伐度司他和去铁酮等)临床上耐受性好，不良反应少，合理用药剂量下暂未报道严重不良反应事件。
附图说明
为了使本发明的内容更容易被清楚的理解，下面根据本发明的具体实施例并结合附图，对本发明作进一步详细的说明，其中
图1是本发明低铁饮食对小鼠脑内铁含量的作用效果图；
图2是本发明低铁饮食对小鼠甲基苯丙胺成瘾的作用效果图；
图3是本发明低铁饮食对小鼠吗啡成瘾的作用效果图；
图4是本发明伐度司他对吗啡成瘾的作用效果图；
图5是本发明去铁酮对吗啡成瘾的作用效果图。
应理解，在本发明范围内，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
下面结合附图和具体实施例对本发明作进一步说明，以使本领域的技术人员可以更好地理解本发明并能予以实施，但所举实施例不作为对本发明的限定。
实施例1低铁饮食对小鼠脑内铁含量的调节作用
1实验材料
本发明使用的C57BL/6J小鼠购自上海斯莱克实验动物有限责任公司，本发明使用的低铁饲料购自江苏协同生物技术有限公司。
2实验方法
2.1小鼠给药方法
雄性C57BL/6J小鼠36只(8周龄，体重22-25g)饲养于SPF级动物房，适应性饲养1周后随机分为正常饮食对照组(3只)和低铁饮食对照组(3只)。低铁饮食组的小鼠持续给予低铁饲料喂养3-4周，正常饮食组的小鼠给予正常饲料喂养。
2.2小鼠脑内铁含量的测定
上述小鼠喂养3-4周后，取小鼠的脑组织。将组织样品放置于聚四氟乙烯硝解内罐，加硝酸5mL浸泡过夜。盖好内盖，旋紧不锈钢外套，放入恒温干燥箱，80℃持续2h，120℃持续2h，160℃持续4h，在箱内自然冷却至室温，打开后加热至酸溶液近干，将硝化液吸入25mL容量瓶中，用少量硝酸溶液(1％)洗涤内罐和内盖3次，洗液合并至容量瓶中并用1％硝酸 定容至刻度。用由电感耦合等离子体质谱仪(ICP-MS)测定铁元素含量。
3实验结果
如图1所示，低铁饮食组小鼠相较于正常饮食组小鼠，纹状体、海马、皮层组织中的铁含量均出现显著性降低，说明低铁饮食可导致的脑内铁含量出现下降。
实施例2低铁饮食对小鼠甲基苯丙胺成瘾的作用
1实验材料
本发明使用的C57BL/6J小鼠购自上海斯莱克实验动物有限责任公司，本发明使用的低铁饲料购自江苏协同生物技术有限公司。
2实验方法
2.1小鼠给药方法
雄性C57BL/6J小鼠36只(8周龄，体重22-25g)饲养于SPF级动物房，适应性饲养1周后随机分为正常饮食+生理盐水对照组(11只)、正常饮食+甲基苯丙胺组(13只)，低铁饮食+生理盐水对照组(13只)、低铁饮食+甲基苯丙胺组(12只)。低铁饮食组的小鼠持续给予低铁饲料喂养3-4周，正常饮食组的小鼠给予正常饲料喂养。对照组小鼠腹腔注射生理盐水，甲基苯丙胺组小鼠腹腔注射甲基苯丙胺(2mg/kg/天)，连续注射4天。
2.2小鼠条件位置偏爱实验评分
使用上海吉量软件科技有限公司的条件位置偏爱箱(实验仪器)作为行为学训练和检测仪器。实验仪器分为伴药箱(黑箱)和非伴药箱(白箱)两个箱体(两个箱体之间可封闭，可连通)。第一天，将小鼠放入实验仪器中(连通状态)自由活动900秒并记录分析小鼠在伴药箱内的活动时间作为基线值。第二天进行毒品成瘾训练，按照分组要求进行给药后将小鼠限制在伴药箱中(封闭状态)训练60分钟/天，共训练四天。训练结束后，第六天将小鼠放入实验仪器中自由活动(连通状态)900秒并记录分析小鼠在伴药箱内的活动时间。将第六天小鼠在伴药箱的活动时间减去第一天小鼠在伴药箱 中内的活动时间(基线)得出差值，此差值即为偏爱分数。
3实验结果
如图2所示，正常饮食+生理盐水对照组和正常饮食+甲基苯丙胺组之间的偏爱分数有显著性差异，说明2mg/kg/天甲基苯丙胺成瘾模型成功建立。正常饮食+甲基苯丙胺组与低铁饮食+甲基苯丙胺组之间的偏爱分数有显著性差异，说明低铁饮食导致的脑内低铁对甲基苯丙胺成瘾具有作用。
实施例3低铁饮食对小鼠吗啡成瘾的作用
1实验材料
本发明使用的C57BL/6J小鼠购自上海斯莱克实验动物有限责任公司，本发明使用的低铁饲料购自江苏协同生物技术有限公司。
2实验方法
2.1小鼠给药方法
雄性C57BL/6J小鼠36只(8周龄，体重22-25g)饲养于SPF级动物房，适应性饲养1周后随机分为正常饮食+生理盐水对照组(10只)、正常饮食+吗啡组(10只)，低铁饮食+生理盐水对照组(8只)、低铁饮食+吗啡组(9只)。低铁饮食组的小鼠持续给予低铁饲料喂养3-4周，正常饮食组的小鼠给予正常饲料喂养。对照组小鼠腹腔注射生理盐水，吗啡组小鼠腹腔注射吗啡(20mg/kg/天)，连续注射7天。
2.2小鼠条件位置偏爱实验评分
使用上海吉量软件科技有限公司的条件位置偏爱箱(实验仪器)作为行为学训练和检测仪器。实验仪器分为伴药箱(黑箱)和非伴药箱(白箱)两个箱体(两个箱体之间可封闭，可连通)。第一天，将小鼠放入实验仪器中(连通状态)自由活动900秒并记录分析小鼠在伴药箱内的活动时间作为基线值。第二天进行毒品成瘾训练，按照分组要求进行给药后将小鼠限制在伴药箱中(封闭状态)训练30分钟/天，共训练七天。训练结束后，第九天将小鼠放入实验仪器中自由活动(连通状态)900秒并记录分析小鼠在伴药箱 内的活动时间。将第九天小鼠在伴药箱的活动时间减去第一天小鼠在伴药箱中内的活动时间(基线)得出差值，此差值即为偏爱分数。
3实验结果
如图3所示，正常饮食+生理盐水对照组和正常饮食+吗啡组之间的偏爱分数有显著性差异，说明20mg/kg/天吗啡成瘾模型被成功建立。正常饮食+吗啡组与低铁饮食+吗啡组之间的偏爱分数有显著性差异，说明低铁饮食导致的脑内低铁对吗啡成瘾具有作用。
实施例4伐度司他对小鼠吗啡成瘾的作用
1实验材料
本发明使用的C57BL/6J小鼠购自上海斯莱克实验动物有限责任公司，本发明使用的伐度司他购自Selleck公司。
2实验方法
2.1小鼠给药方法
雄性C57BL/6J小鼠36只(8周龄，体重22-25g)饲养于SPF级动物房，适应性饲养1周后随机分为生理盐水对照组(10只)、吗啡组(11只)、伐度司他组(10只)和吗啡+伐度司他组(11只)。生理盐水对照组小鼠腹腔注射生理盐水，吗啡组小鼠腹腔注射吗啡(20mg/kg/天)，吗啡+伐度司他组小鼠先腹腔注射伐度司他(10mg/kg/天)，6小时后腹腔注射吗啡(20mg/kg/天)，连续注射7天。
2.2小鼠条件位置偏爱实验评分
使用上海吉量软件科技有限公司的条件位置偏爱箱(实验仪器)作为行为学训练和检测仪器。实验仪器分为伴药箱(黑箱)和非伴药箱(白箱)两个箱体(两个箱体之间可封闭，可连通)。第一天，将小鼠放入实验仪器中(连通状态)自由活动900秒并记录分析小鼠在伴药箱内的活动时间作为基线值。第二天进行毒品成瘾训练，按照分组要求进行给药后将小鼠限制在伴药箱中(封闭状态)训练30分钟/天，共训练七天。训练结束后，第九天将 小鼠放入实验仪器中自由活动(连通状态)900秒并记录分析小鼠在伴药箱内的活动时间。将第九天小鼠在伴药箱的活动时间减去第一天小鼠在伴药箱中内的活动时间(基线)得出差值，此差值即为偏爱分数。
3实验结果
如图4所示，生理盐水对照组和吗啡组之间的偏爱分数有显著性差异，说明20mg/kg/天吗啡成瘾模型成功建立。吗啡组与吗啡+伐度司他组之间的偏爱分数有显著性差异，说明10mg/kg/天伐度司他对吗啡成瘾具有作用。
实施例5去铁酮对小鼠吗啡成瘾的预防作用
1实验材料
本发明使用的C57BL/6J小鼠购自上海斯莱克实验动物有限责任公司，本发明使用的去铁酮购自美国Sigma-Aldrich公司。
2实验方法
2.1小鼠给药方法
雄性C57BL/6J小鼠36只(8周龄，体重22-25g)饲养于SPF级动物房，适应性饲养1周后随机分为生理盐水对照组(8只)、吗啡组(7只)、去铁酮组(9只)和吗啡+去铁酮组(8只)。生理盐水对照组小鼠腹腔注射生理盐水，吗啡组小鼠腹腔注射吗啡(20mg/kg/天)，吗啡+去铁酮组小鼠先给药去铁酮(13mg/mL，1μL)，6小时后再腹腔注射吗啡(20mg/kg/天)，连续注射7天。
2.2小鼠条件位置偏爱实验评分
使用上海吉量软件科技有限公司的条件位置偏爱箱(实验仪器)作为行为学训练和检测仪器。实验仪器分为伴药箱(黑箱)和非伴药箱(白箱)两个箱体(两个箱体之间可封闭，可连通)。第一天，将小鼠放入实验仪器中(连通状态)自由活动900秒并记录分析小鼠在伴药箱内的活动时间作为基线值。第二天进行毒品成瘾训练，按照分组要求进行给药后将小鼠限制在伴药箱中(封闭状态)训练30分钟/天，共训练七天。训练结束后，第九天将 小鼠放入实验仪器中自由活动(连通状态)900秒并记录分析小鼠在伴药箱内的活动时间。将第九天小鼠在伴药箱的活动时间减去第一天小鼠在伴药箱中内的活动时间(基线)得出差值，此差值即为偏爱分数。
3实验结果
如图5所示，生理盐水对照组和吗啡组之间的偏爱分数有显著性差异，说明20mg/kg/天吗啡成瘾模型成功建立。吗啡组与吗啡+去铁酮组之间的偏爱分数有显著性差异，说明去铁酮对吗啡成瘾具有作用。
显然，上述实施例仅仅是为清楚地说明所作的举例，并非对实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引申出的显而易见的变化或变动仍处于本发明创造的保护范围之中。

Claims (10)

  1. 一种降低脑内铁含量的药物在制备预防或/和治疗精神疾病的药物中的应用。
  2. 根据权利要求1所述的应用，其特征在于，所述精神疾病是由毒品或药物成瘾、依赖引起的精神疾病。
  3. 根据权利要求2所述的应用，其特征在于，所述毒品为吗啡或甲基苯丙胺。
  4. 根据权利要求1所述的应用，其特征在于，所述药物为缺氧诱导因子脯氨酰羟化酶抑制剂类药物或铁螯合剂类药物。
  5. 根据权利要求4所述的应用，其特征在于，所述缺氧诱导因子脯氨酰羟化酶抑制剂类药物为式I所示的化合物或其药学上可接受的盐，其中，式I结构为：
    Figure PCTCN2022095270-appb-100001
  6. 根据权利要求1所述的应用，其特征在于，所述铁螯合剂类药物为式II所示的化合物或其药学上可接受的盐，其中，式II结构为：
    Figure PCTCN2022095270-appb-100002
  7. 根据权利要求6所述的应用，其特征在于，所述药学上可接受的盐包括无机酸盐、有机酸盐、烷基磺酸盐和芳基磺酸盐中的一种或多种。
  8. 根据权利要求1所述的应用，其特征在于，所述预防或/和治疗精神疾病的药物还包括药学上可接受的载体。
  9. 根据权利要求8所述的应用，其特征在于，所述载体选自崩解剂、稀释剂、润滑剂、粘合剂、湿润剂、矫味剂、助悬剂、表面活性剂和防腐剂中的一种或多种。
  10. 根据权利要求1所述的应用，其特征在于，所述预防或/和治疗精神疾病的药物的剂型为片剂、胶囊剂、软胶囊剂、颗粒剂、丸剂、口服液、乳剂、干混悬剂、干浸膏剂或注射剂。
PCT/CN2022/095270 2022-02-17 2022-05-26 降低脑内铁含量的药物在制备治疗和/或预防神经精神疾病药物中的应用 WO2023155327A1 (zh)

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