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CN115671106B - Application of morphine - Google Patents

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CN115671106B
CN115671106B CN202110826983.4A CN202110826983A CN115671106B CN 115671106 B CN115671106 B CN 115671106B CN 202110826983 A CN202110826983 A CN 202110826983A CN 115671106 B CN115671106 B CN 115671106B
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morphine
rats
depression
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model
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CN115671106A (en
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吴传斌
曹超
尹绍平
陈航平
高越
罗家全
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Neworld Pharmaceutical Co ltd
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Abstract

The invention relates to a new application of morphine. Animal test results prove that morphine can obviously raise the erection times, sugar water consumption, weight and horizontal crossing number of a rat depression model, improve the blood 5-HT level of rats, quickly achieve the anti-depression effect, and overcome the defect that the conventional treatment method can only take effect for a plurality of weeks.

Description

Application of morphine
Technical Field
The invention relates to the field of medicine, in particular to a new application of morphine.
Background
Depression is one of the most common mental disorders characterized by persistent negative emotions and altered cognitive function. The symptoms of low emotion, suicidal thoughts, interest loss and the like are common clinical symptoms, and serious patients can be accompanied with mental symptoms such as delusions, hallucinations and the like, so that physical and mental health is seriously affected. World Health Organization (WHO) predicts that depression will become the leading cause of disease burden worldwide by 2030. The published reports of the global disease burden assessment institution (GBD) also indicate that depression has become the second greatest source of burden in excluding disabilities affecting work, and its effects on society have become increasingly apparent.
Current treatment for depression includes medication, modified electroconvulsive therapy (MECT), psychotherapy, and the like. However, currently, antidepressants such as fluoxetine, mi Anping, bupropion, venlafaxine and the like are commonly regulated by the brain monoaminergic system, and the effective time of the drugs is slow, and generally 2 to 3 weeks are required for improving clinical symptoms of patients, and the uncontrollable suicide and self-residual risks are extremely high during the period that the patients with depression receive treatment but the drugs are not effective, so that the public safety of society is greatly influenced. There is therefore a need to provide new antidepressants that act rapidly.
Morphine (Morphine) is an opioid receptor agonist, and Morphine and its derivatives are the main drugs clinically used for relieving severe pain, are the most potent analgesics used worldwide, and are often used for treating severe cancer pain according to the requirements of three-step scheme for cancer pain treatment proposed by the world health organization and national drug administration. In addition, morphine is also suitable for acute pain where other analgesics are ineffective, such as severe wounds, war wounds, burns, advanced cancers, etc.
Disclosure of Invention
Based on this, the object of the present invention is to provide a new use of morphine in the preparation of a medicament for the prevention and/or treatment of depression.
The specific technical scheme is as follows:
use of morphine or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof in the preparation of a medicament for the prevention and/or treatment of depression.
In some of these embodiments, the depression is major depression.
In some of these embodiments, the major depressive disorder is treatment-resistant depression.
In some of these embodiments, morphine can improve the lack of pleasure caused by depression in a depressed patient.
In some of these embodiments, morphine can improve weight loss in depressed patients due to depression.
In some of these embodiments, morphine can ameliorate depression-induced and exploratory decline in depressed patients.
In some of these embodiments, morphine can ameliorate the reduced ability to voluntary behavior caused by depression.
In some of these embodiments, morphine increases the level of 5-HT in a depressed patient.
It is another object of the present invention to provide a pharmaceutical composition for preventing and/or treating depression, the active ingredient comprising morphine and other antidepressants.
In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a new application of morphine in preparing medicaments for preventing and treating depression for the first time. Animal test results prove that morphine can obviously raise the erection times, sugar water consumption, weight and horizontal crossing number of a rat depression model, improve the blood 5-HT level of rats, quickly achieve the anti-depression effect, and overcome the defect that the conventional treatment method can only take effect for a plurality of weeks.
Furthermore, animal test results prove that morphine can obviously raise the number of horizontal crossing lattices, erection times, sugar water intake and weight of the rats with major depressive disorder, improve the blood 5-HT level of the rats with major depressive disorder, and can quickly achieve the effect of resisting major depressive disorder.
Drawings
FIG. 1 is a graph of 5-HT concentration in blood versus time for each group of rats in example 1;
FIG. 2 is a graph of 5-HT concentration in blood versus time for each group of rats in example 2.
Detailed Description
The experimental methods of the present invention, in which specific conditions are not specified in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. The various chemicals commonly used in the examples are commercially available.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
The terms "comprising" and "having" and any variations thereof, are intended to cover a non-exclusive inclusion. For example, a process, method, apparatus, article, or device that comprises a list of steps is not limited to the elements or modules listed but may alternatively include additional steps not listed or inherent to such process, method, article, or device.
In the present invention, the term "plurality" means two or more. "and/or", describes an association relationship of an association object, and indicates that there may be three relationships, for example, a and/or B, and may indicate: a exists alone, A and B exist together, and B exists alone. The character "/" generally indicates that the context-dependent object is an "or" relationship.
The present invention will be described in further detail with reference to specific examples.
Example 1: effect test of morphine on mouse model of depression
The experiment is as follows:
1. experimental animals: 30 healthy SD clean rats with the age of 2-3 months and the weight of 200-250g. The experimental animals were randomly divided into 3 groups of blank control group, model group and experimental group, 10 animals per group, and were kept in clean laboratory.
2. The experimental method comprises the following steps:
construction of a rat depression model: rats in the model group and experimental group were subjected to chronic unpredictability mild stimulation (CUNS) to construct a rat depression model, and rats were subjected to various stimuli for 21d after 1 week of adaptive feeding, including: water cut-off, food cut-off, night illumination for 12h, 100dB ringing, braking, restraint, suspension, tail clamping, foot sole electric shock, ice water (4 ℃ for 5 min) swimming, cage closing, heat stress, day and night inversion, 2 kinds/day, 2 times of use, random arrangement, discontinuous occurrence of the same stimulus, and 3 times of each stimulus on average.
And verifying whether the model is successfully built by comparing the model making day 21 with a baseline open field test, a syrup preference test and a weight monitoring result, and if the rat has common behavior characteristics of human depression patients such as continuous sense disappearance, psychomotor inhibition, mood reduction and the like, indicating that the model making of the depression model is successful. The success of the modeling was indicated in this study by three criteria of rat spontaneous activity distance below baseline 2s, sugar water preference reduction over 2s, and weight reduction over 2s being met at the same time.
3. The experimental process comprises the following steps: the experimental group rats were injected intraperitoneally with 2mg/0.5ml morphine hydrochloride solution for single administration treatment on day 2 after successful molding. The human and rat were dosed at 5mg/kg after conversion of body surface area, and the blank group and model group were injected with an equal amount of physiological saline.
Blood was collected 3 times before administration, 1ml each time, and used as a test for 5-HT concentration. Blood sampling was performed every 1h after administration (blood sampling frequency was adjusted to 2 h/time after 12 h; 4 h/time after 24 h; 8 h/time after 36 h), 1ml was collected each time, and used for 5-HT concentration examination.
4. Statistical analysis: SPSS 21 software is adopted to carry out single-factor variance statistical analysis, and experimental data are all thatThe test level is denoted α=0.05.
5 checking the project:
5.1 behavioral observations:
(1) open field test: 1 record was made 1 day before molding and 2 days after administration. Recording was performed in an indoor rest state, with a home-made open wooden box 100cm x 40cm in size, with a completely black inner wall and a bottom divided into equal areas of 25 grids. The rats were placed in a central square and the activity of the rats was recorded for 5 min. The number of horizontal crossing grids is the number of blocks of the rat crossing the bottom surface; the erection times are the times that the two forelimbs leave the ground. The open field experiment mainly reflects the behavior and emotion of animals to the new and abnormal environment, wherein the vertical erection times mainly reflect the exploratory capacity and curiosity of the instability of the rat to the strange environment, and the horizontal crossing number mainly reflects the excitability and autonomy of the rat to the new and abnormal environment.
(2) Sugar water preference experiment: 1 record was made 1 day before molding and 2 days after administration. And (3) carrying out adaptive training of 5% sucrose water at 48h before the experiment, cutting off water for 12h, continuously feeding, and measuring the sugar water consumption in 1h afternoon (15:00-16:00). The sugar water experiment mainly reflects the degree of lack of animal pleasure, and the pleasure lack is a core symptom of depression and is expressed by sugar water intake.
(3) Weight of: 1 weight measurement was performed 1 day before molding and 2 days after administration. Body weight reflects the overall condition of the animal and studies have shown that depressed patients often have clinical weight loss.
5.2ELISA detection of 5-HT: the 5-HT levels were detected using the rat 5-hydroxytryptophan ELISA kit (Shanghai Jiang Lai) following the kit instructions.
6. Experimental results
Behavioral observation:
before the experiment, the differences of the erection times, the sugar water consumption, the weight and the horizontal crossing lattice number of rats in the blank group, the model group and the experiment group have no statistical significance (P is more than 0.05). After experiments, the number of erection times, sugar water consumption, weight and horizontal crossing lattice number of rats in the model group are obviously reduced compared with that of the blank group, the difference is statistically significant (P is less than 0.05), and after intervention treatment through morphine, the number of erection times, sugar water consumption, weight and horizontal crossing lattice number of rats are obviously increased compared with that of the model group, and the difference is statistically significant (P is less than 0.05). The rising frequency of the erection of the rats indicates that the exploratory capacity and curiosity of rats with depression models can be improved after morphine administration; the increase of the number of horizontal crossing lattices of the rat indicates that the voluntary movement capacity and excitability of a depression model rat can be improved after morphine administration; an increase in sugar water consumption indicates that morphine administration can improve the loss of pleasure in rats with models of depression. The results are shown in Table 1 below.
Table 1 rat behavioural comparison 1
In conclusion, the number of horizontal crossing and erection times of rats in the model group are obviously reduced compared with those in the blank group, and the number of horizontal crossing and erection times of rats obviously rise after morphine drying. In addition, the sugar water intake of rats in the model group is obviously reduced compared with that in the blank group, and the sugar water intake of rats in the experimental group is obviously increased compared with that in the model group. Furthermore, the weight of rats in the model group is obviously reduced compared with that of rats in the blank group, and the weight of rats after morphine dry treatment is obviously increased compared with that of rats in the model group. The intervention of morphine is suggested, and the interest of rats in things and the food intake are increased, so that the weight increase of rats is influenced, and the intervention treatment is effective.
5-HT levels: the results are shown in FIG. 1, and the average results of three blood sampling before administration show that the 5-HT level in the blood of rats in the model group and the experimental group is lower than the normal range, which indicates that the model of the depression model of the rats is successful, and the 5-HT level of rats in the blank group is normal. The 5-HT level rapidly increased within 2h after dosing and reached average levels in normal mice within 5h of dosing and did not slowly decrease until 24h later, but remained within normal concentration ranges.
The present experimental study found that morphine was able to excite 5-HT neurons, allowing the level of 5-HT in a patient to be raised to normal levels in a short period of time and maintained at that concentration level continuously, thereby improving symptoms in depressed patients. The morphine can improve clinical symptoms of patients with depression within a few hours, the efficacy can last for 2-3 days, the anti-depression effect can be quickly achieved, the defect that the conventional treatment method can only take effect after a few weeks is overcome, and the morphine is very beneficial to the improvement and stabilization of symptoms of patients with depression.
Example 2: effect test of morphine on major depressive mouse model
The experiment is as follows:
1. experimental animals: 30 healthy SD clean rats with the age of 2-3 months and the weight of 250-300g. (the selection criteria for rats vary due to the longer construction time of the major depressive disorder model) the experimental animals were randomly divided into 3 groups of placebo, model and experimental groups of 10 animals each, kept in clean laboratory.
2. The experimental method comprises the following steps:
construction of a rat major depressive disorder model: the chronic unpredictable mild stimulation (CUNS) method was used to construct a model of major depressive disorder in rats in model and experimental groups, and rats received various stimulations for 10 weeks after 2 weeks of adaptive rearing, including: water cut, food cut, night illumination for 12h, 100dB ringing, braking, restraint, suspension, tail clamping, sole electric shock, ice water (4 ℃ for 5 min) swimming, cage closing, heat stress, day and night inversion, 3 kinds/day, 2 times of use, random arrangement, discontinuous occurrence of the same stimulus, and 3 times of each stimulus on average.
And verifying whether the model is successfully built by comparing the last day of the 10 th week of modeling with a baseline open field test, a syrup preference test and a weight monitoring result, and if the rat has common behavior characteristics of human depression patients such as continuous sense disappearance, psychomotor inhibition, mood reduction and the like, indicating that the model of the major depression is successful. The success of the modeling was indicated in this study by three criteria of spontaneous rat movement distance below baseline for 5s, sugar water preference reduction over 5s, and weight reduction over 5s being met at the same time.
3. The experimental process comprises the following steps: the experimental group rats were injected intraperitoneally with 2mg/0.5ml morphine hydrochloride solution for single administration treatment on day 2 after successful molding. The human and rat were dosed at 5mg/kg after conversion of body surface area, and the blank group and model group were injected with an equal amount of physiological saline.
Blood was collected 3 times before administration, 1ml each time, and used as a test for 5-HT concentration. Blood sampling was performed every 1h after administration (blood sampling frequency was adjusted to 2 h/time after 12 h; 4 h/time after 24 h; 8 h/time after 36 h), 1ml was collected each time, and used for 5-HT concentration examination.
4. Statistical analysis: SPSS 21 software is adopted to carry out single-factor variance statistical analysis, and experimental data are all thatThe test level is denoted α=0.05.
5 checking the project:
5.1 behavioral observations:
(1) open field test: 1 record was made 1 day before molding and 2 days after administration. Recording was performed in an indoor rest state, with a home-made open wooden box 100cm x 50cm in size, with a completely black inner wall and a bottom divided into equal areas of 25 grids. The rats were placed in a central square and the activity of the rats was recorded for 8 min. The number of horizontal crossing grids is the number of blocks of the rat crossing the bottom surface; the erection times are the times that the two forelimbs leave the ground. The open field experiment mainly reflects the behavior and emotion of animals to the new and abnormal environment, wherein the vertical erection times mainly reflect the exploratory capacity and curiosity of the instability of the rat to the strange environment, and the horizontal crossing number mainly reflects the excitability and autonomy of the rat to the new and abnormal environment.
(2) Sugar water preference experiment: 1 record was made 1 day before molding and 2 days after administration. And (3) carrying out adaptive training of 5% sucrose water at 48h before the experiment, cutting off water for 12h, continuously feeding, and measuring the sugar water consumption in 1h afternoon (15:00-16:00). The sugar water experiment mainly reflects the degree of lack of animal pleasure, and the pleasure lack is a core symptom of major depression and is expressed by sugar water intake.
(3) Weight of: 1 weight measurement was performed 1 day before molding and 2 days after administration. Body weight reflects the overall condition of animals, and studies have shown that major depressive patients often have clinical weight loss.
5.2ELISA detection of 5-HT: the 5-HT levels were detected using the rat 5-hydroxytryptophan ELISA kit (Shanghai Jiang Lai) following the kit instructions.
6. Experimental results
Behavioral observation:
before the experiment, the differences of the erection times, the sugar water consumption and the horizontal crossing lattice number of rats in the blank group, the model group and the experiment group have no statistical significance (P is more than 0.05). After experiments, the number of erection times, sugar water consumption, weight and horizontal crossing lattice number of rats in the model group are obviously reduced compared with that of the blank group, the difference has statistical significance (P is less than 0.05), and after intervention treatment through morphine, the number of erection times, sugar water consumption, weight and horizontal crossing lattice number of rats in the experiment group are obviously increased compared with that of rats in the model group, and the difference has statistical significance (P is less than 0.05). The rise of the erection times of the rats indicates that the exploratory capacity and curiosity of the rats with the major depressive disorder model can be improved after morphine administration; the increase of the number of horizontal crossing lattices of the rats indicates that the voluntary movement capacity and excitability of rats with major depressive disorder models can be improved after morphine administration; an increase in sugar water consumption indicates that morphine administration can improve the loss of pleasure in rats with major depressive disorder models. The results are shown in Table 2 below.
Table 2 rat behavioural comparison 2
In conclusion, the number of horizontal crossing lattices and the erection times of rats in the major depressive disorder model group are obviously reduced compared with those of rats in the blank group, the number of horizontal crossing lattices of the rats is obviously increased after morphine intervention treatment, and the erection times are obviously increased. In addition, the sugar water intake of rats in the major depressive disorder model group is obviously reduced compared with that of rats in the blank group, and the sugar water intake of rats in the experimental group is obviously increased compared with that of rats in the major depressive disorder model group. Furthermore, the weight of rats in the major depressive disorder model group is obviously reduced compared with that of rats in the blank group, and the weight of rats after morphine dry treatment is obviously increased compared with that of rats in the major depressive disorder model group. Indicating that after morphine stem prediction, rats are interested in things and have increased food intake, thereby influencing the weight increase of rats and having effective intervention treatment.
5-HT levels: the results are shown in FIG. 2, and from the average results of three blood sampling prior to dosing, the 5-HT levels in the blood of rats in the model group and the experimental group were lower than the normal range, indicating that the model of major depression was successful, whereas the 5-HT levels in rats in the blank group were normal. The 5-HT level rapidly increased within 2h after dosing and reached the average level of normal mice rapidly within 5h of dosing and continued to act, gradually decreasing after 20h, but still within the normal concentration range. The results show that after single administration of morphine, the mind of the patients with major depression, such as depression, attempting suicide, can be rapidly relieved, and the duration of the efficacy is long, and even if the 5-HT level is obviously reduced after 24 hours, the level is still higher than the average level of depressed rats.
Example 3: addiction test
1. Experimental animals:
20 healthy male and female half SD clean rats, 2-3 months old, and body weight 200-250g. The experimental animals were randomly divided into a blank group and a morphine group, and 2 groups of 10 animals were fed in a clean laboratory.
2. The experimental method comprises the following steps:
daily at 08 am: 00 and 20 pm: 00 intraperitoneal injections made of morphine hydrochloride solution (2 mg/0.5 ml), and the human and rat were dosed at 5mg/kg after conversion of body surface area, and the control group was injected with an equivalent amount of physiological saline for 4 weeks. After the end of the administration, the administration was stopped, and the clean laboratory was kept for 1 week, and the number of behaviors such as standing, cleaning fur, stretching, wet dog-like trembling, licking yin, biting tooth array number, ptosis, etc. of the rat were observed and recorded within 1 week. It is believed that the behavior of rats, such as erection, skin clearance, stretching, wet dog-like trembling, licking of the vagina, tooth arrays, ptosis, etc., is a central withdrawal response resulting from sudden withdrawal of opioid during continuous ingestion.
3. Statistical analysis: SPSS 21 software is adopted to carry out single-factor variance statistical analysis, and experimental data are all thatThe test level is denoted α=0.05.
4. Experimental results: the rats in each group above were observed for withdrawal and weight change within 1 week after discontinuation of dosing, and the results are shown in table 3 below:
TABLE 3 evaluation test of addiction to ratsn=10)
As can be seen from the results in Table 3, when the rats were continuously injected intraperitoneally for 4 weeks, no significant withdrawal reaction occurred and the difference was not significant by comparing the withdrawal reaction count and statistics with the blank control group and the morphine group. The fact that P is more than 0.005 and no significant difference exists shows that morphine in the dosage of the invention can not produce withdrawal symptoms, and has low addiction and good safety.
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.

Claims (6)

1. Use of morphine or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention and/or treatment of major depressive disorder.
2. The use according to claim 1, wherein morphine improves the lack of pleasure caused by major depression in patients with major depression.
3. The use according to claim 1, wherein morphine improves the weight loss in major depressive patients due to major depression.
4. The use according to claim 1, wherein morphine improves the decline in exploratory capacity of patients suffering from major depression due to major depression.
5. The use according to claim 1, wherein morphine improves the decrease in the ability of major depressive patients to act autonomously due to major depression.
6. The use according to claim 1, wherein morphine increases the level of 5-HT in a major depressive patient.
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