CN115337307A - New application of butorphanol or salt thereof in preparation of antidepressant drug - Google Patents
New application of butorphanol or salt thereof in preparation of antidepressant drug Download PDFInfo
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- CN115337307A CN115337307A CN202211153683.5A CN202211153683A CN115337307A CN 115337307 A CN115337307 A CN 115337307A CN 202211153683 A CN202211153683 A CN 202211153683A CN 115337307 A CN115337307 A CN 115337307A
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- depression
- butorphanol
- rats
- butorphanol tartrate
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Biomedical Technology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a new application of butorphanol or a salt thereof or a derivative thereof or a prodrug thereof or a stereoisomer thereof in preparing antidepressant drugs. The invention discovers the new medicinal value of the butorphanol and the salt thereof, and a large number of experiments prove that the clinical symptoms of the depressive patients can be obviously improved after the pharmaceutical effective dose of the butorphanol is administered to the depressive patients, and the clinical symptoms of the depressive patients can also be effectively improved after the pharmaceutical effective dose of the butorphanol is administered to the refractory depressive patients within a safe range. The discovery greatly enriches the medication scheme of depression and brings good news to depression patients.
Description
Technical Field
The invention relates to the technical field of medicaments, in particular to a new application of butorphanol or a salt thereof in preparing antidepressant medicaments.
Background
Depression is a common mental disease, 3 hundred million people are ill globally, serious harm is caused to physical and mental health, life quality, occupation and social function of patients, and the major reason for suicide is caused. Depression has become one of the leading causes of global disease burden, reaching $ 2000 billion per year in the united states alone. According to the WHO global burden of disease studies, depressive disorders account for 10% of disability caused by non-infectious diseases. Epidemiological surveys conducted in 17 developed countries worldwide have shown that on average 1 out of every 20 people have experienced depression in the past 1 year. The literature reports that the lifetime prevalence rate of the norwegian depression is as high as more than 35%. The number of antidepressant drugs used is increasing, from 7.7% in 1999-2002 to 12.7% in 2011-2014. In the united states, 15% of people have used antidepressants.
Generally, depression is classified into mild, moderate and major depression according to the severity of the disease, moderate depression should be subject to medical intervention, and major depression should be subject to normative medical treatment. The depression can be divided into non-treatment-resistant depression and treatment-resistant depression according to the responsiveness to medical intervention, the treatment-resistant depression refers to a patient who cannot satisfactorily relieve depression symptoms of patients with severe or bipolar depression after reasonable and standard treatment by 2 or more antidepressant drugs, and the treatment-resistant depression usually shows more serious life quality reduction and social and occupational ability damage compared with the non-treatment-resistant depression; the concomitant diseases have higher prevalence rate, the suicide tendency is more obvious, and the hospitalization frequency or time is 2 times of that of non-refractory depression. Common susceptibility factors of refractory depression include advanced age, dissimilarity and autism, other mental disorders or personality deficiency. The patients account for more than 30 percent of patients with major depression, and are the difficult points, hot spots and problems to be solved urgently in clinical therapeutics of depression. According to the manual of mental illness diagnosis and statistics, fifth edition of the United states, clinical diagnosis of major depression requires at least 5 clinical symptoms and persists for more than 2 weeks. Common clinical manifestations of major depressive disorder include lowered mood or increased pleasure, lack of interest and value, and feelings of guilt, inconsistent with the environment; decreased thinking ability and less concentration; anorexia and/or loss of physical quality; insomnia or hypersomnia; psychomotor excitation, and even schizophrenia-like symptoms such as hallucinations and delusions; feeling of fatigue or behavioral stiffness; suicide tendency or behavior, etc.
Clinically used antidepressant drugs are classified into the following categories according to their chemical structures and mechanisms of action: (1) a selective 5-hydroxytryptamine reuptake inhibitor; (2) 5-hydroxytryptamine and norepinephrine reuptake inhibitors; (3) norepinephrine and dopamine reuptake inhibitors; (4) a selective norepinephrine reuptake inhibitor; (5) 5-hydroxytryptamine blocking and reuptake inhibitors; (6) an alpha 2 adrenergic receptor blocker or a noradrenergic and specific 5 hydroxytryptamine antidepressant; (7) melatonin-acting antidepressants; (8) tricyclic antidepressants, including heterocyclic or tetracyclic antidepressants developed on this basis; (9) (ii) a monoamine oxidase inhibitor; the medicine for treating depression is prepared with plant medicine or Chinese patent medicine. In addition, several candidate antidepressant compounds with novel mechanisms of action are also in non-clinical and clinical studies, such as phosphodiesterase inhibitors with the activity of upregulating cyclic adenosine monophosphate response element binding protein transcription, mitogen-activated protein kinase modulators that upregulate the level of cell survival promoting factor Bcl-2 expression and other compounds that mechanistically upregulate Bcl-2 expression [ pramipexole ], agonists of metabotropic glutamate receptors ii/iii that modulate glutamate over-release, compounds that downregulate sodium channel function inhibiting glutamate release [ Li Lu thiazole (riluzole) ], alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (alpha-amino 3-hydroxy-5-methyl-4-isoxazole), AMPA) receptor agonists that upregulate brain-derived neurotrophic factor expression, N-methyl-D-aspartate receptor blockers (ketamine and meibominone) that increase neuronal plasticity and neuronal survival, glial receptor blockers that upregulate glial release, glucocorticoid receptor blockers, corticotropin-releasing corticotropin receptors, and glucocorticoid receptor blockers that promote glial release.
At present, the problems of slow response (response within 2-3 weeks), limited curative effect (ineffective for at least 1/3 of depression patients), serious adverse reaction, incapability of well controlling suicide tendency in the early stage of medication, lack of effective antidepressant medicines for patients with refractory depression and the like exist in the antidepressant medicine. Therefore, the research and development of the medicine which has good curative effect and can effectively treat the refractory depression has important significance on the anti-depression treatment.
Butorphanol is an opiate receptor partial agonist, mainly excites kappa 1 receptors, has weak blocking effect on the receptors, can relieve moderate and severe pain, is clinically commonly used for treating various cancer pains, postoperative pains and the like, and can also be used as a medicament before anesthesia.
Disclosure of Invention
Based on the above, the invention provides a new application of butorphanol or a salt thereof in preparing antidepressant drugs.
The invention comprises the following technical scheme.
Use of butorphanol or a salt or derivative thereof or a prodrug or a stereoisomer thereof in the manufacture of a medicament for the treatment of depression.
In some of these embodiments, the depression is major depressive disorder.
In some of these embodiments, the depression is treatment-resistant depression.
In some of these embodiments, the depression is non-pain-induced depression.
In some of these embodiments, the depression is one associated with aberrant NMDA receptor expression.
In some of these embodiments, the depression is depression associated with aberrant expression of NR1 receptors and/or NR2B receptors.
Use of butorphanol or a salt or a derivative or a prodrug or a stereoisomer thereof in the manufacture of a medicament for inhibiting the expression of NMDA receptors.
Use of butorphanol or a salt or derivative thereof or a prodrug or a stereoisomer thereof in the manufacture of a medicament for inhibiting the expression of NR1 receptors and/or NR2B receptors.
Use of butorphanol tartrate in the manufacture of a medicament for the treatment of depression.
Use of butorphanol tartrate in the manufacture of a medicament for the treatment of major depressive disorder.
Use of butorphanol tartrate in the manufacture of a medicament for the treatment of treatment-resistant depression.
Use of butorphanol tartrate in the manufacture of a medicament for the treatment of depression associated with aberrant NMDA receptor expression.
Use of butorphanol tartrate in the manufacture of a medicament for the treatment of depression associated with aberrant expression of NR1 and/or NR2B receptors.
Use of butorphanol tartrate in the preparation of a medicament for inhibiting the expression of NMDA receptors.
Use of butorphanol tartrate in the manufacture of a medicament for inhibiting the expression of NR1 receptors and/or NR2B receptors.
In some of these embodiments, butorphanol tartrate ameliorates anhedonia, weight loss, decreased exploration capacity, cognitive dysfunction, decreased desire to live, and/or decreased ability to voluntary behavior to activate in depressed patients due to depression.
In some embodiments, the medicament is in the form of nasal spray, injection, suppository, sublingual buccal, pill, tablet, capsule, sustained release agent, controlled release agent.
A pharmaceutical composition for preventing and treating depression is prepared from pharmaceutically acceptable adjuvants and active ingredients, wherein the active ingredients comprise butorphanol or salts thereof or derivatives thereof or prodrugs thereof or stereoisomers thereof.
In some embodiments, the pharmaceutical composition is in the form of nasal spray, injection, suppository, sublingual buccal, pill, tablet, capsule, sustained release agent, controlled release agent.
An aqueous solution of butorphanol tartrate for the treatment of depression, the concentration of butorphanol tartrate in the aqueous solution being 0.1 mg/mL -1 ～8mg·mL -1 。
A Chinese medicinal composition for treating refractory depressionAn aqueous solution of butorphanol tartrate, wherein the concentration of butorphanol tartrate in the aqueous solution of butorphanol tartrate is 1 mg/mL -1 ～8mg·mL -1 。
In some of these embodiments, the concentration of butorphanol tartrate in the aqueous solution is 1 mg-mL -1 ～6mg·mL -1 。
In some of these embodiments, the concentration of butorphanol tartrate in the aqueous solution is 2 mg-mL -1 ～6mg·mL -1 。
In some of these embodiments, the concentration of butorphanol tartrate in the aqueous solution is 3 mg-mL -1 ～5mg·mL -1 。
In some of these embodiments, the concentration of butorphanol tartrate in the aqueous solution is 4 mg-mL -1 。
Pain can trigger depressive symptoms to some extent, called painful depression (e.g., post-partum depression caused by pain), which are different from the pathogenesis of non-painful/major/refractory depression, caused by pain, in fact, by an adverse mood caused by pain, not in the true sense. Painful depression does not cause changes in the expression of receptors such as NMDA associated with depression, whereas the expression of NMDA receptors NR1 and NR2B in hippocampal tissues of major/treatment-refractory depression patients is abnormal, which is completely different from painful depression. Namely, the pain is the primary cause of painful depression, and thus when pain is relieved, the condition of depression is also improved. In this respect, drugs with analgesic action may alleviate the symptoms of depression caused by pain to some extent, for example, improve postpartum depression caused by pain by promoting the opioid receptor kappa 1 The expression of the Chinese medicinal composition achieves the effect of easing pain, thereby relieving depression mood. The inventor of the invention proves that the butorphanol has the function of relieving the painful depression through experimental research. But whether butorphanol also has a non-pain-induced depression/major/treatment-resistant depressionTherapeutic action? There is no relevant literature report. The inventor of the invention further discovers through a large number of experimental studies that butorphanol and salts thereof can inhibit the expression of NMDA receptors (especially NR1 and NR2B receptors), and thus can be used for treating major depressive disorder/treatment-resistant depressive disorder related to abnormal expression of NMDA receptors (especially NR1 and NR2B receptors).
The invention discovers the new medicinal value of the butorphanol and the salt thereof, and a large number of experiments prove that after the pharmaceutical effective dose of the butorphanol is administered to a depression patient, the clinical symptoms of the depression patient (such as anhedonia, weight reduction, exploration capacity reduction, cognitive dysfunction, reduction of desire for survival, and/or reduction of the activity capacity of autonomous behavior and the like caused by depression) can be obviously improved, and after the large dose of the butorphanol within a safe range is administered to a treatment-resistant depression patient, the clinical symptoms (such as anhedonia, weight reduction, exploration capacity reduction, cognitive dysfunction, reduction of desire for survival, and/or reduction of the activity capacity of autonomous behavior and the like caused by treatment-resistant depression) can be effectively improved. The discovery greatly enriches the medication scheme of depression and brings good news for depression patients.
Detailed Description
The technical solution of the present invention is further illustrated by the following specific examples. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.
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 non-exclusive inclusions. For example, a process, method, apparatus, article, or apparatus that comprises a list of steps is not limited to only those steps or modules recited, but may alternatively include other steps not recited, or may alternatively include other steps inherent to such process, method, article, or apparatus.
The "plurality" referred to in the present invention means two or more. "and/or" describes the association relationship of the associated object, indicating that there may be three relationships, for example, a and/or B, which may indicate: a exists alone, A and B exist simultaneously, and B exists alone. The character "/" generally indicates that the former and latter associated objects are in an "or" relationship.
The following are specific examples.
Example 1 Depression (DP) rat experiment
1 Material
1.1 Experimental animals
SPF male SD rat 70, 2-3 months old, body mass (200 + -20) g.
1.2 drugs and reagents
Self-made butorphanol tartrate solution
2. Method of producing a composite material
2.1 preparation of the drug
The rats are gavaged with 1 mL/kg per day -1 For example, the mass concentration is 0.1 mg/mL -1 The preparation method of the butorphanol tartrate solution comprises the following steps: precisely weighing 10mg of butorphanol tartrate, dissolving in 100mL of purified water to obtain a solution with a mass concentration of 0.1 mg/mL -1 This is the dose group 1. Solutions of butorphanol tartrate were prepared for other dose groups in the same manner: dose group 2 was 0.5 mg. ML -1 The butorphanol tartrate solution of (1 mg. ML) in the dosage group 3 -1 The butorphanol tartrate solution of the dosage group 4 is 2 mg/mL -1 The butorphanol tartrate solution of the formula (5) is 4 mg. Multidot.mL -1 The solution of butorphanol tartrate.
2.2 animal groups
SD rats had free diet drinking water, and after 1 week of acclimation, they were randomly assigned to 7 groups: normal group, model group, dose group 1, dose group 2, dose group 3, dose group 4, dose group 5, 10 of each group.
2.3 Depression model establishment
CUMS induction is selected for model preparation, 1-2 different stimulations are given to the rat every day, the stimulation modes are different every day, and are not repeated and irregular within 3d, so that the rat cannot predict certain stimulation. The specific stimulation mode comprises tail clamping for 10min, fasting for 24h, water prohibition for 24h, reversal of day and night, shaking for 15min, wetting the padding for 12h, binding for 3h, foot electric shock and tail suspension for 15min, and flash frequency illumination and cold water swimming at 10 ℃ for 10min. And (4) the molding time lasts for 5 weeks, the rat body mass is weighed before molding, and sugar water preference and behavioral experimental records are made. After the model is made, the body mass of the rat is reduced, the sweet water preference is reduced, the pleasure disappears, the spontaneous activity and the exploration behavior are weakened, the hope degree is presented in forced swimming, and the disorder of cognitive function appears, which indicates that the model is made successfully.
2.4 dosing and Morris Water maze training
The rats in each group are administrated according to body constitution, and are converted according to equivalent dose conversion formula between animal and human body, and the daily administration dose of rats after conversion of butorphanol tartrate dose groups 1, 2, 3, 4 and 5 is 0.1 mg/kg -1 ，0.5mg·kg -1 ，1mg·kg -1 ，2mg·kg -1 ，4mg·kg -1 . The normal group and the model group were subjected to the gavage with distilled water for 3 weeks, and the dose groups 1, 2, 3, 4, and 5 were administered with the calculated dose for 3 weeks, respectively. Performing water maze training simultaneously for the last 1 week of intragastric administration, continuously training for 5d, then resting for 1d, and immediately performing water maze test after the last 1 times of administration every other day.
2.5 detection of Depression-like behavior of rats by behavioral experiments such as sweet water preference, open field experiment, forced swimming and the like
Before molding, rats are trained for sweet water hobby, and 2 drinking bottles with the same specification are placed in each mouse cage. On day 1, both bottles are 1% sugar water, on day 2, 1% sugar water and distilled water are replaced by one bottle respectively, the positions of the two bottles are exchanged at intervals of 1h, on day 3, the user is fasted and water is forbidden, and after 24h, sugar water preference test is carried out; open field test: enclosing a closed space by a wood board with length, width and height (100, 50cm), keeping the room quiet and dim in light, dividing the bottom of the space into 25 grids, measuring the horizontal score of 1 score when the rat moves 1 grid, measuring the vertical score of 1 score when the front two feet are away from the ground 1 time, and recording the horizontal score and the vertical score of the rat in 5 min; forced swimming experiment: the rat is placed in a transparent container with the height of 50cm and the diameter of 30cm so that the rat cannot escape, the survival desire of the rat is observed within 6min, the first 2min is not timed, and the immobility time within 4min is recorded.
2.6 statistical analysis the experimental data were statistically analyzed using SPSS 21 software, the group comparisons were analyzed using one-way anova, and the data were measured to
Is represented by P<0.05 indicates that the difference is statistically significant.
3 results
3.1 compared with the normal group, the influence of the model group on the body quality of the DP rat is obviously reduced (P < 0.05); compared with the model group, after 3 weeks of administration, the body mass of rats 1, 2, 3, 4 and 5 in the butorphanol tartrate dose groups is obviously increased, the difference has statistical significance (P is less than 0.05), and the body mass increases of rats 3, 4 and 5 in the butorphanol tartrate dose groups are most obvious. See table 1.
Table 1 effect of butorphanol tartrate on body mass of DP model rats (
n＝10)
Note: (1) comparison with Normal group P<0.05； (2) Comparison with model group P<0.05 (in tables 1-6.)
3.2 Effect on DP rat carbohydrate preference and behaviourology
3.2.1 Effect on DP rat carbohydrate preference
Compared with the normal group, the sugar water preference of the rats in the model group is obviously reduced (P < 0.05); compared with the model group, after the administration for 3 weeks, the sugar water preference of the rats in the butorphanol tartrate dose groups 1, 2, 3, 4 and 5 is obviously improved (P is less than 0.05), and the anhedonia degree of the rats is obviously improved. See table 2.
Table 2 effect of butorphanol tartrate on DP model rat sugar water preference ((s))
n＝10)
3.2.2 Effect on autonomous Activity in open field experiments in DP rats
The horizontal score and the vertical score of the rats in the model group are obviously reduced compared with the normal group (P < 0.05); compared with the model group, the horizontal scores and the vertical scores of the butorphanol tartrate dose groups 1, 2, 3, 4 and 5 are obviously improved (P < 0.05), and the autonomic behavior activity of rats is improved. See table 3, table 4.
Table 3 effect of butorphanol tartrate on horizontal movement in DP model rats: (
n＝10)
Table 4 effect of butorphanol tartrate on vertical movement of DP model rats: (
n＝10)
3.2.3 Effect on the degree of despair in forced swimming of DP rats
Compared with the normal group, the rats in the model group show more desperate behaviors when in forced swimming, and the immobility time of the rats is obviously prolonged (P < 0.05); compared with the model group, the rats struggle for longer time after administration in the butorphanol tartrate dose groups 1, 2, 3, 4 and 5, the immobility time is obviously shortened (P < 0.05), the survival desire of the rats is promoted, and the depression-like despair degree of the rats is improved. See table 5.
Table 5 effect of butorphanol tartrate on forced swimming of DP model rats (
n＝10)
3.3 Effect on spatial learning and memory ability of DP rats
Compared with the normal group, the escape latency of the model group rats is obviously prolonged (P < 0.05); compared with the model group, the escape latency of rats in the 1, 2, 3, 4 and 5 butorphanol tartrate dose groups is obviously shortened (P < 0.05); meanwhile, in tests, the tartaric acid butorphanol dosage groups 4 and 5 have strong purpose on the 3 rd quadrant, which prompts that the tartaric acid butorphanol dosage groups can effectively improve the space learning and memory ability of DP rats, and particularly the tartaric acid butorphanol dosage groups with high dosage are most obvious. See table 6.
TABLE 6 influence of butorphanol tartrate on the spatial learning capacity of DP model rats: (
n＝10)
The DP model rats have reduced physical mass and show obvious behavioral changes in depression, which indicates successful modeling. After rats in a dose group are treated by the butorphanol tartrate solution, the physical quality of DP rats is obviously increased, the cognitive dysfunction of DP rats induced by CUMS is effectively improved, the activity ability of autonomous behaviors, the anhedonia degree, the desire for survival and the despair degree of depression are obviously improved, and the butorphanol tartrate can effectively improve the depression expression of DP rats in the aspect of behaviourology.
Example 2 treatment-resistant Depression (TRD) rat experiment
1 Material
1.1 Experimental animals
SPF male SD rat 70, 2-3 months old, body mass (200 + -20) g.
1.2 drugs and reagents
Self-made butorphanol tartrate solution
2. Method of producing a composite material
2.1 preparation of the drug
The rat is gavaged with 1 mL/kg every day -1 For example, the mass concentration is 0.1 mg/mL -1 The preparation method of the butorphanol tartrate solution comprises the following steps: precisely weighing 10mg of butorphanol tartrate, dissolving in 100mL of purified water to obtain a solution with a mass concentration of 0.1 mg/mL -1 This is the dose group 1. Solutions of butorphanol tartrate were prepared for other dose groups in the same manner: dose group 2 was 0.5 mg. ML -1 The butorphanol tartrate solution of the dosage group 3 is 1 mg/mL -1 The butorphanol tartrate solution of (1) has a dosage group of 4 mg. Multidot.mL -1 The butorphanol tartrate solution of the formula (5) is 4 mg. Multidot.mL -1 The solution of butorphanol tartrate.
2.2 animal groups
SD rats had free diet drinking water, and after 1 week of adaptive feeding, they were randomly divided into 7 groups: normal group, model group, dose group 1, dose group 2, dose group 3, dose group 4, dose group 5, 10 of each group.
2.3 Depression model establishment
CUMS induction is selected for model preparation, 2-3 different stimulations are given to the rat every day, the stimulation modes are different every day, and are not repeated and irregular within 3d, so that the rat cannot predict certain stimulation. The specific stimulation mode comprises clamping tail for 10min, fasting for 24h, water-depriving for 24h, shaking cage for 15min by reversing day and night and shaking, wetting padding for 12h, binding for 3h, electrically shocking foot and hanging tail for 15min, and flashing frequency light and swimming for 10min with cold water at 10 ℃. And (4) the molding time lasts for 10 weeks, the rat body mass is weighed before molding, and sugar water preference and behavioral experimental records are made. After the model is made, the body mass of the rat is reduced, the sweet water preference is reduced, the pleasure disappears, the spontaneous activity and the exploration behavior are weakened, the hope degree is presented in forced swimming, and the disorder of cognitive function appears, which indicates that the model is made successfully.
2.4 dosing and Morris Water maze training
The rats in each group are administrated according to physical quality, and converted according to equivalent dose conversion formula between animal and human body, and the daily administration dose of rats after conversion of butorphanol tartrate in the groups 1, 2, 3, 4 and 5 is 0.1 mg/kg -1 ，0.5mg·kg -1 ，1mg·kg -1 ，2mg·kg -1 ，4mg·kg -1 . The normal group and the model group were subjected to the gavage with distilled water for 3 weeks, and the dose groups 1, 2, 3, 4, and 5 were administered for 5 weeks, respectively, in the calculated dose. Performing water maze training simultaneously for the last 1 week of intragastric administration, continuously training for 5d, then resting for 1d, and immediately performing water maze test after the last 1 times of administration every other day.
2.5 detection of Depression-like behavior of rats by behavioral experiments such as sweet water preference, open field experiment, forced swimming and the like
Before molding, rats are trained for sweet water hobby, and 2 drinking bottles with the same specification are placed in each mouse cage. On day 1, both bottles are 1% sugar water, on day 2, 1% sugar water and distilled water are replaced by one bottle respectively, the positions of the two bottles are exchanged at intervals of 1h, on day 3, the user is fasted and water is forbidden, and after 24h, sugar water preference test is carried out; open field test: enclosing a closed space by a wood board with length, width and height (100, 50cm), keeping the room quiet and dim in light, dividing the bottom of the space into 25 grids, measuring the horizontal score of 1 score when the rat moves 1 grid, measuring the vertical score of 1 score when the front two feet are away from the ground 1 time, and recording the horizontal score and the vertical score of the rat in 5 min; forced swimming experiment: the rat is placed in a transparent container with the height of 50cm and the diameter of 30cm so that the rat cannot escape, the survival desire of the rat is observed within 6min, the first 2min is not timed, and the immobility time within 4min is recorded.
2.6 statistical analysis the experimental data were statistically analyzed using SPSS 21 software, the group comparisons were analyzed using one-way anova, and the data were measured to
Is represented by P<0.05 indicates that the difference is statistically significant.
3 results
3.1 compared with the normal group, the influence of the TRD rat body mass is obviously reduced (P < 0.05); compared with the model group, after 5 weeks of administration, the body mass of the butorphanol tartrate dose groups 1 and 2 was not significantly increased, suggesting that the dose had no effect on TRD rats, and in addition, the body mass of the rats of the dose groups 3, 4 and 5 was significantly increased, and the difference had statistical significance (P < 0.05), while the body mass of the butorphanol tartrate dose group 5 was most significantly increased. See table 7.
Table 7 effect of butorphanol tartrate on TRD model rat body mass (
n＝10)
Note: (1) comparison with Normal group P<0.05； (2) Comparison with model group P<0.05 (in tables 7-12)
3.2 Effect on TRD rat sugar Water preference and behaviourology
3.2.1 Effect on TRD rat sugar Water preference
Compared with the normal group, the sugar water preference of the rats in the model group is obviously reduced (P < 0.05); compared with the model group, after 5 weeks of administration, the sugar preference of the butorphanol tartrate dose groups 1 and 2 is not obviously improved, the sugar preference of rats of the dose groups 3, 4 and 5 is obviously improved (P is less than 0.05), the anhedonia degree of the rats is obviously improved, and particularly the dose group 5 is most obviously improved. See table 8.
Table 8 effect of butorphanol tartrate on TRD model rat sugar water preference ((r))
n＝10)
3.2.2 Effect on the autonomic Activity of TRD rats in open field experiments
The horizontal score and the vertical score of the rats in the model group are obviously reduced compared with the normal group (P < 0.05); compared with the model group, the horizontal scores and the vertical scores of the butorphanol tartrate dose groups 3, 4 and 5 are obviously improved (P < 0.05), and the autonomic behavior activity of rats is improved. See tables 9 and 10.
Table 9 effect of butorphanol tartrate on horizontal movement of TRD model rats: (
n＝10)
TABLE 10 Effect of butorphanol tartrate on TRD model rat vertical movement: (
n＝10)
3.2.3 Effect on the degree of despair of TRD rats in forced swimming
Compared with the normal group, the rats in the model group show more desperate behaviors when in forced swimming, and the immobility time of the rats is obviously prolonged (P < 0.05); compared with the model group, the rats 3, 4 and 5 in the butorphanol tartrate dose group after administration struggle for a longer time, the immobility time of the rats is obviously shortened (P < 0.05), the survival desire of the rats is promoted, and the depression-like despair degree of the rats is improved. See table 11.
TABLE 11 Effect of butorphanol tartrate on forced swimming of TRD model rats: (
n＝10)
3.3 Effect on spatial learning and memory ability of TRD rats
Compared with the normal group, the escape latency of the model group rats is obviously prolonged (P < 0.05); compared with the model group, the escape latency of rats 3, 4 and 5 in the butorphanol tartrate dose groups is obviously shortened (P < 0.05), particularly the high dose of butorphanol tartrate is most obvious. See table 12.
Table 12 effect of butorphanol tartrate on spatial learning ability of TRD model rats (
n＝10)
From the data, the butorphanol tartrate has no effect on the body mass, the autonomous activity, the anhedonia degree and the survival desire and even the depressive-like despair degree of the TRD model rat at low dose (dose groups 1 and 2), but the effect appears when the dose is gradually increased (dose group 3), but the significant improvement cannot be achieved, the dose is continuously increased (dose groups 4 and 5), the body mass of the TRD model rat is obviously increased, the CUMS-induced cognitive dysfunction of the TRD model rat is effectively improved, and the autonomous behavior activity, the anhedonia degree and the survival desire and even the depressive-like despair degree of the TRD model rat are obviously improved. This indicates that high doses of butorphanol tartrate are behaviorally effective in improving the depressive manifestations in TRD rats.
Example 3: TRD model NMDA receptor expression detection in rat brain hippocampal tissue
1 Material
1.1 Experimental animals
Male Wistar rats 45, 2-3 months old, with a body mass of 200-250g were used as the subjects.
1.2 drugs and reagents
Self-made butorphanol tartrate solution and normal saline
2. Method of producing a composite material
2.1 preparation of the drug
The preparation method of the butorphanol tartrate solution comprises the following steps: precisely weighing 400mg of butorphanol tartrate, dissolving in 100mL of purified water to obtain the drug with the mass concentration of 4 mg.mL -1 The solution of butorphanol tartrate.
2.2 animal groups
SD rats had free diet drinking water, and after 1 week of adaptive feeding, were randomly divided into 3 groups: normal group, model group, experimental group, 15 per group.
2.3 establishment of refractory Depression (TRD) model
CUMS induction is selected to carry out TRD model preparation on rats in a model group and an experimental group, 2-3 different stimulations are given to the rats every day, the stimulation modes are different every day, and the stimulation modes are not repeated and irregular within 3d, so that the rats cannot predict certain stimulation. The specific stimulation mode comprises tail clamping for 10min, fasting for 24h, water prohibition for 24h, reversal of day and night, shaking for 15min, wetting the padding for 12h, binding for 3h, foot electric shock and tail suspension for 15min, and flash frequency illumination and cold water swimming at 10 ℃ for 10min. The molding time lasted 10 weeks.
2.4 administration
The rats in each group are administrated according to physical quality, and converted according to equivalent dose conversion formula between animal and human body, and the daily administration dose of the rats in the butorphanol tartrate experimental group is 4mg kg -1 And (3) carrying out intragastric perfusion with distilled water in the normal group and the model group, taking tissues after administration for 12h, and carrying out protein detection on the hippocampal tissues.
2.5 Western-blot detection method
The total protein in the hippocampus tissue of the rats in the above 3 groups is extracted by Western-blot method, centrifuged at 4 deg.C and 12,000r/min for 10min, and the supernatant is subjected to electrophoresis. Preparing 4% concentrated gel and 10% separation gel according to the formula, performing vertical electrophoresis at 100V, 20min,120V and 90min and electrotransformation at 100V and 90min after spotting. After completion, the NC membrane was taken out and blocked with 5% skim milk for 2h, washed with tbst for 5min × 3 times, cut according to molecular weight and added with NRI, NR2B, actin primary antibody of 1. The following day the NC membranes were removed, washed 5min x 3 times with TBST, incubated 2h at room temperature with the addition of 1. Calculating the gray value of the protein band, taking the gray value/actin gray value of the target gene as the protein content, setting the average value of the target gene protein content of the normal group as 100, and calculating the protein content of the model group and the experimental group. Antibodies were provided by Alomone corporation.
2.6 statistical analysis the experimental data were statistically analyzed using SPSS 21 software, the comparisons between groups were analyzed using one-way anova, and the data were measured to
Is represented by P<0.05 indicates that the difference is statistically significant.
3 results
NMDA receptors are divided into types of NR1, NR2A/B/C/D, NR A/B and 533A/B, wherein the functions of NR1 and NR2B are most clear and are closely related to the functions of a nervous system, and researches show that the expression of NMDA receptors NR1 and NR2B in hippocampal tissues of a rat model of refractory depression is abnormal and higher than that of healthy rats, so that the experiment establishes a rat model of refractory depression and characterizes the occurrence and improvement of depression by the content of NR1 and NR 2B.
The results are shown in Table 13: the protein contents of NR1 and NR2B in the hippocampal tissues of the model group rats are higher than those of the empty normal group and the experimental group, the difference has statistical significance (P is less than 0.005), and the model building is successful. The protein contents of NR1 and NR2B in hippocampal tissues of rats in an experimental group subjected to butorphanol desiccation are equivalent to those of rats in a normal group, which shows that butorphanol can effectively inhibit the expression of NMDA, so that the depression symptom of the rats is improved. From this result, the NMDA receptor is the target of the effect of butorphanol on major/treatment-resistant depression.
TABLE 13 Effect of butorphanol tartrate on the expression levels of NR1 and NR2B receptors in rat hippocampus
| Group (n = 15) | NR1 | NR2B |
| Normal group | 100.0±9.4 | 100.0±7.8 |
| Model set | 256.4±7.2 | 209.8±3.5 |
| Experimental group | 106.1±7.6 | 105.9±7.4 |
| F | 1783 | 1346 |
| P | ＜0.05 | ＜0.05 |
Example 4: open field and sugar water preference test of pain type depression model rat
1 materials
1.1 Experimental animals
Male SD rats 30, 2 to 3 months old, with a body mass of 200 to 250g were used as the subjects.
1.2 drugs and reagents
Self-made butorphanol tartrate solution and normal saline
2. Method of producing a composite material
2.1 preparation of the drug
The preparation method of the butorphanol tartrate solution comprises the following steps: precisely weighing 400mg of butorphanol tartrate, dissolving in 100mL of purified water to obtain the drug with the mass concentration of 4 mg.mL -1 The solution of butorphanol tartrate.
2.2 animal groups
SD rats had free diet drinking water, and after 1 week of adaptive feeding, were randomly divided into 3 groups: normal group, model group, experimental group, 10 per group.
2.3 establishment of Complete Freund's Adjuvant (CFA) arthritis-induced painful Depression rat model
After the rats of the model group and the experimental group are subjected to sevoflurane inhalation anesthesia, 50 mu l of CFA is injected into the right ankle joint cavity of the rat, and the rat model with the pain type depression can be obtained by freely drinking water and feeding for 2 weeks on a standard diet under a normal environment.
2.4 administration of drugs
The rats in each group are administrated according to physical quality, and are converted according to an equivalent dose conversion formula between animals and human bodies, and the daily administration dose of the rats in the butorphanol tartrate experimental group is 4 mg/kg -1 And carrying out open field test and sugar water preference test 12h after administration.
2.5 open field test and sugar water preference test
Before modeling, rats are trained on sweet water hobby, and 2 drinking bottles with the same specification are placed in each mouse cage. On day 1, replacing two bottles with 1% sugar water, on day 2, replacing one bottle of each of 1% sugar water and distilled water, exchanging positions of the two bottles at intervals of 1h, on day 3, fasting and water-depriving, and performing sugar water preference test after 24 h; open field test: a closed space is enclosed by a wood board with length, width and height (100, 50cm), the room is kept quiet, light is dim, the bottom of the space is divided into 25 grids, a rat moves 1 grid to count the horizontal score for 1, the front two feet are separated from the ground 1 time to count the vertical score for 1, and the horizontal score and the vertical score of the rat in 5min are recorded.
2.7 statistical analysis the experimental data were statistically analyzed using SPSS 21 software, the group comparisons were analyzed using one-way anova, and the data were measured to
Is represented by P<0.05 indicates that the difference is statistically significant.
3 results
The results of the sugar water preference test and the open field test are shown in tables 14-16 below.
Table 14 effect of butorphanol tartrate on sugar water preference in rats model for painful depression: (
n＝10)
Table 15 effect of butorphanol tartrate on horizontal movement in rats model for painful depression: (
n＝10)
Table 16 effect of butorphanol tartrate on vertical movements of rats model for painful depression: (
n＝10)
From the above results, complete Freund's Adjuvant (CFA) arthritis rats successfully built a pain-type depression model, and rats co-morbid with pain and depression showed depressed rat characteristics: the sweet water preference degree is obviously reduced, the horizontal shuttling frequency is obviously reduced, the vertical frequency is also obviously reduced, and the depression performance is improved after the butorphanol is administrated.
Example 5: detection of NMDA receptor and opioid receptor kappa 1 content in blood of rats tested by pain depression model
1 Material
1.1 Experimental animals
Male SD rats 30, 2 to 3 months old, with a body mass of 200 to 250g were used as the subjects.
1.2 drugs and reagents
Self-made butorphanol tartrate solution and normal saline
2. Method for producing a composite material
2.1 preparation of the drug
The preparation method of the butorphanol tartrate solution comprises the following steps: precisely weighing 400mg of butorphanol tartrate, dissolving in 100mL of purified water, wherein the mass concentration of the drug is 4 mg/mL -1 。
2.2 animal groups
SD rats had free diet drinking water, and after 1 week of adaptive feeding, they were randomly divided into 3 groups: normal group, model group, experimental group, 10 of each group.
2.3 establishment of Complete Freund's Adjuvant (CFA) arthritis-induced painful Depression rat model
After the rats of the model group and the experimental group are subjected to sevoflurane inhalation anesthesia, 50 mu l of CFA is injected into the right ankle joint cavity of the rat, and the rat model with the pain type depression can be obtained by freely drinking water and feeding for 2 weeks on a standard diet under a normal environment.
2.4 administration
The rats in each group are administrated according to physical quality, and are converted according to an equivalent dose conversion formula between animals and human bodies, and the daily administration dose of the rats in the butorphanol tartrate experimental group is 4 mg/kg -1 Normal group sum modePerfusing the stomach with distilled water, taking blood after administration for 12h, and detecting the content of opioid receptor kappa 1 by an enzyme-linked immunosorbent assay method; at the same time, the tissue was collected and protein detection of hippocampal tissue was performed as described in example 3.
2.5 detection kit (enzyme-linked immunosorbent assay) for opioid receptor kappa 1 in blood
After blood is taken from the 3 groups of rats, an enzyme-linked immunosorbent assay method is adopted, and the operation is carried out according to the kit operation instructions, so as to detect the content of the opioid receptor kappa 1. The opioid receptor kappa 1 detection kit was purchased from Wuhan cloud clone technologies, inc.
2.6 measurement of NMDA receptor expression in rat hippocampal tissues as described in example 3.
2.7 statistical analysis of experimental data Using SPSS 21 software, comparison between groups Using one-way analysis of variance, data metering
Is represented by P<0.05 indicates that the difference is statistically significant.
3 results
Pain causes depression to some extent, and both are in an aggravating relationship with each other, so that when pain is relieved, depression is also improved. As can be seen from the experimental results of table 17: the content of opioid receptor kappa 1 in the blood of the model group rats is lower than that of the normal group and the experimental group, and the difference has statistical significance (P is less than 0.005), which indicates that the modeling is successful. The content of the opioid receptor kappa 1 in blood of the rats in the experimental group subjected to butorphanol intervention is equivalent to that of the rats in the normal group, which shows that butorphanol can effectively promote the expression of the opioid receptor kappa 1, so that the analgesic effect is shown, and the depression state is improved because pain is relieved. This example, in combination with example 4, demonstrates that butorphanol can improve the symptoms of depression caused by pain by alleviating pain.
It can also be seen from the experimental results of table 17: there was no difference in the protein content of NR1, NR2B in the hippocampal tissues of the normal group, model group and experimental group rats. This suggests that the symptoms of depression caused by pain are independent of NMDA receptor expression, and the pathogenesis is different from major/refractory depression. For painful depression, the main effect of butorphanol is analgesia, depression symptoms are improved through analgesia, and the action target point of butorphanol is completely different from that of major/refractory depression, namely the treatment mechanism is completely different.
TABLE 17 Effect of butorphanol tartrate on the opioid receptor kappa 1 in pain-type depressive model rats
| Group (n = 10) | Opioid receptor kappa 1 (ng/ml) | NR1 | NR2B |
| Normal group | 39.44±3.42 | 100.0±12.6 | 100.0±14.7 |
| Model set | 12.06±2.26 | 100.0±12.0 | 100.0±12.0 |
| Experimental group | 38.76±2.18 | 100.0±12.8 | 100.0±12.4 |
| F | 339 | / | / |
| P | ＜0.01 | / | / |
The results of the above experiments are combined to show that: the butorphanol and the salt thereof can inhibit the expression of NMDA receptors (especially NR1 and NR2B receptors), so that the butorphanol and the salt thereof can be used for treating treatment-resistant depression related to abnormal expression of the NMDA receptors (especially NR1 and NR2B receptors). A large number of experiments prove that after a pharmaceutically effective amount of butorphanol is administered to a depression patient, the clinical symptoms of the depression patient (anhedonia, weight reduction, exploration capacity reduction, cognitive dysfunction, urge for survival reduction, autonomous behavior activity reduction and the like caused by depression) can be obviously improved, and after a large amount of butorphanol within a safety range is administered to a treatment-resistant depression patient, the clinical symptoms of the depression patient (anhedonia, weight reduction, exploration capacity reduction, cognitive dysfunction, urge for survival reduction, autonomous behavior activity reduction and the like caused by treatment-resistant depression) can be effectively improved. The discovery greatly enriches the medication scheme of depression and brings good news to depression patients (especially to major/refractory depression patients).
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (10)
1. Use of butorphanol or a salt or derivative thereof or a prodrug or a stereoisomer thereof in the manufacture of a medicament for the treatment of depression.
2. Use according to claim 1, wherein the depression is major depression and/or treatment resistant depression.
3. The use as claimed in claim 1, wherein the depression is a depression associated with aberrant NMDA receptor expression.
4. Use of butorphanol or a salt or derivative thereof or a prodrug or a stereoisomer thereof in the manufacture of a medicament for inhibiting the expression of an NMDA receptor.
5. Use according to any one of claims 1 to 4, characterized in that the salt is butorphanol tartrate.
6. Use according to claims 1-4, characterized in that butorphanol tartrate improves anhedonia, weight loss, decreased exploration capacity, cognitive dysfunction, decreased desire to live, and/or decreased ability to voluntary behavior activities in depression patients caused by depression.
7. The use according to claims 1-4, wherein the medicament is in the form of nasal spray, injection, suppository, sublingual buccal, pill, tablet, capsule, sustained release, controlled release.
8. A pharmaceutical composition for preventing and treating depression is characterized by being prepared from pharmaceutically acceptable auxiliary materials and active ingredients, wherein the active ingredients comprise butorphanol or salts thereof or derivatives thereof or prodrugs thereof or stereoisomers thereof; the dosage form of the pharmaceutical composition is nasal spray, injection, suppository, sublingual buccal preparation, pill, tablet, capsule, sustained release agent and controlled release agent.
9. An aqueous solution of butorphanol tartrate for the treatment of depression, wherein the concentration of butorphanol tartrate in the aqueous solution of butorphanol tartrate is 0.1 mg-mL -1 ～8mg·mL -1 。
10. An aqueous solution of butorphanol tartrate for the treatment of treatment-resistant depression, wherein the concentration of butorphanol tartrate in the aqueous solution of butorphanol tartrate is 1 mg-mL -1 ～8mg·mL -1 。
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105777849A (en) * | 2016-04-23 | 2016-07-20 | 何淑琼 | Pharmaceutical composition of butorphanol tartrate and medical application thereof |
| CN111904947A (en) * | 2019-05-07 | 2020-11-10 | 江苏恒瑞医药股份有限公司 | Pharmaceutical composition for injection and preparation method thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105777849A (en) * | 2016-04-23 | 2016-07-20 | 何淑琼 | Pharmaceutical composition of butorphanol tartrate and medical application thereof |
| CN111904947A (en) * | 2019-05-07 | 2020-11-10 | 江苏恒瑞医药股份有限公司 | Pharmaceutical composition for injection and preparation method thereof |
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| Title |
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| 张珺等: "右美托咪定复合布托啡诺静脉镇痛对二次剖宫产术后镇痛效果及产后抑郁的影响", 《齐齐哈尔医学院学报》, vol. 40, no. 16, pages 2025 - 2027 * |
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