WO2023000271A1 - 水合氯醛在制备抑制苯丙胺类中枢神经兴奋剂复吸和依赖的药物中的应用 - Google Patents

水合氯醛在制备抑制苯丙胺类中枢神经兴奋剂复吸和依赖的药物中的应用 Download PDF

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WO2023000271A1
WO2023000271A1 PCT/CN2021/107945 CN2021107945W WO2023000271A1 WO 2023000271 A1 WO2023000271 A1 WO 2023000271A1 CN 2021107945 W CN2021107945 W CN 2021107945W WO 2023000271 A1 WO2023000271 A1 WO 2023000271A1
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chloral hydrate
amphetamine
central nervous
drug
stimulants
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French (fr)
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朱英杰
蒋辰宇
胡靖怡
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Shenzhen Institute of Advanced Technology of CAS
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Shenzhen Institute of Advanced Technology of CAS
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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
    • A61K31/11—Aldehydes
    • 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

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  • the invention belongs to the field of medicines, and in particular relates to the application of chloral hydrate in the preparation of medicines for inhibiting the relapse and dependence of amphetamine central nervous stimulants.
  • Drug addiction is a chronic relapsing brain disease.
  • Long-term use of ephedrines such as ephedrine hydrochloride and methamphetamine (also known as methamphetamine) can lead to dependence and addiction.
  • methamphetamine also known as methamphetamine
  • Methamphetamine is a new type of synthetic psychoactive drug. According to the "China Narcotics Control Report" in recent years, the number of methamphetamine abusers in China is on the rise, surpassing the number of traditional amphetamine drug abusers.
  • Methamphetamine is highly stimulant and highly addictive after use, and can have permanent effects on the central nervous system.
  • Methamphetamine is a lipophilic molecule that can promote the release of monoamine neurotransmitters in the central nervous system.
  • a structural analogue of monoamine neurotransmitters it can inhibit the normal function of such transmitter transporters to a certain extent. It leads to abnormal transmission of synaptic transmitter information, which has complex effects on individual reward behavior, learning, memory and cognitive functions.
  • methamphetamine addicts Long-term use of methamphetamine by individuals can lead to sharp weight loss, "meth mouth", anxiety, irritability, tachycardia, loss of appetite, hallucinations, and aggressive behavior after short-term withdrawal. Overdose can cause central nervous system acute Or chronic poisoning, resulting in critical illnesses such as hematogenous cerebral edema, and even death. In addition, smoking more than five times a month for more than two years will cause the smoker to have obvious symptoms of a mental patient, and these symptoms are difficult to cure once they occur. Methamphetamine addicts not only lose their ability to work, but also have aggressive behaviors against family members and others, and the probability of criminal cases among drug addicts is on the rise every year.
  • methamphetamine also imposes a heavy burden on the national economy.
  • RAND Corporation of the United States calculated that the economic burden caused by the use of methamphetamine in the United States in 2005 was about 23.4 billion US dollars.
  • meth addiction and abuse has become a burden on society and families.
  • Chloral hydrate is commonly used clinically for anesthesia and sedation, and is one of the commonly used anesthetics in animal experiments. Clinically, the combination of chloral hydrate and clonidine can treat the withdrawal syndrome of newborns. In morphine-dependent rats, a single chloral hydrate pretreatment transiently suppressed the expression of naloxone-mediated withdrawal symptoms.
  • the inventor's published research results show that before the morphine conditioned place preference (conditioned place preference, CPP) is established, rats are given intraperitoneal injections of medium doses of chloral hydrate for 6 consecutive days, and the morphine CPP in rats cannot be established. The above results indicate that chloral hydrate can inhibit withdrawal symptoms and disrupt the acquisition of morphine reward memory. There is no report on the effect of chloral hydrate in the treatment of different stages of methamphetamine addiction.
  • the invention provides the application of chloral hydrate in the treatment of central psychostimulant dependence and relapse.
  • the present invention provides the following technical solutions.
  • the invention provides the application of chloral hydrate in treating relapse of amphetamine-type central nervous stimulants.
  • the present invention provides the following technical solutions.
  • One aspect of the present invention provides a method for inhibiting relapse of amphetamine-type central nervous stimulants in a subject and reducing dependence on amphetamine-type central nervous stimulants in a subject, which includes administering a therapeutically effective amount of chloral hydrate.
  • Another aspect of the present invention provides a method for inhibiting conditioned place preference or habitual drug-seeking caused by amphetamine-type central nervous system stimulants, which comprises administering a therapeutically effective amount of chloral hydrate.
  • the method is for non-diagnostic and therapeutic purposes.
  • the dose of chloral hydrate administered in the method is 20-500mg/kg, such as 30mg/kg, 40mg/kg, 50mg/kg, 60mg/kg, 70mg/kg, 80mg/kg , 90mg/kg, 100mg/kg, 150mg/kg, 200mg/kg, 250mg/kg, 300mg/kg, 350mg/kg, 400mg/kg, 450mg/kg, 500mg/kg.
  • the time of giving chloral hydrate in the described method is while giving the amphetamine central nervous stimulant, and after drug withdrawal, or give after amphetamine central nervous stimulant addiction and drug withdrawal .
  • Another aspect of the present invention provides the use of chloral hydrate in the preparation of drugs for inhibiting the relapse of amphetamine-type central nervous stimulants and reducing the dependence of subjects on amphetamine-type central nervous stimulants.
  • Another aspect of the present invention provides the use of chloral hydrate in the preparation of drugs for inhibiting conditioned place preference or habitual drug-seeking caused by amphetamine-type central nervous system stimulants.
  • Another aspect of the present invention provides a pharmaceutical composition for inhibiting relapse or dependence on amphetamine-type central nervous stimulants, wherein chloral hydrate is the only active ingredient in the pharmaceutical composition.
  • the amphetamine central nervous system stimulant is selected from: methamphetamine, methylenedioxymethamphetamine, 3,4-methylenedioxyamphetamine and its stereoisomers, polymorphs , metabolites, prodrugs, hydrates, pharmaceutically acceptable salts and mixtures.
  • the pharmaceutical composition further includes a pharmaceutically acceptable carrier.
  • the dosage form of the pharmaceutical composition is selected from the group consisting of oral agents, injections, and sprays.
  • the dosage form of the pharmaceutical composition can be administered by a route selected from the following group: oral administration, injection (subcutaneous, intramuscular, intravenous), mucosal administration, transdermal administration and intraperitoneal administration medicine.
  • the subject is a mammal, such as a human, a macaque, a rat or a mouse.
  • the present invention proves that chloral hydrate can effectively reduce the conditioned position preference of amphetamine-type central nervous stimulants, reduce habitual drug seeking and relapse after withdrawal, thereby proving that chloral hydrate can treat relapse caused by amphetamine-type central nervous stimulants. Inhalation, and can reduce dependence on amphetamine-type central nervous system stimulants.
  • Chloral hydrate is currently widely used clinically, especially in pediatric sedation. Low-dose chloral hydrate has little clinical side effects and is safe and reliable. Because chloral hydrate has been clinically used as a drug, it is safe and reliable, so once animal experiments confirm its effectiveness, it can be directly used in the treatment of addicted patients.
  • FIG. 1 is a schematic diagram of the treatment of rat methamphetamine CPP and chloral hydrate in Example 1.
  • CPP is divided into three stages: adaptation period (pre-conditioning), conditioning period (conditioning) and detection period (test).
  • T1 Baseline level CPP test.
  • T1 CPP test after establishment of methamphetamine preference.
  • T2 CPP test after the chloral hydrate administration period.
  • T3 After the end of the chloral hydrate administration cycle, the CPP test was performed again after 14 days.
  • Fig. 2 is the result figure of embodiment 1, high dose chloral hydrate (100mg/kg) significantly reduces the maintenance of rat METH CPP.
  • Normal saline and 50mg/kg chloral hydrate had no significant effect on the CPP score at T2, that is, the scene preference level of rats paired with methamphetamine did not change; while 100mg/kg chloral hydrate significantly reduced T2
  • the CPP scores of rats showed significantly lower levels of scene preference for methamphetamine pairings. And low CPP scores can be maintained until T3.
  • ns no significant difference; *, p ⁇ 0.05.
  • T0 the residence time of the rats in the dosing chamber at baseline
  • T1 the residence time of the rats in the dosing chamber after the methamphetamine preference was established.
  • T2 After the chloral hydrate administration period, the rats stay in the dosing room.
  • T3 14 days after the administration of chloral hydrate, the residence time of the rats in the dosing chamber.
  • Fig. 3 is the result graph of embodiment 2, chloral hydrate significantly reduces the self-administration frequency of methamphetamine in rats.
  • A Continuous administration of 50mg/kg dose of chloral hydrate to rats for 3 days reduced the number of drug seeking but did not reach statistical significance;
  • B Continuous administration of 100mg/kg dose of chloral hydrate to rats for 3 days significantly reduced drug-seeking times in rats. ns, no significant difference; *, p ⁇ 0.05.
  • Fig. 4 is the result graph of embodiment 3, chloral hydrate significantly reduces the relapse of methamphetamine in rats.
  • the normal saline group which significantly increased the number of active hole touches (active poke)
  • the number of touches in the active hole was related to the regression of the last day. ratio did not change significantly.
  • Extinction represents the data of the last day of the extinction phase.
  • amphetamine-type central nervous system stimulant refers to a class of pharmaceutical compounds or pharmaceutical compositions that contain an amphetamine structure or amphetamine-like structural core and are converted from amphetamine, including but not limited to methamphetamine , Amphetamine, Methylenedioxymethamphetamine, 3,4-Methylenedioxyamphetamine and its stereoisomers, polymorphs, solvates, hydrates, metabolites, prodrugs, pharmaceutically acceptable salt and mix.
  • terapéuticaally effective amount means an amount, as defined below, sufficient for the treatment to be effective when administered to a mammal in need of such treatment.
  • active ingredient refers to a compound in a pharmaceutical composition that has a pharmacological effect when administered to an organism (such as a mammal), and is intended to cover not only the compound, but also pharmaceutically acceptable salts, pharmaceutically acceptable Accepted salts or esters, hydrates, polymorphs and prodrugs.
  • prodrug refers to a compound comprising a chemical group that can be transformed in vivo and/or isolated from the remainder of the molecule to provide the active drug, a pharmaceutically acceptable salt thereof, or a biologically active metabolite thereof.
  • polymorphs refers to different crystal structures of a crystalline compound. Different polymorphs may result, for example, from the presence of different crystal packing structures (packing polymorphs) or from the presence of different conformers of the same molecule (conformational polymorphs).
  • combination dosage form refers to a unit dosage form (such as a single drug, tablet, capsule, ampule, suppository or other unit dosage form).
  • solvate refers to a complex formed by combining a compound with a solvent.
  • hydrate refers to a complex formed by combining a compound with water.
  • pharmaceutically acceptable salt of a given compound refers to salts that retain the biological effectiveness and properties of the given compound.
  • the term "pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agents are incompatible with the active ingredients, they are contemplated for use in therapeutic compositions. Supplementary active ingredients can also be incorporated into the compositions.
  • the "inhibiting the relapse of amphetamine-type central nervous system stimulants” refers to reducing the driving force of a subject who becomes addicted to amphetamine-type central nervous system stimulants and becomes addicted again after drug withdrawal. Said inhibition refers to the ability to reduce any of the above-mentioned driving forces.
  • the "reducing or inhibiting dependence on amphetamine-type central nervous system stimulants” refers to reducing the habitual drug-seeking behavior of a subject after becoming addicted to amphetamine-type central nervous system stimulants.
  • the inhibition or reduction refers to reducing the frequency of habitual drug-seeking or prolonging the interval of drug-seeking.
  • the animals used in this experiment were 6-14 week old male SD rats.
  • the animals were 6 weeks old when they arrived in the animal room, and were paired and divided into 2 per cage according to their body weight.
  • the conditional place preference equipment consists of four self-designed three-box behavior boxes of the same size and a camera (produced by Luo Ri, model LRCP0680_1080P) located at 1.5 meters on the top of the box.
  • the black polyethylene behavior box (length ⁇ width ⁇ height, 70cm ⁇ 25cm ⁇ 30cm) is divided into a side box (length ⁇ width ⁇ height, 30cm ⁇ 25cm ⁇ 30cm) and a middle box ( length x width x height, 30cm x 25cm x 30cm).
  • the two side boxes have different visual (different wallpaper on the side walls) and tactile cues (fine grid polyethylene baseboard on one side, rough black sandpaper on the other); the black middle box has a black glossy baseboard.
  • the animal self-administration equipment is 8 self-administration boxes (Anlai Software Technology Co., Ltd., Ningbo, China). There are two nasal contact holes on the movable panel on one side of the box, one of which is the active hole. When the animal triggers this hole, there will be 70 ⁇ L 0.2 mg/mL of METH was injected into the vein of the rat and there were 20s of drug administration cues (sound and light), and the other was an inactive hole, and there was no drug administration or drug administration cues when touching this hole. In order to prevent the animals from overdosing, there was a 20s blank period (time out) after each administration, during which the rats did not receive any administration from the active hole in their nose.
  • the water supply port in the center of the panel is opened.
  • 70 ⁇ L of 5% sucrose water will flow out from the water outlet, but there is no such reaction in the inactive well.
  • the animal's nose touch behavior will be transmitted to the software system on the computer in real time (Anlai Software Technology Company, Ningbo, China).
  • CPP is divided into three stages (Figure 1): adaptation period (pre-conditioning), conditioning period (conditioning) and detection period (test).
  • Adaptation period (days 1-3): remove the doors on both sides, and allow the rats to freely explore the three boxes for 15 minutes after intraperitoneal injection of normal saline, and the rats are on the non-preferred side of the box on the third day (that is, the side where the METH box is set).
  • the data of staying on one side) was used as the reference value (T0), wherein the box on the preferred side of the rat was set as the normal saline box, and the non-preferred side was set as the METH box.
  • Conditioning period (days 4-11): On the 4th day, 0.25 mg/kg or 0.5 mg/kg methamphetamine was injected intraperitoneally, and the rats were confined in a METH box for 45 minutes. After 24 hours, intraperitoneal injection of normal saline, and then confined in the normal saline box for 45min. This is done 4 times.
  • Test period (Day 12, 18, 31): On the day of the test, the doors on both sides were removed, and the rats were allowed to freely explore the entire CPP box for 15 minutes after intraperitoneal injection of saline. On the 12th, 18th and 31st days, the test was carried out to detect the data of staying on the side of the non-preferred box (that is, the side where the METH box was set), and recorded as T1, T2 and T3.
  • Chloral hydrate/normal saline treatment the animals were randomly divided into three groups: normal saline group, chloral hydrate 50 mg/kg and chloral hydrate 100 mg/kg. On days 13-18, three groups of animals were injected with normal saline and chloral hydrate each day.
  • the self-administration sugar water training was carried out when the rats were 12 weeks old.
  • the specific steps of the training were as follows: when the rat touched the active hole, there was 70 ⁇ L of 5% sucrose water as a reward, accompanied by 20 seconds of sound and a cage light as a clue to the sugar water; while touching the inactive hole, there was no response. Train 2 hours a day for 6 consecutive days. Afterwards, the rats were anesthetized with 3% pentobarbital sodium and carried out self-administration catheterization surgery.
  • the silicone tube inner diameter 0.32mm, outer diameter 0.64mm, Dow, the United States
  • METH self-administration training is carried out.
  • the training program is FR1 (fixed ratio 1), and the time out time is 20s.
  • the rat’s nose touches the active hole once to receive an intravenous injection of METH (0.2mg/mL) 70 ⁇ L, and the administration is accompanied by sound and light cues, no drug administration nor sound and light cues when nasal touches the inactive orifice.
  • the self-administered METH number of animals reaches a stable value after continuous training for 6 days (the change of the number of administrations per day is not more than 10%), the animals are randomly divided into three groups and given to the animals respectively after the 6-10 day self-administration training Inject physiological saline, 50 mg/kg chloral hydrate or 100 mg/kg chloral hydrate intraperitoneally, record and analyze whether there is a significant difference in the self-administration times of the three groups of animals.
  • the rats After the accidental use of addictive substances, due to the rewarding effect of drugs and the negative reinforcement effect after withdrawal, some individuals will form habitual use of drugs. In order to make the individual quickly form a habitual drug-seeking behavior, the rats first received 6 days of self-supply sugar water behavioral training to learn that touching the active hole by nose can get rewards, and then self-supply METH training.
  • This part includes three parts: learned drug seeking, extinction and relapse.
  • 13-week-old rats underwent self-administration catheterization surgery and recovered for 3-5 days after surgery. Afterwards, the rats carried out Meth self-administration training (FR1, time out 20s) for 12 days, training for 2 hours every day. Rats that achieved self-feeding more than 10 times per day for the last three days were subjected to extinction training. During the extinction training, there was no clue of drug administration and accompanying medicine when the animal touched any hole with its nose, and the training was carried out for 1 hour every day. When the standard of no more than 10 active holes is reached for three consecutive days, the rebreathing test will be carried out.
  • rats were given intraperitoneal injection of different doses of chloral hydrate or normal saline for 5 consecutive days.
  • rats will get a conditioned cue (light and sound) immediately after entering the self-medication box, and the subsequent nasal touch only activates the conditioned cue but does not trigger the drug pump, and the test lasts for 1 hour.
  • Drug addiction is divided into different phases: incidental use in the initial phase, habitual drug seeking (dependence) and relapse after withdrawal. Among them, relapse is divided into conditioned cues and relapse caused by the drug itself. These different stages can be simulated by animal models.
  • the present invention simulates methamphetamine dependence and relapse stages by using the habitual place preference and self-administration model of methamphetamine in rats, and proves that giving rats different concentrations of chloral hydrate in these stages can reduce the effect of amphetamine-type central nervous system stimulants.
  • Dependence reduce relapse after withdrawal.

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Abstract

水合氯醛在制备抑制苯丙胺类中枢神经兴奋剂复吸和依赖的药物中的应用。具体公开了一种用于抑制受试者苯丙胺类中枢神经兴奋剂复吸、降低受试者对苯丙胺类中枢神经兴奋剂依赖的方法，其包括施用治疗有效量的水合氯醛。还公开了水合氯醛在制备抑制苯丙胺类中枢神经兴奋剂复吸、降低受试者对苯丙胺类中枢神经兴奋剂依赖的药物中的用途。水合氯醛目前广泛用于临床尤其是儿科的镇静，低剂量的水合氯醛在临床上副作用小，安全可靠。因为水合氯醛已为临床使用药物，安全可靠，所以一旦动物实验证实其有效性，可以直接用于成瘾病人的治疗。

Description

水合氯醛在制备抑制苯丙胺类中枢神经兴奋剂复吸和依赖的药物中的应用 技术领域
本发明属于药物领域，具体涉及水合氯醛在制备抑制苯丙胺类中枢神经兴奋剂复吸和依赖的药物中的应用。
背景技术
药物成瘾是一种慢性复发性的脑疾病。麻黄碱类药物，例如盐酸麻黄碱和去氧麻黄碱(又称甲基苯丙胺)，长期使用会产生依赖和成瘾。目前国内甲基苯丙胺成瘾人数已经超过阿片类药物成瘾数，成为滥用的头号毒品。甲基苯丙胺(Methamphetamine,METH)，俗称冰毒，是一种新型合成型精神兴奋性毒品。根据最近几年的《中国禁毒报告》，甲基苯丙胺的滥用人数在国内呈现上升趋势，已超过传统的苯丙胺类毒品滥用人数。根据2019年《中国禁毒报告》，在240.4万名现有吸毒人员中，滥用冰毒人员135万名，占56.1％，冰毒已取代海洛因成为我国滥用人数最多的毒品。甲基苯丙胺在使用后具有强烈兴奋性和高度成瘾性，并且会对中枢神经系统产生永久性影响。甲基苯丙胺是一种亲脂性分子，其可以促进中枢神经系统中单胺类神经递质释放，同时作为单胺类神经递质结构类似物，一定程度抑制此类递质转运体的正常功能，导致突触递质信息传递异常，从而对个体奖赏行为，学习记忆与认知功能产生复杂影响。个体对甲基苯丙胺的长期使用会导致体重锐减，“甲基口腔”，焦虑烦躁，心动过速，食欲不振，出现幻觉以及短期戒断后的攻击性行为，过量服用可导致中枢神经系统急性或慢性中毒，产生血源性脑水肿等危重病情，甚至死亡。此外，每月吸食五次以上，两年以上的吸食时间会使吸食者产生明显的精神病人的症状，这些症状一旦产生很难治愈。甲基苯丙胺吸食者不仅丧失了工作能力，并且吸食者会对家人和他人产生攻击性行为，每年毒品吸食者的犯罪案件概率呈现上升趋势。甲基苯丙胺的使用对国家经济也造成沉重负担，美国RAND公司在2009年计算得出，在2005年美国甲基苯丙胺使用造成的经济负担约合234亿美元。综上所述，冰毒成瘾和滥用已经成为社会和家庭的负担。
水合氯醛在临床上常用于麻醉和镇静，并且是动物实验中常用的麻醉剂之一。临床上，水合氯醛和可乐宁共用可以治疗新生儿的戒断综合症。对于吗啡依赖的大鼠，单次水合氯醛预处理即可短暂性抑制由纳洛酮介导的戒断症状的表达。本发明人已发表的研究结果表明，在吗啡条件性位置偏好(conditioned place preference,CPP)建立之前，给予大鼠连续6天中剂量水合氯醛腹腔注射，大鼠吗啡CPP不能建立。以上结果表明水合氯醛能抑制戒断症状和破坏吗啡奖赏记忆的获得。目前尚未有报道水合氯醛在治疗甲基苯丙胺的成瘾不同阶段的效果。
发明内容
针对甲基苯丙胺等精神兴奋药的依赖和复吸问题，本发明提供了水合氯醛在治疗中枢精神兴奋药依赖和复吸方面的用途。为了实现上述目的，本发明提供了以下技术方案。
针对苯丙胺类中枢神经兴奋剂的复吸问题，本发明提供了水合氯醛在治疗苯丙胺类中枢神经兴奋剂复吸方面的用途。为了实现上述目的，本发明提供了以下技术方案。
本发明一个方面提供了一种用于抑制受试者苯丙胺类中枢神经兴奋剂复吸、降低受试者对苯丙胺类中枢神经兴奋剂依赖的方法，其包括施用治疗有效量的水合氯醛。
本发明另一个方面提供了一种用于抑制苯丙胺类中枢神经兴奋剂引起条件性位置偏好或习惯性觅药的方法，其包括施用治疗有效量的水合氯醛。
在本发明的技术方案中，所述的方法为非诊断和治疗目的的。
在本发明的技术方案中，所述的方法中给予水合氯醛的剂量为20-500mg/kg，例如30mg/kg、40mg/kg、50mg/kg、60mg/kg、70mg/kg、80mg/kg、90mg/kg、100mg/kg、150mg/kg、200mg/kg、250mg/kg、300mg/kg、350mg/kg、400mg/kg、450mg/kg、500mg/kg。
在本发明的技术方案中，所述的方法中给予水合氯醛的时间为给予苯丙胺类中枢神经兴奋剂的同时，以及停药以后，或者在苯丙胺类中枢神经兴奋剂成瘾并停药后给予。
本发明另一个方面提供了水合氯醛在制备抑制苯丙胺类中枢神经兴奋剂复吸、降低受试者对苯丙胺类中枢神经兴奋剂依赖的药物中的用途。
本发明另一个方面提供了水合氯醛在制备抑制苯丙胺类中枢神经兴奋剂引起的条件性位置偏好或习惯性觅药的药物中的用途。
本发明再一个方面提供一种抑制苯丙胺类中枢神经兴奋剂复吸或依赖的药物组合物，其中水合氯醛作为药物组合物中的唯一活性成分。
在本发明的技术方案中，苯丙胺类中枢神经兴奋剂选自：甲基苯丙胺、亚甲二氧甲基苯丙胺、3,4-亚甲二氧基苯丙胺和其立体异构体、多晶型物、代谢物、前药、水合物、药学上可接受的盐和混合物。
在本发明的技术方案中，所述药物组合物还包括药学上可接受的载体。
在本发明的技术方案中，所述药物组合物的剂型选自下组：口服剂、注射剂、喷雾剂。
在本发明的技术方案中，所述药物组合物的剂型可通过选自下组的途径给药：口服给药、注射(皮下、肌肉、静脉)、粘膜给药、经皮给药和腹腔给药。
在本发明的技术方案中，受试者为哺乳动物，例如为人、猕猴、大鼠或小鼠。
有益效果
本发明证明了水合氯醛可以有效地降低苯丙胺类中枢神经兴奋剂条件性位置偏好，降低习惯性觅药和戒断后复吸，从而证明水合氯醛可以治疗苯丙胺类中枢神经兴奋剂引起的复吸、并可以降低对苯丙胺类中枢神经兴奋剂的依赖。
水合氯醛目前广泛用于临床尤其是儿科的镇静，低剂量的水合氯醛在临床上副作用小，安全可靠。因为水合氯醛已为临床使用药物，安全可靠，所以一旦动物实验证实其有效性，可以直接用于成瘾病人的治疗。
附图说明
图1为实施例1大鼠甲基苯丙胺CPP和水合氯醛处理示意图。CPP分为三个阶段：适应期(pre-conditioning)，条件化期(conditioning)和检测期(test)。在第一次测试(T1)后，动物被随机分组后接受水合氯醛或者生理盐水的治疗，之后进行第二次(T2)和第三次(T3)测试来验证治疗效果。T0：基线水平CPP测试。T1：建立甲基苯丙胺偏好后CPP测试。T2：水合氯醛给药周期结束后CPP测试。T3：水合氯醛给药周期结束后，经过14天再次进行CPP测试。
图2为实施例1的结果图，高剂量水合氯醛(100mg/kg)显著地降低了大鼠METH CPP的维持。生理盐水和50mg/kg的水合氯醛对T2时的CPP分数无明显的影响，即大鼠对甲基苯丙胺配对的场景偏好水平没有变化；而100mg/kg的水合氯醛显著地降低了T2时的CPP分数，大鼠对甲基苯丙胺配对的场景偏好水平显著降低。且低CPP分数可以维持到T3。ns,无显著性差异；*，p<0.05。T0：大鼠基线给药室停留时间，T1：建立甲基苯丙胺偏好后，大鼠在给药室内停留时间。T2：水合氯醛给药周期结束后，大鼠在给药室内停留时间。T3：水合氯醛给药结束14天后，大鼠在给药室内停留时间。
图3为实施例2的结果图，水合氯醛显著性降低了大鼠甲基苯丙胺的自给药次数。(A)连续给予大鼠3天50mg/kg剂量的水合氯醛降低了觅药次数但是没有达到统计显著性；(B)连续给予大鼠3天100mg/kg剂量的水合氯醛显著性地降低了大鼠的觅药次数。ns，无显著性差异；*，p<0.05。
图4为实施例3的结果图，水合氯醛显著地降低了大鼠甲基苯丙胺的复吸。与生理盐水组明显地增加active孔触碰次数(active poke)相比，100mg/kg水合氯醛处理的大鼠暴露于伴药的环境线索后，active孔的触碰次数与最后一天的消退相比并无显著变化。说明水合氯醛处理组大鼠(n＝7)对甲基苯丙胺给药线索不敏感，生理盐水组(n＝7)对甲基苯丙胺给药 线索非常敏感。Extinction代表消退阶段最后一天数据，在消退阶段每天训练后给予大鼠水合氯醛(CH)或者生理盐水(Saline)腹腔注射；Relapse代表复吸阶段数据。***：p<0.001,ns:没有显著差异。
具体实施方式
术语“苯丙胺类中枢神经兴奋剂”是指含有苯丙胺结构或苯丙胺类似结构母核的，且由苯丙胺转换而来的中枢神经的一类药用化合物或药用组合物，包含但不限于甲基苯丙胺、安非他命、亚甲二氧甲基苯丙胺、3,4-亚甲二氧基苯丙胺和其立体异构体、多晶型物、溶剂化物、水合物、代谢物、前药、药学上可接受的盐和混合物。
术语“治疗有效量”是指当向需要这种治疗的哺乳动物施用时足以使治疗起作用的如下定义的量。
术语“活性成分”是指药用组合物中的化合物，当向生物体(例如哺乳动物)施用时具有药理作用，且意图不仅涵盖化合物，而且涵盖化合物的药学上可接受的盐、药学上可接受的盐或酯、水合物、多晶型物和前药。
术语“前药”是指包含在体内可以转化和/或从分子的剩余部分分离出来，以提供活性药品、其药学上可接受的盐或其生物活性代谢物的化学基团的化合物。
术语“多晶型物”是指结晶化合物的不同晶体结构。不同的多晶型物可能例如由于不同晶体堆积结构(堆积多晶型)的存在或由于相同分子的不同构象异构体(构象多晶型)的存在引起。
术语“组合剂型”是指含有两种或更多种活性成分(例如，水合氯醛和苯丙胺类中枢神经兴奋剂)的组合的单位剂型(例如单药、片剂、胶囊、安瓿、栓剂或其它单位剂型)。
术语“溶剂化物”是指通过将化合物和溶剂组合而形成的络合物。
术语“水合物”是指通过将化合物和水组合而形成的络合物。
术语给定化合物的“药学上可接受的盐”是指保留给定化合物的生物有效性和特性的盐。
如本文所使用，术语“药学上可接受的载体”包含任何和所有溶剂、分散介质、包衣、抗细菌剂和抗真菌剂、等张剂以及吸收延迟剂等。这类介质和试剂用于药学活性物质的用途是所属领域众所周知的。除非任何常规介质或试剂与活性成分不相容，否则考虑将其用于治疗组合物中。还可以将补充性活性成分并入组合物中。
在本发明的技术方案中，所述的“抑制苯丙胺类中枢神经兴奋剂复吸”是指降低受试者在苯丙胺类中枢神经兴奋剂成瘾并停药后再次吸食成瘾的驱动力。所述的抑制指能够降低上 述驱动力任意一种程度。
在本发明的技术方案中，所述的“降低或抑制苯丙胺类中枢神经兴奋剂依赖”是指降低受试者在苯丙胺类中枢神经兴奋剂成瘾后产生的习惯性的觅药的行为。所述的抑制或降低指能够降低习惯性的觅药的次数或延长其觅药的间隔。
为了使本发明的上述目的、特征和优点能够更加明显易懂，下面对本发明的具体实施方式做详细的说明，但不能理解为对本发明的可实施范围的限定。
实验动物及药品
本实验所使用动物为6-14周大雄性SD大鼠。动物到动物房时6周大，根据体重被配对分为2只每笼，动物饲养在温度(22±1℃)和湿度(45±5％)稳定的环境中，光照条件为12小时光照/黑暗(光照时间为7:00-19:00或者8:00-20:00)，动物可以自由饮水和取食。每周对动物handle 2-3次，以减少人为处理对动物产生压力所带来的误差。所有实验都经过了中国科学院深圳先进技术研究院伦理委员会批准。晶体水合氯醛(纯度>＝98％),购买于Sigma-Aldrich(中国)，根据实验剂量溶解于灭菌的0.9％的生理盐水为10％和20％的溶液。
实验设备
条件性位置偏爱设备由四个自行设计的大小相同的三箱体行为箱和位于箱顶1.5米处摄像头(骆日出品，型号LRCP0680_1080P)组成。黑色聚乙烯行为箱(长×宽×高，70cm×25cm×30cm)被中间的两个隔板分为大小相同的侧箱(长×宽×高，30cm×25cm×30cm)和一个中间箱(长×宽×高，30cm×25cm×30cm)。两个侧箱具有不同的视觉(侧壁不同的壁纸)和触觉线索(一侧底板为细网格聚乙烯底板，另一侧为粗糙的黑色砂纸)；黑色中间箱的底板为黑色光滑底板。中间箱和侧箱之间有可移动小门。动物的行为由录像设备记录并传到电脑，之后用Anymaze软件(格罗贝尔生物科技公司，上海，中国)分析动物在各个箱体的停留时间。
动物自给药设备为8个自给药箱(安来软件科技公司，宁波，中国)，箱体一侧的活动面板上有两个鼻触孔，其中一个为active孔，动物触发此孔会有70μL的0.2mg/mL的METH注射至大鼠静脉并且有20s的给药线索(声音和灯光)，另外一个为inactive孔，触碰此孔无给药也无给药线索。为了防止动物过量给药，每次给药后有一个20s的空白期(time out)，在此期间大鼠鼻触active孔无任何给药。当进行自给糖水训练时，面板中央的给水口打开。动物触碰active孔会有70μL 5％蔗糖水从出水口流出，而inactive孔则无此反应。动物的鼻触行为将被实时传递到电脑上的软件系统(安来软件科技公司，宁波，中国)。
实施例1水合氯醛对大鼠METH CPP维持的影响
CPP分为三个阶段(图1)：适应期(pre-conditioning)，条件化期(conditioning)和检测期(test)。
适应期(第1-3天)：移除两侧门，大鼠在腹腔注射生理盐水后允许其自由探索三箱体15min，其中大鼠第3天在非偏爱箱一侧(即设置METH箱的一侧)停留的数据作为基准值(T0)，其中大鼠偏爱的一侧箱设置为生理盐水箱，而非偏爱的一侧设置为METH箱。
条件化期(第4-11天)：第4天腹腔注射甲基苯丙胺0.25mg/kg或者0.5mg/kg，将大鼠限制在METH箱内45min。24小时后，腹腔注射生理盐水，再将其限制在生理盐水箱内45min。如此进行4次配对。
测试期(第12,18,31天)：测试当天，移除两侧门，腹腔注射生理盐水后允许大鼠自由探索整个CPP箱体15min。在第12,18和31天分别进行测试检测非偏爱箱一侧(即设置METH箱的一侧)停留的数据，并记为T1，T2和T3。
水合氯醛/生理盐水处理：将动物随机分为生理盐水组，水合氯醛50mg/kg和水合氯醛100mg/kg三个组。在第13-18天，每天向三组动物分别注射生理盐水和水合氯醛。
所有数据都是使用Graphpad Prism 7.0(Graphpad,San Diego,美国)进行分析，显著性水平为p<0.05。
为了验证水合氯醛是否可以降低METH的奖赏性记忆，首先建立了METH的CPP模型，在大鼠CPP建立之后(T1)给予不同剂量的水合氯醛和生理盐水处理，之后再测试CPP的维持情况(T2和T3)。如图2所示，生理盐水和50mg/kg的水合氯醛处理对T2的CPP分数没有影响，但50mg/kg水合氯醛组T3时的CPP分数略有下降，这可能因为水合氯醛的慢性效果。而100mg/kg剂量的水合氯醛显著性地降低了T2时的CPP分数，且低CPP分数一直维持到T3。以上结果表明，水合氯醛的处理会降低大鼠METH CPP的维持，且随着剂量的增加起效时间缩短。
实施例2水合氯醛对大鼠METH习惯性觅药的影响
在大鼠12周大时进行自给药糖水训练。训练的具体步骤为，当大鼠触碰active孔的时候有70μL的5％蔗糖水作为奖励，同时伴有20s的声音和笼灯作为给糖水线索；而触碰inactive孔则没有任何反应。每天训练2h，连续训练6天。之后，大鼠用3％戊巴比妥钠麻醉后进行自给药埋管手术，将医用导管一端的硅胶管(内径0.32mm，外径0.64mm,陶氏，美国)插入右侧动脉，进入长度约为3cm。手术后动物恢复3-5天，期间每只动物每天给予0.2mL庆大霉素注射(10万单位/mL)防止感染。之后进行METH自给药训练，训练程序为FR1(fixed ratio 1),time out时间为20s，鼠鼻触一次active孔即可得到一次静脉注射METH(0.2mg/mL) 70μL，给药时伴随着声音和灯光线索，鼻触inactive孔则无给药也无声音和灯光线索。每天训练2h，连续训练6天后动物的自给METH次数达到稳定值(每天给药次数的变化不超过10％)，将动物随机分为三组并且在第6-10天自给药训练后分别给予动物腹腔注射生理盐水，水合氯醛50mg/kg或水合氯醛100mg/kg，记录并且分析三组动物的自给药次数是否有显著性差异。
所有数据都是使用Graphpad Prism 7.0(Graphpad,San Diego,美国)进行分析，显著性水平为p<0.05。
在偶然性的使用成瘾性物质后，由于药物的奖赏效应和戒断后的负性强化效应，一部分个体会形成习惯性的用药。为了使得个体迅速形成习惯性的觅药行为，大鼠首先接受了6天的自给糖水行为学训练习得鼻触active孔可以获得奖赏，之后进行自给METH训练。在METH的自给次数保持稳定值后，每天训练后给予大鼠不同剂量的水合氯醛水合氯醛注射，如图3所示，生理盐水组合50mg/kg组的给药次数与基础值相比，没有显著性的变化，而100mg/kg组的给药次数显著性低于基础值。以上结果表明高剂量的水合氯醛可以显著性地降低大鼠习惯性觅药次数。
实施例3水合氯醛对大鼠伴药线索诱导的METH复吸的影响
该部分包括习得性觅药、消退和复吸三部分。13周大的大鼠进行自给药埋管手术，术后恢复3-5天。之后，大鼠进行12天的Meth自给药训练(FR1，time out 20s)，每天训练2h。对于最后三天每天达到自给10次以上的大鼠进行消退训练。消退训练时，动物鼻触任何孔都无给药和伴药线索，每天训练1h。当达到连续三天active孔不高于10次的标准后进行复吸实验。每天消退训练后给予大鼠腹腔注射不同剂量的水合氯醛或者生理盐水，连续给药5天。对于伴药线索引起的复吸实验，大鼠进入自给药箱后会马上得到一次条件线索(灯光和声音)，随后的鼻触只激活条件线索但没有触发给药泵，测试持续1h。
所有数据都是使用Graphpad Prism 7.0(Graphpad,San Diego,美国)进行分析，显著性水平为p<0.05。
重复性的复吸是治愈成瘾的一大障碍。在戒断后，给药时的环境线索是导致复吸的一大诱因。为了检测水合氯醛对环境线索引起的复吸的影响，建立了大鼠METH的复吸模型。在消退训练后，大鼠接受生理盐水或者100mg/kg的水合氯醛腹腔注射，如图4所示，结果表明与生理盐水组相比，连续5天100mg/kg水合氯醛处理可以显著性地降低大鼠的复吸，表现为复吸时的鼻触次数和消退最后一天的次数无明显差异。
药物成瘾分为不同的阶段：初始阶段的偶然性用药，习惯性的觅药(依赖)和戒断后的复吸。其中复吸又分为条件性线索和药物本身引起的复吸。这些不同的阶段均可以由动物模型来模拟。本发明利用大鼠甲基苯丙胺的习惯位置偏好和自给药模型模拟了甲基苯丙胺依赖和复吸阶段，证明在这些阶段给予大鼠不同浓度的水合氯醛治疗能够降低对苯丙胺类中枢神经兴奋剂依赖，降低戒断后复吸。

Claims (10)

  1. 一种用于抑制受试者苯丙胺类中枢神经兴奋剂复吸、降低受试者对苯丙胺类中枢神经兴奋剂依赖的方法，其特征在于，其包括施用治疗有效量的水合氯醛。
  2. 一种用于抑制苯丙胺类中枢神经兴奋剂引起条件性位置偏好或习惯性觅药的方法，其特征在于，其包括施用治疗有效量的水合氯醛。
  3. 根据权利要求1或2所述的方法，其特征在于，所述的方法中给予水合氯醛的时间为给予苯丙胺类中枢神经兴奋剂的同时，以及停药以后，或者在苯丙胺类中枢神经兴奋剂成瘾并停药后给予。
  4. 根据权利要求1或2所述的方法，其特征在于，所述的方法中给予水合氯醛的剂量为20-500mg/kg。
  5. 水合氯醛在制备抑制苯丙胺类中枢神经兴奋剂引起的条件性位置偏好或习惯性觅药的药物中的用途。
  6. 水合氯醛在制备抑制苯丙胺类中枢神经兴奋剂复吸、降低受试者对苯丙胺类中枢神经兴奋剂依赖的药物中的用途。
  7. 抑制苯丙胺类中枢神经兴奋剂复吸或依赖的药物组合物，其特征在于，其中水合氯醛作为药物组合物中的唯一活性成分。
  8. 根据权利要求1所述的药物组合物，其特征在于，所述药物组合物还包括药学上可接受的载体。
  9. 根据权利要求1所述的药物组合物，其特征在于，所述药物组合物的剂型选自下组：口服剂、注射剂、喷雾剂
  10. 根据权利要求1-4任一项所述的方法，或根据权利要求5-6任一项所述的用途，或根据权利要求7-9任一项所述的药物组合物，其特征在于，苯丙胺类中枢神经兴奋剂选自：甲基苯丙胺、亚甲二氧甲基苯丙胺、3,4-亚甲二氧基苯丙胺和其立体异构体、多晶型物、代谢 物、前药、水合物、药学上可接受的盐和混合物。
PCT/CN2021/107945 2021-07-22 2021-07-22 水合氯醛在制备抑制苯丙胺类中枢神经兴奋剂复吸和依赖的药物中的应用 Ceased WO2023000271A1 (zh)

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