CN111991406A - New use of gastrodin in suppressing opioid addiction - Google Patents

Abstract

The present invention relates to new medicinal uses of gastrodin, gastrodin preparations and pharmaceutical compositions containing them in the treatment of opioid addiction. The present invention verifies that gastrodin has a significant anti-oxycodone drug addiction effect through a rat behavioral pharmacology experimental method. Therefore, gastrodin can be applied to the development of anti-addiction drugs through further experimental studies.

Description

New use of gastrodin in suppressing opioid addiction

technical field

The invention relates to the field of traditional Chinese medicines, in particular to new uses of gastrodin, gastrodin preparations and pharmaceutical compositions containing them in treating opioid addiction.

Background technique

Opioids are the first choice for the treatment of second and third order-chronic moderate and severe pain in cancer pain because of their precise analgesic effect. Common opioids such as morphine, oxycodone, fentanyl, tramadol, etc., among which oxycodone-containing preparations include paracetamol, oxycodone extended-release tablets (Tylline) and oxycodone hydrochloride extended-release tablets ( OxyContin) is the world's first-selling and most frequently used analgesic drug. Since oxycodone is an opioid mu and κ dual agonist, its addiction-related mu opioid receptor affinity is only 1/5~1/10 that of morphine, and the equivalent analgesic effect is 2/2 of that of morphine. Therefore, it is considered by many domestic pain departments and oncologists as a low risk of addiction and safe and effective. However, sales of oxycodone in North America have increased dramatically in recent years, and its illegal abuse has created a serious public crisis. Oxycodone has reportedly become the most addictive and abused prescription opioid in North America, and oxycodone has been Considered the entry point drug for heroin addiction. Although there have not been a large number of reports of oxycodone drug addiction in my country at present, due to people's lack of awareness of drug dependence and the lack of strict review of indications and doses in the sales process of some pharmacies, it will inevitably lead to the use of oxycodone. Oxycodone, represented by opioid addiction, continues to emerge.

At present, clinical drug addiction patients mainly use methadone, compound buprenorphine and other drugs for treatment, but methadone itself has the risk of addiction, and buprenorphine has a capping effect, so it is necessary to develop new drugs and non-drug treatment methods. , to deal with substance abuse addiction.

Chinese traditional medicine has been researching drugs for detoxification since the Ming Dynasty. There are Lin Zexu's famous detoxification prescription "Ji Suan Pill" (ginseng, angelica, Bupleurum, Tianma, astragalus, aconite, Atractylodes, licorice), He Shutian's "prescription prescription". Addiction Pills (Aconite, Astragalus, Gastrodia, Cimicifuga, Bupleurum, Angelica, Agarwood, Zhigancao, Coptidis, Scutellaria, Soot), etc. After analysis, the drugs used in detoxification prescriptions in past dynasties are mainly to detoxify and attack pathogens, stop spasm and soothe the nerves, and strengthen the body and tonic. Wait. Among them, "Du Xiaoshu", which uses gastrodia elata as an important formula, has a 100% withdrawal rate for opioid-addicted patients after 15 days of treatment.

Gastrodia elata is the dry tuber of the orchid Gastrodia elata Bl. It is a precious traditional Chinese medicine in China, with the traditional effects of relieving wind and relieving spasm, calming liver-yang, dispelling wind and dredging collaterals. Gastrodin is one of the most important medicinal components. Modern pharmacological studies have shown that gastrodin has significant central nervous system regulating effects, such as anticonvulsant, antidepressant, sedative and hypnotic, analgesic, nootropic, etc., as well as cardiovascular system, immune system regulation. However, after reviewing the relevant literature at home and abroad, only the research report on the intervention of gastrodin on methamphetamine addiction in rats was found, but there was no research report on the effect of gastrodin on opioid addiction. Therefore, in order to clarify the therapeutic effect of gastrodin on opioid addiction, we studied the anti-addiction effect of gastrodin through rat behavioral experiments.

The invention relates to the application of gastrodin, a preparation developed with gastrodin as raw material and a pharmaceutical composition containing gastrodin or gastrodin preparation in treating opioid addiction.

SUMMARY OF THE INVENTION

Based on the above reasons and reasons, the main purpose of the present invention is to develop gastrodin for the prevention and treatment of drug addiction, and to lay a foundation for the development of anti-opioid receptor drug addiction.

In order to achieve the above object, the technical scheme of the present invention is:

First, a rat addiction model was established. Oxycodone was used as an addiction-inducing drug, and it was administered in continuous and intermittent ways of different concentrations and different times. In order to observe the effect of gastrodin on addicted rats more intuitively, the lateral ventricle administration method was selected. The craving for oxycodone in addicted rats showed a rebound increase after intubation in the lateral ventricle, and the established model was successful.

Then, after testing, the amount of drug inhalation and the number of licks in the gastrodin low-dose group and the gastrodin high-dose group were significantly lower than those in the control group. Ketone cravings.

The main purpose of the present invention is to propose that gastrodin can be used for opioid receptor drug addiction represented by oxycodone. Other preparations, such as tablets, capsules, granules, pills, suppositories, films, glues, ointments, powders, injections, mixtures, oral liquids, syrups, wines, sols, emulsions or eye drops, etc. In various forms, the medicines of the above-mentioned dosage forms can be prepared according to conventional methods in the pharmaceutical field. In addition, it also includes a pharmaceutical composition containing gastrodin, the pharmaceutical composition comprising chemical medicine or Chinese medicinal materials, decoction pieces and Chinese medicinal extracts.

The advantages of the present invention are:

The inhibitory effect of gastrodin on oxycodone-addicted rats was visually verified by using behavioral pharmacology experimental methods, which provided a scientific basis for the application of gastrodin and gastrodin-containing pharmaceutical compositions in anti-opioid receptor drug addiction.

Detailed ways

In order to illustrate the present invention in more detail, the following preparation examples are given. However, the scope of the present invention is not limited to this.

Example 1: Oxycodone addiction model experiment

1.1 Experimental materials

1.1.1 Animals: 10 healthy young 7-8 week-old DSS (Dahl/Salt sensitive rat) rats, weighing 180-200 g, provided by Changchun Yisi Laboratory Animal Technology, animal license number SCXK (Ji) -2019-0003. The rats were fed with standard chow, free access to food and water, 12 hours of light at 8:00 am every day, and the room temperature was kept at (25 ± 2 °C). During the experiment, food and water were fasted and noise interference was avoided.

1.1.2 Experimental reagent: oxycodone hydrochloride (Beijing Huasu Pharmaceutical Co., Ltd.).

1.1.3 Experimental equipment: conditioned place preference device (Med Associates, USA); self-administration experimental device (modified by conditioned place preference device, including two external drinking bottle stoppers (one of which is connected to the infusion pump drug delivery device), A series of devices such as licking and testing water bottle mouth data acquisition and control system, constant speed infusion pump).

1.2 Experimental steps:

1.2.1 Preparation of Oxycodone Solution

Precisely weigh an appropriate amount of oxycodone, dissolve it in double distilled water, prepare a stock solution of oxycodone with a mass concentration of 0.2 mg·mL ^-1 , and then dilute to a concentration of 0.025 mg·mL ^-1 and 0.05 mg·mL -1 respectively ^{. 1} and 0.1 mg·mL ^-1 of oxycodone solution, stored at 4 ℃ for later use.

1.2.2 Mode of administration

Oxycodone is administered continuously and then intermittently, and the concentration is increasing. The details are as follows: in the first week, it was administered once a day, 1 hour each time, with a dose of 0.025 mg·mL ^-1 ; in the second week, every Administered once every two days for 4 hours at a dose of 0.025 mg·mL ^-1 ; once every two days in the third week for 4 hours at a dose ^of 0.05 mg·mL ¹ ; in the fourth week, once every two days, each time for 4 hours, the dose is 0.1 mg·mL ^-1 ; in the fifth week, once every two days, each time for 4 hours, the dose is is 0.2 mg/mL.

1.2.3 Detection indicators and data processing

The body weight of the rats before each administration was recorded, the Anilab SuperState Version 4.0 software recorded the number of licks of the rats, and each 10 consecutive licks was recorded as a reward of 1 drop of 60 μL oxycodone solution, according to the reward of each rat The number of times to calculate the inhalation of oxycodone (mg·kg ^-1 ). The results were expressed as mean ± SD, and SPSS 20.0 software was used for statistical analysis.

1.3 Experimental results

First, the rats were given the lowest dose of oxycodone solution (0.025 mg·mL ^-1 ), and it can be seen from Table 1 that the number of licks and the amount of drugs inhaled by the rats within 1 h each day in the first week showed an increasing trend. Then, starting from the second week, the administration time was increased to 4 h, and the concentration of oxycodone solution was increased, and each concentration was administered 3 times. During the change of different administration methods, two days of withdrawal were implemented. Expect. Table 2 shows that the thirst for oxycodone in rats showed a trend of increasing first and then decreasing. When the concentration of oxycodone solution was 0.05 mg·mL ^-1 , the number of times of licking and the amount of drug inhalation reached the highest, followed by 0.1 mg·mL ^-1 concentration, and when the oxycodone solution increased to 0.2 mg·mL ^-1 , the craving for oxycodone in rats decreased accordingly, and this change trend was consistent with the law of drug addiction. Therefore, the optimal concentration of oxycodone was determined to be 0.05 mg·mL ^-1 for the subsequent oxycodone addiction rat model.

Table 1 Intake of oxycodone by rats in the first week (n=10)

Table 2 The intake of oxycodone in rats from 2 to 5 weeks (n=10)

Example 2: Model experiment of microdialysis in rat lateral ventricle

2.1 Experimental materials

2.1.1 Animals: Female DSS (Dahl/Salt sensitive rat) rats are the same as "1.1.1". Free access to food and water, room temperature maintained at (25 ± 2 ℃), light for 12 hours at 8:00 am every day, fasting and no water and noise interference during the experiment.

2.1.2 Experimental Reagents: Oxycodone Hydrochloride (Beijing Huasu Pharmaceutical Co., Ltd.), Isoflurane (Wuxi Bomeidi Biotechnology Co., Ltd.), Carprofen (Qingdao Kangdeen Pharmaceutical Co., Ltd.), En Norfloxacin (Tianjin Ruipu Bio-Pharmaceutical Co., Ltd.).

2.1.3 Experimental instruments: rat brain stereotaxic apparatus (Reward Life Sciences Co., Ltd.); dental benchtop drill (Shanghai Huanxi Medical Instrument Co., Ltd.); conditioned place preference device (Med Associates, USA); self-administration Experimental device (modified by the conditional position preference device, including two external drinking bottle stoppers, a series of devices such as lick test water bottle data acquisition and control system, constant-speed infusion pump, etc.). M2250 microdialysis catheter (BAS, USA).

2.2 Experimental steps

2.2.1 Embedding of the microdialysis catheter in the lateral ventricle of the rat

After the rats were anesthetized with the respiratory anesthetic isoflurane (2.5%), the head hair was shaved, fixed on the brain stereotaxic instrument, and the head skin was fully disinfected with iodophor and 70% alcohol, respectively, and then cut open to expose the skull. The middle suture, with the anterior fontanel as the origin, is positioned 1.6 mm behind the bregma, and 0.92 mm on the right side of the sagittal suture. Carefully adjust the rotation of the dental drill to drill a small hole with a diameter of about 0.6 mm, taking care to drill through the skull without damaging the brain , insert the cannula for brain injection with a depth of 3.0 mm. In addition, drill 3 more small holes before and after drilling for fixing screws. Take the tray powder to fix the catheter and screws, and insert the catheter nut. After the rats resumed their activities, they were reared in single cages. Before surgery, carprofen (5 mg·kg ^-1 ) and enrofloxacin (5 mg·kg ^-1 ) were subcutaneously injected for 3 consecutive days.

2.2.2 Consolidation of the oxycodone addiction model

The body weight changes of the rats were monitored daily, and after returning to the preoperative body weight, oxycodone was administered again, once every two days, for 4 h each time, with a dose of 0.05 mg·mL ^-1 , and the licking drug was recorded. The number of times and the number of rewards, the amount of oxycodone inhaled (mg·kg ^-1 ) was calculated, and the rat's thirst for oxycodone was not lower than the preoperative level, that is, the addiction model was successful.

2.3 Experimental results

During the operation, always pay attention to the anesthesia of the rat, and stop the bleeding in time to prevent the microdialysis catheter from falling off caused by infection. It can be seen from Table 3 that the body weight of the rats increased compared with that before operation. When 0.05 mg·mL ^-1 oxycodone was given again, the number of licks and the amount of drugs inhaled by the rats were higher than those of 0.2 mg·mL ^-1 oxycodone before operation. The craving increased, but did not reach the inhalation dose of 0.05 mg·mL ^-1 oxycodone at the time of modeling. Therefore, an oxycodone-addicted rat lateral ventricle microdialysis model was successfully established.

Table 3 Oxycodone intake of rats after operation (n=10)

Example 3: Intervention experiment of gastrodin on oxycodone-addicted rats

3.1 Experimental materials

3.1.1 Animals and groupings: 18 healthy young 8-week-old female DSS (Dahl/Salt sensitive rat) rats, weighing 180-200 g, provided by Changchun Yisi Laboratory Animal Technology, animal license number SCXK (Ji) -2019-0003. After modeling of oxycodone addiction, the rats were randomly divided into three groups after lateral ventricle microdialysis, 6 rats in each group, namely control group, gastrodin low-dose group (50 μg) and high-dose group (200 μg). . All were fed with standard feed, with free access to food and water, 12 hours of light at 8:00 am every day, and room temperature maintained at (25 ± 2 °C), fasting before the experiment and avoiding noise interference.

3.1.2 Experimental reagents: gastrodin (Shanghai Yuanye Biotechnology Co., Ltd., batch number: B21243, purity ≥98%); NaCl, KCl, CaCl ₂ , MgCl ₂ , Na ₂ HPO ₄ , NaH ₂ PO ₄ (Beijing Chemical Factory) ) are all analytically pure.

3.1.3 Experimental Instruments: Rat Brain Stereotaxic Instrument (Reward Life Sciences Co., Ltd.); Dental Desktop Drill (Shanghai Huanxi Medical Instrument Co., Ltd.); Conditioned Place Preference Device (Med Associates, USA); Self-administration Experimental device (modified by the conditional position preference device, including a series of devices such as two external drinking bottle stoppers, lick test water bottle data acquisition and control system, constant-speed infusion pump, etc.); M2250 microdialysis probe (BAS, USA); Micro syringe pump (Swedish CMA company).

3.2 Experimental steps

3.2.1 Solution Preparation

Preparation of cerebrospinal fluid: Dissolve 8.66 g of NaCl, 0.224 g of KCl, 0.206 g of CaCl ₂ , and 0.163 g of MgCl ₂ in 500 mL of purified water; respectively take 0.214 g of Na ₂ HPO ₄ and 0.027 g of NaH ₂ PO ₄ and dissolve in 500 mL of pure water in water. The above two solutions were sterilized and then refrigerated at 4 °C. Before use, the above two solutions were mixed in equal proportions, adjusted to pH 7.0, and filtered with a 0.22 μm microporous membrane for use.

Preparation of gastrodin solution: Accurately weigh 20 mg of gastrodin, use the above cerebrospinal fluid to prepare a 50 mg·mL ^-1 solution, filter with a 0.22 μm microporous membrane, and set aside.

3.2.2 Oxycodone addiction model

Oxycodone is administered continuously and then intermittently, and the concentration is increasing. The details are as follows: in the first week, it was administered once a day, 1 hour each time, with a dose of 0.025 mg·mL ^-1 ; in the second week, every Administered once every two days for 4 hours at a dose of 0.025 mg·mL ^-1 ; once every two days in the third week for 4 hours at a dose ^of 0.05 mg·mL ¹ .

The microdialysis catheter was embedded in the lateral ventricle of each rat according to the method of "2.2.1", and the body weight changes were monitored daily after the operation. Each administration for 4 hours, the administration dose was 0.05 mg·mL ^-1 , the number of licks was recorded, and the inhaled amount of oxycodone was calculated. The thirst for oxycodone in rats was not lower than that before operation, which was recorded as addiction. Model succeeded.

3.2.3 Administration of gastrodin

After the rats were anesthetized with the respiratory anesthetic isoflurane (2.5%), the screw cap of the catheter was unscrewed, and the inner needle with matching diameter was used to dredge the pipeline, and then the sterilized inner needle for injection was connected with the microinjection pump to adjust the microinjection. The pump flow rate was 1 μL·min ^-1 , the high-dose group was injected with 4 μL (200 μg), the low-dose group was injected with 1 μL (50 μg) gastrodin solution, and the control group was injected with a corresponding volume of cerebrospinal fluid, which was slowly and carefully removed 5 minutes after the injection was completed. inner needle, and then screw in the nut.

3.3 Experimental results

According to the previous oxycodone model administration method, firstly, 0.025 mg·mL ^-1 concentration of oxycodone solution was administered daily for 1 h, and then 0.025 mg·mL ^-1 and 0.050 mg·mL ^-1 concentrations of oxycodone were administered at intervals of 1 day. Codone 4 h, the results are shown in Table 4. The number of licks and the amount of drug inhalation increased significantly at different administration time, interval and concentration, and the rats in this addiction model were sensitive to two concentrations of oxycodone. The craving for the solution was also significantly higher than the previous inhalation of the same concentration of oxycodone.

Table 4 Establishment of oxycodone addiction model in rats (n=18)

When the lateral ventricle microdialysis catheter was placed in 18 rats for one week (no oxycodone solution was given during the operation), when the body weight and state of the rats returned to the preoperative level, the administration of oxycodone (0.05 mg·mL) was continued. ^-1 ), as a result, the thirst for oxycodone in each rat showed a jumping increase, the number of licking drugs for oxycodone in the same time period was more than twice that of the preoperative, and the inhaled amount of oxycodone was also nearly two times that before the operation. times, indicating that the operation did not affect the addiction of rats to oxycodone, and the model was successfully established.

Table 5 Addiction to oxycodone in rats after lateral ventricle microdialysis (n=18)

Eighteen rats were randomly divided into 3 groups, with 6 rats in each group. After 15 minutes of injection, the control group, the gastrodin low-dose group (50 μg) and the gastrodin high-dose group (200 μg) were placed in the rats in each group immediately. In the self-administration experimental device, oxycodone solution with a concentration of 0.05 mg·mL ^-1 was administered. The results are shown in Table 6. It can be seen that the number of licking of the rats in the high-dose gastrodin group was significantly lower than that in the control group ( p <0.05); compared with the control group, the high-dose gastrodin significantly reduced the number of rats Inhalation of oxycodone ( p < 0.01). Moreover, low-dose gastrodin also significantly inhibited the inhalation of oxycodone in rats ( p <0.05); although there was no significant difference in the number of licks in the low-dose gastrodin group compared with the control group, the number of licks in the low-dose group was also significantly different. reduce. It can be seen that gastrodin has a certain inhibitory effect on oxycodone-addicted rats, and can be developed as an addictive drug that interferes with opioid receptor drugs represented by oxycodone.

Table 6 Intervention of gastrodin on oxycodone-addicted rats (n=6)

Example 4: Preparation of gastrodin-containing preparations

4.1 Preparation process: take gastrodin as a raw material, add excipients required for different dosage forms, and produce according to the preparation technology of each dosage form.

4.2 Indications: Anti-opioid addiction; for the treatment of opioid addiction and withdrawal.

The above are only preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements and improvements made within the spirit and principles of the present invention are included in the protection scope of the present invention. Inside.

Claims (5)

1. The new purposes of gastrodin (Gastrodin, CAS 62499-27-8), is characterized in that, is used for preparing the medicine and health care product for the treatment of opioid addiction.

2. The use according to claim 1, wherein the dosage form of the medicament includes a solid dosage form and a liquid dosage form. 3. The use according to claim 2, wherein the solid dosage forms include tablets, capsules, granules, pills, suppositories, films, glues, ointments or powders. 4. The use according to claim 2, wherein the liquid dosage form comprises injection, mixture, oral liquid, syrup, wine, sol, emulsion or eye drops. 5. The application of a pharmaceutical composition in the treatment of opioid addiction, the composition comprising the gastrodin or gastrodin preparation according to any one of claims 1-4.