A medicament for treating and / or preventing methamphetamine addiction

Abstract

The application discloses a medicine for treating and / or preventing methamphetamine addiction, and belongs to the technical field of medicines. The application first discovers the effect of 4-(di(1H-indol-3-yl)methyl)phenol (DIM-C-pPhOH) in treating and / or preventing methamphetamine addiction. The 4-(di(1H-indol-3-yl)methyl)phenol has a synergistic inhibitory effect on two drug-seeking responses of goal-directedness and habituation, can simultaneously intervene in different neural circuits of addictive memory, has a more comprehensive and more stable anti-rehabilitation effect, and provides a new candidate medicine, i.e., 4-(di(1H-indol-3-yl)methyl)phenol, for treating and / or preventing methamphetamine addiction, so as to contribute to the early solution of the difficult problems of methamphetamine addiction withdrawal and relapse, and the elimination of the harm of methamphetamine addiction to physical health and social safety and stability.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a medicament for treating and / or preventing methamphetamine addiction. Background Technology

[0002] Substance addiction is a global problem that threatens public health and social security, among which methamphetamine (commonly known as crystal meth) is a serious culprit. Compared to traditional opioids, methamphetamine (MA) produces a stronger euphoria, causes greater harm to the body, and is more difficult to quit. The intense psychological cravings associated with methamphetamine addiction trap patients in a vicious cycle of initial use, withdrawal, craving, and relapse, seriously endangering their physical and mental health and social security. Therefore, the treatment and prevention of methamphetamine addiction are of great value: Methamphetamine users experience a persistent, high-level, and pathological state of excitement, accompanied by nervous system disorders, muscle tremors, acute mental disorders (such as hallucinations and delusions), and chronic toxic mental illness; it can cause serious heart diseases such as arrhythmia, high blood pressure, and myocardial infarction; overdose can even lead to acute poisoning and death; in the long run, it can also cause rapid weight loss, loss of appetite, ulcers, abscesses, and damage to the immune system, increasing the risk of infectious diseases (such as hepatitis and AIDS), and causing complications such as hepatitis and sepsis; it can also lead to anxiety, depression, paranoia, and even violent tendencies or self-harm, destroying family relationships, increasing the risk of crime, and endangering social stability.

[0003] The specific mechanisms underlying methamphetamine addiction and the resulting psychological cravings remain unclear. Clinically, there is no specific antidote for methamphetamine addiction; treatment primarily relies on a comprehensive approach to help patients recover: 1) Drug therapy, including antidepressants, anti-anxiety medications, and mood stabilizers, mainly used to alleviate withdrawal symptoms; 2) Psychotherapy, employing cognitive behavioral therapy and motivation enhancement therapy to help patients change erroneous cognitive patterns and boost their confidence in quitting; 3) Behavioral intervention, through behavioral modification training, enabling patients to learn to identify situations that trigger drug use and cultivate healthy alternative behaviors; 4) Social support, with family therapy and support groups providing emotional support to help patients rebuild their social networks and reduce the risk of relapse; 5) Long-term rehabilitation management, including regular follow-up visits, psychological counseling, and social function recovery training, continuously monitoring the patient's withdrawal status.

[0004] Developing effective drugs to treat and / or prevent methamphetamine addiction, and explaining the mechanisms of methamphetamine relapse and psychological craving from a molecular and cyclical perspective, will provide a theoretical basis for finding precise interventions in clinical practice. Summary of the Invention

[0005] The purpose of this invention is to provide a medicine for treating and / or preventing methamphetamine addiction, so as to provide a compound with a more comprehensive and stable effect in preventing and treating methamphetamine addiction and relapse.

[0006] To achieve the above objectives, the present invention provides a medicament for treating and / or preventing methamphetamine addiction, wherein the medicament uses 4-(di(1H-indol-3-yl)methyl)phenol as its active ingredient, and the structural formula of 4-(di(1H-indol-3-yl)methyl)phenol is as follows: .

[0007] Therefore, the present invention provides a drug for treating and / or preventing methamphetamine addiction, the specific technical effects of which are as follows: (1) This invention is the first to discover the role of 4-(di(1H-indol-3-yl)methyl)phenol (DIM-C-pPhOH) in the treatment and / or prevention of methamphetamine addiction; 4-(di(1H-indol-3-yl)methyl)phenol has a synergistic inhibitory effect on both goal-directed and habituation-based drug-seeking responses, and can simultaneously intervene in different neural circuits of addiction memory, thus having a more comprehensive and stable anti-relapse effect; (2) This invention provides a new candidate drug for the treatment and / or prevention of methamphetamine addiction—4-(di(1H-indol-3-yl)methyl)phenol, which contributes to overcoming the difficulties of methamphetamine addiction withdrawal and easy relapse as soon as possible, and eliminating the harm of methamphetamine addiction to physical health and social security and stability.

[0008] The technical solution of the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. Attached Figure Description

[0009] To more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings used in the description of the embodiments of the present invention will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0010] Figure 1 These are the statistical results of the effective nasal touch count in the embodiments of the present invention; wherein express p <0.01; *express p <0.001; ns indicates no statistically significant difference; Figure 2 This is the statistical result of the number of invalid nasal touches in the embodiments of the present invention; where ns indicates no statistically significant difference; Figure 3 These are the results of the investigation of the target-oriented drug-finding response in the embodiments of the present invention; wherein express p <0.01; *express p<0.001; ns indicates no statistically significant difference; Figure 4 These are the results of the habituation drug-seeking response investigation in the embodiments of the present invention; wherein express p <0.05; ns indicates no statistically significant difference. Detailed Implementation

[0011] The technical solution of the present invention will be further described below with reference to the accompanying drawings and embodiments.

[0012] To make the objectives, technical solutions, and advantages of this application clearer, more thorough, and more complete, the technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings and embodiments. The following detailed descriptions are all illustrations of embodiments, intended to provide further detailed explanation of the present invention. Unless otherwise specified, all technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains.

[0013] All instruments, equipment, and reagents used in the examples were obtained commercially. Methamphetamine was purchased from the Forensic Science Center of the Ministry of Public Security. The method of use was as follows: 50 mg of methamphetamine was dissolved in 250 mL of 0.009 g / mL sodium chloride aqueous solution, filtered through a 0.22 μm filter, and the solution was prepared fresh before use. DIM-C-pPhOH 4-(bis(1H-indol-3-yl)methyl)phenol was purchased from MCE (CAS: 151358-47-3). The method of use was as follows: 100 mg of DIM-C-pPhOH 4-(bis(1H-indol-3-yl)methyl)phenol was added to 6% DMSO and shaken until clear. Then, 44% polyethylene glycol 300 (PEG300), 5% Tween-80, and 45% physiological saline were added to prepare a working solution with a concentration of 6 mg / mL.

[0014] All methods and steps not detailed in the embodiments are conventional techniques in the art; male SPF-grade SD rats (8-10 weeks old) were purchased from Zhejiang Provincial Laboratory Animal Center (Hangzhou, China); all rats were housed in a temperature-controlled environment, with the temperature maintained at 22±2℃ and the relative humidity controlled at 50±10%, following a 12-hour light-dark cycle (lighting time from 6 pm to 6 am); all rats had free access to food and water during the experiment; all animal experiments were conducted in accordance with the "Guidelines for the Care and Use of Laboratory Animals of the National Institutes of Health" (8th edition) and were approved by the Ethics Committee of the Laboratory Animal Center of Ningbo University Affiliated Kangning Hospital; All measurements in this embodiment used independent samples, and the data are expressed as mean ± standard deviation of the mean. Statistical analysis was performed using Graphpad Prism 9. One-way ANOVA was conducted for data that met the homogeneity of variance, and pairwise comparisons were performed using Tukey's multiple comparisons post-hoc tests. Nonparametric tests were performed for samples that did not meet the homogeneity of variance. The significance level of the tests was set at 0.05.

[0015] Example 1 A self-administration (SA) model was constructed using male SPF-grade SD rats (8-10 weeks old) weighing 280-300g. The SA model drives the experiment through the animal's active behavior and can more accurately simulate human addictive behavior.

[0016] This study employed operant self-administration, based on the "operant conditioning" theory proposed by behaviorist psychologist B.F. Skinner. The experimental setup consisted of a modified Skinner box, including a soundproof enclosure (50cm×50cm×40cm), a training cage (30cm×30cm×25cm), an infusion pump, a cage light, two nasal cannulas, and a drug delivery system. Computerized programming controlled and recorded the participants' behavior. Methamphetamine, as a pharmacologically positive reinforcing agent, exhibited a reward effect.

[0017] In the experiment, rats learned to associate nasal touch with the effective orifice (operant response) with the outcome; that is, nasal touch elicited drug injection (unconditioned stimulus, US) and auditory-visual cues such as infusion pump activation and cage light illumination (conditioned stimulus, CS). As the experiment progressed, the rats gradually learned this association and developed stable self-administration behavior. After an extinction phase, these behaviors could be re-activated by auditory-visual cues or drug ignition stimuli, manifesting as a resumption of drug-seeking behavior.

[0018] In this experiment, referencing the experimental design of Anderson et al., the initial self-administration phase of rats was termed the reward phase, used to study drug-taking behavior; the nasal touch behavior of rats after withdrawal and re-exposure to auditory-light conditioned cues was termed cue-induced reinstatement, used to study drug-seeking behavior.

[0019] The specific steps are as follows: S1. Jugular vein catheterization surgery.

[0020] (1) Preparation of intravenous cannula: The intravenous cannula consists of two parts, including a 3-4cm thin silicone tube (OD 0.94mm, ID 0.51mm) and an 8-10cm PE20 (OD 1.09mm, ID 0.38mm) flexible tube. Immerse one end of the silicone tube in a small amount of chloroform for about 30 seconds to soften it, then insert the expanded end into the PE20 tube 1.5cm, adjusting the direction so that the bending direction of the two tubes is the same, thus obtaining the prepared intravenous cannula. Tie a flat knot at the junction of the silicone and PE20 tubes, and trim the end of the silicone tube into a bevel.

[0021] (2) Surgery: Before surgery, surgical instruments such as scissors, forceps, fine vascular scissors, and puncture needles were autoclaved and thoroughly disinfected along with the intravenous catheter by immersing them in 75% alcohol. The intravenous catheter was repeatedly rinsed and moistened with heparin / physiological saline (50U / mL) before surgery. Rats were anesthetized by intramuscular injection of Sutent 50 (50mg / kg) plus atropine sulfate (0.1ml / kg), and surgery began after the righting reflex disappeared.

[0022] Perform local skin preparation and alcohol disinfection at the pulsating point of the right neck triangle. Then, make a 1-2 cm incision approximately 1 cm lateral to the midline. Slowly open the incision using blunt forceps and perform blunt dissection. After blunt dissection, the characteristic V-shaped crossing of the distal end of the external jugular vein can be observed; the vascular incision is expected to be located below this crossing. Continue blunt dissection with forceps to clean the tissue and membrane surrounding the vessel, keeping it moist and ensuring a clear view. Use curved forceps to pry open and enlarge the perforation from the posterior side of the vessel, then secure it with suture. Use vascular scissors to cut a small V-shaped incision at a 45-degree angle (1 / 3 the width of the vessel diameter). Insert a guide needle into the vessel, then insert the thin end of the prepared cannula until part of the thicker tube is also inserted (note that the depth should not exceed the distance from the incision to the heart). After removing the guide needle, confirm the correct position and check the patency of the vessel. Connect a 1 mL flat-tipped syringe containing heparin / saline and aspirate. If bleeding occurs, the position is accurate; if the cannula cannot be aspirated, the cannula position needs to be adjusted. When ligating, first ligate the proximal end, then the distal end. Use a suture needle to pass through the insertion site, ligate it securely after passing through a layer of muscle. Use a skin needle to insert the tube subcutaneously under the right armpit, exiting through the midline of the back of the neck. Finally, check patency again, replace the plug, suture the skin, disinfect, apply erythromycin ointment to the wound, and put on a vest.

[0023] (3) Postoperative care: Prepare heparin / amikacin (10,000 units / kg) and administer via jugular vein cannula (0.1 mL / kg) for three consecutive days to fight infection. After each training session, flush the cannula daily or with heparin / saline (50 U / mL) via jugular vein cannula and promptly connect the plug to maintain patency and prevent vascular embolism. Rats were allowed free access to food and water after surgery and could begin behavioral training 5-7 days after recovery.

[0024] S2. Construct a reward model for methamphetamine self-administration.

[0025] Postoperative rats in S1, recovering for 5-7 days, were subjected to a 15g daily food restriction but no water restriction. A fixed ratio (FR) of 0.05mg / kg / infusion of methamphetamine was used for training, where FR1 (one effective nasal touch triggers one dose) was used for training. Each training session lasted 4 hours, conducted during the rats' dark cycle (starting at 9 am daily). Before training, the rats were placed in training cages, and the dorsal catheter was connected to the administration system in the cage, securing the connection. The entire administration tubing was filled with drug before connection to eliminate dead space. Upon start of training, the nasal touch light illuminated, and the cage light went out. When a rat touched an effective nasal touch, the effective nasal touch light went out, the white cage light illuminated, and the peristaltic pump sounded. After the injection, a 20-second refractory period followed, during which only nasal touch responses were recorded, but nasal touch no longer triggered drug injection. After the refractory period, the cage light went out, the nasal touch light illuminated, and the next administration cycle began.

[0026] The maximum daily dose was set at 1 mg. Training ended when the maximum dose was reached or the training time reached 4 hours, and the rats were returned to their cages. The rats underwent 10-14 training sessions until the maintenance criteria were met in the last 3 rounds: (1) at least 10 injections per round; (2) a variation of <20% in the number of injections over 3 consecutive rounds; and (3) an effective nasal touch count of 80% or more of the total nasal touch count.

[0027] S3, Cue-induced reinstatement test for methamphetamine.

[0028] After establishing the methamphetamine self-administration reward model in rats (S2), they underwent a 14-day withdrawal period in neutral cages, with free access to food and water, and no exposure to any drug-related audio-visual cues. This was followed by a 5-day environmental extinction program. During extinction, the rats were returned to their original training cages, but the drug administration system was removed. After the program was initiated, the cage light and nasal touch light were turned off, and the rats' nasal touch responses were automatically recorded. Nasal touch responses did not trigger drug administration or audio-visual cues. Each extinction period lasted 2 hours. The successful extinction criterion was: fewer than 15 effective nasal touches over two consecutive days; this criterion was typically achieved after 5 days of extinction. Rats that reached the extinction criterion could be subjected to a cue-induced relapse test the day afterward.

[0029] Rats that reached the extinction criteria underwent a 2-hour cue-induced relapse test the following day. The test procedure used the same FR1 protocol as self-administered drug training, but the key difference was that there was no real-time drug reinforcement during the test. At the start of the program, an uncoupled conditioned cue stimulus was given (a white cage light illuminates for 5 seconds, while the drug pump runs once, simulating the sound of drug administration) to reactivate drug-related memories. Subsequently, when the rat touched a valid nasal contact, a full conditioned cue stimulus (cage light illuminates + drug pump sound) was triggered again for 5 seconds. If the rat touched an invalid nasal contact, the stimulus was only recorded and had no consequences.

[0030] S4. Differentiation and Quantification of Two Types of Drug-Seeking Responses: To specifically assess the effect of the test drug on drug-seeking behavior driven by different motivations, based on the results of each effective nasal touch operation, it was precisely divided into two categories: (1) Goal-oriented drug-seeking response: refers to effective nasal touch behaviors that directly trigger conditioned cue stimuli. This type of response is driven by the goal (acquiring cues), depends on the behavior-outcome coupling relationship, and reflects the rat's active pursuit of the value of drug cues. (2) Habitual drug-seeking response: refers to effective nasal touch behaviors that occur within 5 seconds of the conditioned cue stimulus being presented. During this period, nasal touch operations cannot trigger new cue stimuli. This type of response is a manifestation of the habitual association between stimulus and response, which is detached from the expectation of the current behavioral outcome and is an automated, habitual behavioral pattern.

[0031] S5. Efficacy evaluation: If the test drug has therapeutic potential, it will significantly reduce the total number of effective nasal touches recorded in the relapse test.

[0032] S6. Dosage and Results.

[0033] After the final extinction training, rats were randomly divided into three groups of six rats each, with three dosage groups: 0 mg / kg, 10 mg / kg, and 20 mg / kg. All rats were administered DIM-C-pPhOH 4-(bis(1H-indol-3-yl)methyl)phenol via intraperitoneal injection one hour before the re-inhalation test. The results of the effective nasal touches within two hours of the start of the re-inhalation test are as follows: Figure 1 As shown, intraperitoneal injection of DIM-C-pPhOH reduces the number of effective nasal touch responses in a dose-dependent manner, at 10 mg / kg ( P =0.003) and 20mg / kg ( P Intraperitoneal injection of α=0.0002 significantly reduced cue-induced relapse behavior in rats.

[0034] The statistical results of invalid nasal touches within 2 hours of the start of the re-inhalation test are as follows: Figure 2 As shown, there was no significant difference in ineffective nasal touch response among the three groups. P=0.5519), indicating that the effect of DIM-C-pPhOH 4-(bis(1H-indol-3-yl)methyl)phenol on behavior is limited to effective nasal contact and is specific. The observed behavioral inhibition effect is a direct result of the specific pharmacological action of the DIM antagonist, rather than non-specific inhibition of motor function.

[0035] Analysis of specific drug-seeking response types, results as follows Figure 3 and Figure 4 As shown, intraperitoneal injection of DIM-C-pPhOH simultaneously reduces target-oriented drug-seeking behavior in a dose-dependent manner. P =0.0022) and habitual drug-seeking behavior ( P =0.0032). This indicates that in the classic addiction relapse paradigm, DIM-C-pPhOH 4-(bis(1H-indol-3-yl)methyl)phenol can significantly reduce methamphetamine addiction relapse behavior, suggesting that inhibiting Nr4a1 can effectively treat methamphetamine addiction.

[0036] By distinguishing between goal-oriented and habitual drug-seeking responses, the efficacy is demonstrated to stem from the synergistic inhibition of both goal-oriented and habitual drug-seeking responses. This suggests that the drug can simultaneously intervene in different neural circuits of addictive memory (e.g., circuits involving reward value assessment and prefrontal cortex regulation, as well as circuits involving the dorsal striatal habituation circuit), thereby producing a more comprehensive and robust relapse prevention effect.

[0037] Therefore, this invention is the first to discover the role of 4-(di(1H-indol-3-yl)methyl)phenol (DIM-C-pPhOH) in the treatment and / or prevention of methamphetamine addiction; 4-(di(1H-indol-3-yl)methyl)phenol has a synergistic inhibitory effect on both goal-directed and habituation-based drug-seeking responses, and can simultaneously intervene in different neural circuits of addiction memory, resulting in a more comprehensive and stable anti-relapse effect; it provides a new candidate drug for the treatment and / or prevention of methamphetamine addiction—4-(di(1H-indol-3-yl)methyl)phenol, contributing to the early overcoming of the difficulties in quitting methamphetamine addiction and the high relapse rate, and eliminating the harm of methamphetamine addiction to physical health and social security and stability.

[0038] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can still be made to the technical solutions of the present invention, and these modifications or equivalent substitutions cannot cause the modified technical solutions to deviate from the spirit and scope of the technical solutions of the present invention.

Claims

The use of 1,4-(bis(1H-indol-3-yl)methyl)phenol in the preparation of drugs for treating and / or preventing methamphetamine addiction, characterized in that: The drug uses 4-(di(1H-indol-3-yl)methyl)phenol as its active ingredient; the structural formula of 4-(di(1H-indol-3-yl)methyl)phenol is: .

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