CN114601819A - Application of chloral hydrate in inhibiting opium drug relapse - Google Patents

Abstract

The invention discloses an application of chloral hydrate in inhibiting opium drug relapse. Specifically disclosed is a method for inhibiting opioid relapse in a subject comprising administering a therapeutically effective amount of chloral hydrate. Also discloses the application of the chloral hydrate in preparing the medicine for inhibiting the relapse of the opioid. Animal experiments prove that the chloral hydrate can effectively reduce behavioral sensitization caused by opioid drugs, thereby proving that the chloral hydrate can treat the relapse of the opioid drugs.

Description

Application of a kind of chloral hydrate in inhibiting opioid relapse

technical field

The invention belongs to the field of medicine, in particular to the application of chloral hydrate in inhibiting the relapse of opioids.

Background technique

Scientific research and clinical evidence over the past few decades have shown that drug addiction is a chronic brain disease.

The opioid crisis has been an urgent problem facing many countries in recent years. Due to the widespread use of prescription opioids and the large influx of heroin, as of 2016, about 62.3 million people in the United States have taken prescription opioids at least once, and about 2.6 million people are opioid addicts, about 42,000 people per year. People die from opioid overdose. As an analgesic, morphine is very effective in the treatment of various pains, especially acute pain and advanced cancer pain, and is often used to treat pain that other painkillers are ineffective. However, morphine users become dependent on morphine after continuous use for more than a week and become addicted with increasing use. The addictive nature of morphine greatly hinders its clinical application.

Chloral hydrate is commonly used in clinical anesthesia and sedation, and is one of the commonly used anesthetics in animal experiments. Clinically, co-administration of chloral hydrate and clonidine can treat neonatal opioid withdrawal syndrome. In morphine-dependent rats, a single pretreatment with chloral hydrate transiently suppressed the expression of naloxone-mediated withdrawal symptoms. The published research results of the present inventors show that, before the establishment of morphine conditioned place preference (CPP), rats were given intraperitoneal injection of medium dose chloral hydrate for 6 consecutive days, and morphine CPP could not be established in rats. These results suggest that chloral hydrate can inhibit opioid withdrawal symptoms and disrupt the acquisition of morphine reward memory. However, being able to suppress withdrawal symptoms does not necessarily mean suppressing relapse. Opioid withdrawal symptoms refer to spontaneous physical symptoms after opioid receptor antagonists (such as naloxone) or no antagonists are given after a period of drug use. Wet dog shaking and diarrhea. Relapse refers to the phenomenon of re-use of the drug or the enhancement of certain symptoms after the use of the addictive drug under the action of the driving force (or craving) to take the addictive drug after addiction and withdrawal. (eg behavioral sensitization). Relapse and withdrawal symptoms are neither identical nor directly necessarily related.

For addictive drugs, especially for medical use, there is still no good solution to the problem of relapse after addiction.

SUMMARY OF THE INVENTION

Aiming at the problem of relapse of opioids, the present invention provides the use of chloral hydrate in treating relapse of opioids. In order to achieve the above objects, the present invention provides the following technical solutions.

One aspect of the present invention provides a method for inhibiting opioid relapse in a subject comprising administering a therapeutically effective amount of chloral hydrate.

Another aspect of the present invention provides a method for inhibiting opioid-induced behavioral sensitization comprising administering a therapeutically effective amount of chloral hydrate.

In the technical solution of the present invention, the method is for non-diagnostic and therapeutic purposes.

In the technical scheme of the present invention, the dosage of chloral hydrate administered in the method is 0.1-500 mg/kg.

In the technical solution of the present invention, in the method, chloral hydrate is administered at the same time as the opioid drug is administered, and after drug withdrawal, or after opioid addiction and drug withdrawal.

Another aspect of the present invention provides the use of chloral hydrate in the preparation of a drug for inhibiting opioid relapse.

Another aspect of the present invention provides the use of chloral hydrate in the preparation of a medicament for inhibiting opioid-induced behavioral sensitization.

Another aspect of the present invention provides a pharmaceutical composition for inhibiting opioid relapse, wherein chloral hydrate is the only active ingredient in the pharmaceutical composition.

Yet another aspect of the present invention provides an analgesic combination dosage form comprising at least one opioid and chloral hydrate.

In the technical scheme of the present invention, the opioid is selected from the group consisting of: alfentanil, buprenorphine, butorphanol, carfentanil, codeine, diperidone, fentanyl, hydrocodone, hydrogen Morphinone, oxycodone, oxymorphone, levorphanol, lofentanyl, morphine, pethidine, methadone, remifentanil, heroin, tramadol, etorphine, dihydroetorphine, supra Fentanyl and its stereoisomers, polymorphs, metabolites, prodrugs, hydrates, pharmaceutically acceptable salts and mixtures.

In the technical solution of the present invention, the pharmaceutical composition further includes a pharmaceutically acceptable carrier.

In the technical solution of the present invention, the dosage form of the pharmaceutical composition is selected from the group consisting of oral preparations, injections, and sprays.

In the technical solution of the present invention, the dosage form of the pharmaceutical composition can be administered by a route selected from the group consisting of oral administration, injection (subcutaneous, intramuscular, intravenous), mucosal administration, transdermal administration and intraperitoneal administration medicine.

In the technical scheme of the present invention, the subject is a mammal, such as a human, a rhesus monkey, a rat or a mouse.

beneficial effect

The present invention proves that chloral hydrate can effectively reduce morphine-induced behavioral sensitization, and thus proves that chloral hydrate can treat morphine-induced relapse.

Chloral hydrate is currently widely used for clinical sedation, especially in pediatrics. Low-dose chloral hydrate has less side effects in clinical practice and is safe and reliable. Because chloral hydrate has been used clinically, it is safe and reliable, so once animal experiments confirm its effectiveness, it can be directly used in the treatment of addicted patients.

Description of drawings

Figure 1 is the experimental flow chart. Among them, A is the experimental process of the morphine group; B is the experimental process of the normal saline group. M represents that the mice were intraperitoneally injected with morphine on the same day; S represented that the mice were intraperitoneally injected with normal saline on the same day; S/CH represented that the mice were intraperitoneally injected with chloral hydrate saline solution or normal saline on the same day.

Figure 2 is the establishment of the morphine behavioral sensitization model. Among them, A is the experimental arrangement of behavioral sensitization; B is the change curve of the exercise volume of the mice in the normal saline group (n=6) and the morphine group (n=9) on days 1-20. M/S represents that the mice were intraperitoneally injected with morphine or normal saline on the day; S represented that the mice were intraperitoneally injected with normal saline on the same day. Morphine is morphine, Saline is saline, *** indicates significant difference, and p<0.001.

Figure 3 shows the results of low-dose chloral hydrate (50 mg/kg) reducing behavioral sensitization to morphine in mice. Among them, A. morphine group exercise amount and the effect of different doses of chloral hydrate (50mg/kg, 100mg/kg) and normal saline on morphine behavioral sensitization, and the bar in each group represents the injection of normal saline on the 0th day and the first day. The amount of exercise after 1, 4, 7, 10, 13 and 20 days of morphine injection; B. The comparison between the three groups after conversion to the percentage of exercise (the ratio of the exercise amount on the 20th day to the exercise amount on the 13th day), among which the Saline group Group A, that is, the group injected with morphine on days 1, 4, 7, 10, 13 and 20, and only given normal saline on days 14-18), CH50 group is group B, that is, groups 1, 4, 7, 10, Morphine was injected on days 13 and 20, and 50 mg chloral hydrate/kg body weight was administered on days 14-18. The ratio of exercise volume on day 20 to exercise volume on day 13, CH100 group was group C (ie, morphine group, and was administered on days 14-18). 100 mg chloral hydrate/kg body weight) the ratio of the exercise amount on the 20th day to the exercise amount on the 13th day, and the ordinate is the daily movement distance of the mouse in the horizontal direction. * means significant difference, p<0.05, ns means no significant difference.

Fig. 4 The results of no significant effect of chloral hydrate on the activity level of the normal saline group. Among them, A. The amount of exercise in the normal saline group and the effects of different doses of chloral hydrate (50mg/kg, 100mg/kg) and normal saline on morphine behavioral sensitization, the bars in each group represent the 0, 1, 4, The exercise volume after 7, 10, 13 and 20 days of injection of normal saline; B. The comparison between the three groups after conversion to the percentage of exercise volume (the ratio of the exercise volume on the 20th day to the exercise volume on the 13th day). Among them, the Saline group is the D group (that is, the normal saline group, and only normal saline is given for 14-18 days), and the CH50 group is the E group (that is, the normal saline group, and 50 mg chloral hydrate/kg body weight is given for 14-18 days) Experimental results, the CH100 group is the F group (ie, the normal saline group, and 100 mg of chloral hydrate/kg body weight was administered for 14-18 days). The ordinate is the daily movement distance of the mice in the horizontal direction. * means significant difference p<0.05, ns means no significant difference.

Detailed ways

In order to make the above objects, features and advantages of the present invention more clearly understood, the specific embodiments of the present invention will be described in detail below, but should not be construed as limiting the scope of the present invention.

The term "opioid" refers to a pharmaceutical compound or composition containing an opioid, including but not limited to alfentanil, buprenorphine, butorphanol, carfentanil, codeine, piperone, fentanyl, hydrocodone, hydromorphone, oxycodone, oxymorphone, levorphanol, lofentanil, morphine, meperidine, methadone, remifentanil, heroin, tramadol , etorphine, dihydroetorphine, sufentanil and its stereoisomers, polymorphs, solvates, hydrates, metabolites, prodrugs, pharmaceutically acceptable salts and mixtures.

The term "therapeutically effective amount" refers to an amount, as defined below, sufficient to effect the treatment when administered to a mammal in need of such treatment.

The term "active ingredient" refers to a compound in a pharmaceutical composition that has a pharmacological effect when administered to an organism (eg, a mammal), and is intended to encompass not only the compound, but also pharmaceutically acceptable salts, pharmaceutically acceptable salts of the compound. Accepted salts or esters, hydrates, polymorphs and prodrugs.

The term "prodrug" refers to a compound comprising a chemical group that can be transformed and/or separated from the remainder of the molecule in vivo to provide the active drug product, a pharmaceutically acceptable salt thereof, or a biologically active metabolite thereof.

The term "polymorph" refers to different crystal structures of a crystalline compound. Different polymorphs may arise, for example, by the presence of different crystal packing structures (packing polymorphs) or by the presence of different conformers of the same molecule (conformational polymorphs).

The term "combination dosage form" refers to a unit dosage form (eg, a single drug, tablet, capsule, ampule, suppository, or other unit dosage form) containing a combination of two or more active ingredients (eg, chloral hydrate and an opioid) in combination .

The term "solvate" refers to a complex formed by combining a compound and a solvent.

The term "hydrate" refers to a complex formed by combining a compound and water.

The term "pharmaceutically acceptable salt" of a given compound refers to salts that retain the biological effectiveness and properties of the given compound.

As used herein, 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 medium or agent is incompatible with the active ingredient, it is contemplated for use in the therapeutic composition. Supplementary active ingredients can also be incorporated into the compositions.

In the technical solution of the present invention, the "inhibition of opioid relapse" refers to reducing the driving force of a subject to become addicted to opioid addiction and after drug withdrawal. The suppressing means that any one of the above-mentioned driving forces can be reduced.

Laboratory animals and drugs

The animals used in this experiment were 8-week-old male C57BL/6J mice (Viton Lihua, Beijing, China). Animals were randomly grouped into 5 per cage, and the animals were housed in an environment with stable temperature (22 ± 1°C) and humidity (45 ± 5%) under a light condition of 12 hours light-dark (light hours 7:00-19:00). :00). All experiments were approved by the ethics committee of Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences. Morphine hydrochloride, 10 mg/mL, was purchased from Shenyang First Pharmaceutical Factory (Northeast Pharmaceutical Group, Shenyang, China) and diluted to 2 mg/mL with sterile normal saline before use.

experiment apparatus

The experimental equipment is two white boxes of the same size, the box size is 35cm×25cm×35cm, length×width×height. During the experiment, the box was placed in a noise-proof box with a camera (Microsoft IP Camera, Microsoft, USA) installed on the top of the box. The behavioral data of the animals are transmitted to the computer in real time through the camera, and the movement distance of the mice in the horizontal direction is detected and analyzed.

Example 1 Establishment of morphine behavioral sensitization model in mice and evaluation of the effect of chloral hydrate

The experimental procedures are shown in Figure 1A and Figure 1B (wherein S represents intraperitoneal injection of physiological saline, M represents intraperitoneal injection of morphine, and CH represents intraperitoneal injection of chloral hydrate). Briefly, on day 0, all animals received an intraperitoneal injection of normal saline at a dose of 1.0 mL/kg body weight. Then they were divided into 6 groups with 5-10 mice in each group, of which the three groups A, B and C were morphine groups. On the 1st, 4th, 7th, 10th and 13th days, the animals were given intraperitoneal injection of morphine, morphine The injection volume was 10 mg/kg body weight. The other three groups D, E and F were normal saline groups. The normal saline group was injected with normal saline intraperitoneally, and the injection volume of normal saline was 1 mL/kg body weight.

Then, on days 14-18, different doses of chloral hydrate were given to each group by intraperitoneal injection at 13:00 noon every day. The dose of group A and group D was 0 mg/kg body weight (ie, no chloral hydrate was injected, but normal saline was injected, and the injection volume of normal saline was 1.0 mL/kg body weight), and the dose of group B and E was 50 mg/kg body weight , the dose of group C and group F was 100 mg/kg body weight. On the 20th day, the mice in the morphine group A, B and C groups were injected with the morphine group respectively, and the mice in the normal saline group D, group, E and F groups were respectively injected with the normal saline. During the experiment, the movement distance of the mice in the horizontal direction was monitored every day.

All data were statistically analyzed using SPSS 22 with a significance level of p<0.05.

Analysis of results

The present invention successfully establishes the morphine behavioral sensitization model of mice. The behavioral sensitization model refers to the phenomenon in which the activity of animals gradually increases after repeated and intermittent administration of addictive drugs. Behavioral sensitization is correlated with relapse behavior, and this model was used to screen for drugs to treat relapse. The invention utilizes the morphine behavioral sensitization model of mice to evaluate the effect of chloral hydrate in the treatment of opioid relapse. The establishment method of this model is shown in Figure 2. After six morphine injections (days 1, 4, 7, 10, 13 and 20), compared with the normal saline group, the activity of the mice in the morphine group showed a gradual increase in activity. increased and maintained at a significantly higher level than the normal saline group. This indicates that the mouse model of morphine behavioral sensitization has been successfully established. When evaluating the effect of suppressing relapse, the model is to give morphine injection on the 13th day, and then give the morphine injection after a 1-week interval, that is, on the 20th day. Without the drive to relapse (ie, craving), the activity of the non-addictive drug will drop significantly, while the activity of the addictive drug will remain the same or increase. In other words, if the activity level on the 20th day decreased significantly, the drug administered was considered non-addictive, the experimental animals had no driving force for relapse, and the drug used for the intervention after stopping the injection of morphine achieved the effect of inhibiting relapse.

From the results of the present invention, 50 mg/kg chloral hydrate can significantly reduce the behavioral sensitization to morphine in mice. As shown in Figure 3A, the Saline group is group A (that is, the morphine group, and only normal saline is given on days 14-18). The experimental results on the 0th, 1st, 4th, 7th, 10th, 13th and 20th days, the CH50 group is the B group (ie morphine group, and 50 mg chloral hydrate/kg body weight was administered on days 14-18) Experimental results on days 0, 1, 4, 7, 10, 13 and 20, CH100 group was group C (ie morphine group, and 14- 100 mg chloral hydrate/kg body weight was administered on the 18th day) The experimental results on the 0th, 1st, 4th, 7th, 10th, 13th and 20th days, the ordinate is the daily movement distance of the mouse in the horizontal direction. The last two sets of data for Saline group, CH50 group and CH100 group are the exercise distance on the 13th and 20th days, respectively. The results showed that after 5 injections of chloral hydrate, group B (ie, morphine group, and 50 mg of chloral hydrate/kg body weight on days 14-18) had significantly lower activity on the 6th (20th day) than on the 5th. (13th day), there was a significant difference in activity, and the comparison between groups showed (as shown in Figure 3B) that the percentage change in activity in group C was also lower than that in group A; the percentage change in activity in group B was significantly lower than that in group A group (*p<0.05).

Because chloral hydrate itself has a sedative effect, the decreased activity of animals in the morphine group at the sixth test may be due to the sedative effect of chloral hydrate. Therefore, the present invention also sets three groups of controls as a reference (as shown in Figure 1B). After the first 5 injections of normal saline, the three groups of animals were given normal saline (group D), 50 mg/kg (group E), respectively. And 100mg/kg (F group) intraperitoneal injection of chloral hydrate for 5 days. Saline injections were given during the test period and the animals' activity levels were monitored. The results showed that there was no significant change in the 6th activity of the three groups of animals compared with the 5th exercise ( FIG. 4A ). In addition, there was no significant difference between the three groups in the percentage of activity parameter (Fig. 4B). These results indicated that chloral hydrate had no significant effect on the activity of animals in the sixth session, and that the decrease in activity after 50 mg/kg treatment was due to the inhibitory effect of chloral hydrate on morphine behavioral sensitization. In addition, by comparing the data of group B and group C, it can be seen that although the dose of chloral hydrate given by group C was higher, the amount of exercise on the last day was not lower than that of group B, which also explained from the side. The effect of chloral hydrate is primarily to reduce the urge to relapse, ie, behavioral sensitivity, rather than a calming effect.

From the above results, it can be seen that chloral hydrate can significantly reduce the behavioral sensitization of mice, and can be used to inhibit the relapse of opioids.

Claims (10)

1. A method for inhibiting opioid relapse comprising administering a therapeutically effective amount of chloral hydrate.

2. A method for inhibiting behavioral sensitization induced by opioids comprising administering a therapeutically effective amount of chloral hydrate.

3. Use of chloral hydrate in preparing medicament for inhibiting opium drug relapse.

4. Use of chloral hydrate in the preparation of a medicament for inhibiting behavioral sensitization caused by an opioid.

5. A pharmaceutical composition for inhibiting opioid relapse, wherein chloral hydrate is used as the sole active ingredient in the pharmaceutical composition.

6. The pharmaceutical composition of claim 5, in a dosage form for administration by a route selected from the group consisting of: oral administration, injection, mucosal administration, transdermal administration, and intraperitoneal administration.

7. The pharmaceutical composition of claim 5, further comprising a pharmaceutically acceptable carrier.

8. The pharmaceutical composition of claim 5, in a dosage form selected from the group consisting of: oral preparation, injection, and spray.

9. An analgesic combination comprising at least one opioid and chloral hydrate.

10. The method according to claim 1 or 2, the use according to claim 3 or 4, the pharmaceutical composition according to any one of claims 5 to 8, the combination dosage form according to claim 9, wherein the opioid is selected from the group consisting of: alfentanil, buprenorphine, butorphanol, carfentanil, codeine, risperidone, fentanyl, hydrocodone, hydromorphone, oxycodone, oxymorphone, levorphanol, lofentanil, morphine, meperidine, methadone, remifentanil, heroin, tramadol, etorphine, dihydroetorphine, sufentanil and stereoisomers, polymorphs, metabolites, prodrugs, hydrates, pharmaceutically acceptable salts and mixtures thereof.

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