CN111228262A - Application of bulleyaconitine A in preparing drug-relief medicine - Google Patents
Application of bulleyaconitine A in preparing drug-relief medicine Download PDFInfo
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- CN111228262A CN111228262A CN202010116194.7A CN202010116194A CN111228262A CN 111228262 A CN111228262 A CN 111228262A CN 202010116194 A CN202010116194 A CN 202010116194A CN 111228262 A CN111228262 A CN 111228262A
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- bulleyaconitine
- morphine
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- 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
- A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
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- 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
- A61P25/20—Hypnotics; Sedatives
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- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/36—Opioid-abuse
Abstract
The invention relates to the field of medicaments, in particular to application of bulleyaconitine A in preparing a drug-relief medicament. The mouse pharmacodynamic test result shows that the bulleyaconitine A can inhibit the conditioned place preference induced by morphine, has obvious relieving effect on the heroin dependence and jump promotion reaction, and can obviously reduce the enhancement effect of methamphetamine on the autonomous activity of the mouse. The bulleyaconitine A can be used for preparing drug-relief medicine.
Description
Technical Field
The invention relates to the field of medicaments, in particular to application of bulleyaconitine A in preparing a drug-relief medicament.
Background
Drugs are substances that change one's behavior, mood, attention, thinking and will after use, and cause psychological and physiological dependence. Drugs include opium, heroin, methamphetamine (methamphetamine), morphine, marijuana, cocaine, and other narcotics and psychotropic drugs regulated by national regulations that cause cravings, according to article 357 of the national institute of public harmony. The Chinese drug form report of 2018 indicates that 240.4 drug addicts exist in the country. Wherein 135 million people abusing the ice poison account for 56.1 percent; 88.9 million heroin abuses, accounting for 37%; ketamine was abused 6.3 million, accounting for 2.6%. The ice toxin has replaced heroin and becomes the drug with the most abused number in China.
Drugs can first damage the brain of a person, affect central nervous system functions, and cause confusion, anxiety, depression, and the like. Some people generate hostile conflict to induce confusion, paranoia and delusions; secondly, the functions of the heart and the brain are influenced, the memory, attention, computing power and judgment of the brain can be reduced, the thinking of people is slow, the reactivity is poor, the immunity is reduced, and the people are easily infected by various viruses and bacteria; again, normal reproductive capacity, as well as dysregulated function of muscle movement, can be affected.
The method for treating drug intoxication is generally treated by a hibernation therapy, a subtraction method, an attack-by-poison method and a small-toxicity-to-large-toxicity method at home and abroad, but the therapies have disadvantages and cannot fundamentally solve the influence and existence of drugs on human bodies.
Therefore, the medicine which fundamentally solves the influence of drugs on human bodies has important practical significance.
Disclosure of Invention
In view of the above, the invention provides an application of bulleyaconitine A in preparing a drug-breaking medicine. The mouse pharmacodynamic test result shows that the bulleyaconitine A can inhibit the conditioned place preference induced by morphine, has obvious relieving effect on the heroin dependence and jump promotion reaction, and can obviously reduce the enhancement effect of methamphetamine on the autonomous activity of the mouse. The bulleyaconitine A can be used for preparing drug-relief medicine.
In order to achieve the above object, the present invention provides the following technical solutions:
bulleyaconitine A (BlA for short) is aconitine separated from Aconitum carmichaeli (Aconitum georgeeicomber), has chemical name of (l α,6 α,14 α,16 β) tetrahydro-8, 13, 14-triol-20-ethyl-1, 6, 16-trimethoxy-4-methoxymethyl-8-acetoxy-14- (4' -p-methoxybenzyl ester) -aconitane, and is called as bulleyaconine A (structural formula I).
The bulleyaconitine A has obvious analgesic and anti-inflammatory effects. The traditional Chinese medicine composition is clinically applied to rheumatic and rheumatoid arthritis, lumbar muscle strain, scapulohumeral periarthritis, limb sprain, contusion and the like. Rheumatic diseases, cervical spondylosis, nonspecific low back pain and the like belong to common chronic pain diseases of the old.
The invention provides application of bulleyaconitine A in preparing a medicament for inhibiting morphine-induced conditional site preference.
In some embodiments of the invention, the weight ratio of the morphine to the bulleyaconitine A is 7.5 (0.125-0.5).
The invention also provides application of bulleyaconitine A in preparing a medicament for relieving heroin dependence and promoting jump reaction.
In some embodiments of the invention, the weight ratio of the heroin to the bulleyaconitine A is (6.25-40): (0.125-0.5).
The invention also provides application of bulleyaconitine A in preparing a medicament for reducing the enhancement effect of methamphetamine on the autonomous activity of mice.
In some embodiments of the invention, the weight ratio of the methamphetamine to the bulleyaconitine A is 2 (0.125-0.5).
On the basis of the research, the invention also provides the application of the bulleyaconitine A in preparing the medicine for treating drug poisoning.
In some embodiments of the invention, the drug comprises one or more of morphine, heroin, or methamphetamine.
In some embodiments of the invention, the effective amount of bulleyaconitine A is not less than 0.125mg/kg mouse body weight.
In some embodiments of the invention, the effective dose of bulleyaconitine A is 0.125mg/kg mouse weight to 0.5mg/kg mouse weight.
In the application provided by the invention, the dosage form of the medicament comprises but is not limited to:
(one) classifying according to the administration route
The classification method is closely related to clinical use by using the same dosage form as a class.
1. The dosage form of the drug administration through the gastrointestinal tract refers to the dosage form that the drug preparation enters the gastrointestinal tract after being orally taken and plays a role of local or systemic absorption, such as common powder, tablets, granules, capsules, solution, emulsion, suspension and the like. Drugs that are easily damaged by acids or enzymes in the gastrointestinal tract generally cannot be used in such simple dosage forms. Oral transmucosal absorption dosage forms do not belong to the gastrointestinal administration dosage forms.
2. Parenteral dosage forms, which are intended to mean all other dosage forms than those administered orally, which can act locally at the site of administration or can exert a systemic effect after absorption:
(1) the injection administration dosage form: such as injections, including intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, intracavity injection and other injection routes.
(2) Respiratory administration dosage forms: such as spray, aerosol, powder spray, etc.
(3) The skin administration dosage form: such as topical solution, lotion, liniment, ointment, plaster, paste, patch, etc.
(4) Mucosal administration forms: such as eye drops, nose drops, eye ointment, gargle, sublingual tablet, sticking film agent, etc.
(5) The cavity administration dosage form is as follows: such as suppository, aerosol, effervescent tablet, drop, dripping pill, etc., and can be used for rectum, vagina, urethra, nasal cavity, auditory canal, etc.
(II) sorting by discrete system
The classification method is convenient for clarifying the characteristics of various preparations by applying the physical and chemical principles, but cannot reflect the requirements of the application position and the application method on the dosage form, and even one dosage form can be divided into a plurality of disperse systems.
1. Solution type: a uniform dispersion system formed by dispersing medicine in a dispersion medium in a molecular or ionic state (particle diameter is less than 1nm) is also called low molecular solution, such as aromatic water, solution, syrup, glycerol, spirit, injection, etc.
2. Colloidal solution type: a uniform dispersion system formed by dispersing a polymer (the diameter of a mass point is 1-100 nm) in a dispersion medium is also called a polymer solution, such as a mucilage, a collodion, a film coating agent and the like.
3. Emulsion type: the oil drug or drug oil solution is dispersed in the dispersion medium in the state of liquid drops to form a non-uniform dispersion system, such as oral emulsion, intravenous injection emulsion, partial liniment, etc.
4. Suspension type: non-uniform dispersion systems, such as a mixture, a lotion, a suspension, etc., in which a solid drug is dispersed in a dispersion medium in a particulate state.
5. Gas dispersion type: a dispersion system in which a liquid or solid drug is dispersed in a gas dispersion medium in a particulate state, such as an aerosol.
6. Fine particle dispersion type: the medicine is dispersed in liquid or solid state in the form of microparticles of different sizes, such as microsphere preparation, microcapsule preparation, nanocapsule preparation, etc.
7. Solid dispersion type: and (3) dispersion system of solid medicine in aggregate state, such as tablet, powder, granule, capsule, pill, etc.
(III) sorting by recipe
This classification cannot encompass all dosage forms and is therefore not commonly used.
1. Leaching preparation: is prepared into dosage forms (fluid extract, tincture, etc.) by leaching method.
2. And (3) sterile preparation: is prepared into dosage forms (such as injection) by sterilization method or aseptic technique.
(IV) classifying according to morphology
The pharmaceutical dosage forms are classified by substance morphology, namely:
1. liquid dosage form: such as aromatic water, solution, injection, mixture, lotion, liniment, etc.
2. Gas formulation: such as aerosols, sprays, and the like.
3. Solid dosage form: such as powder, pill, tablet, pellicle, etc.
4. Semi-solid dosage form: such as ointments, suppositories, pastes, and the like.
The dosage forms are not limited herein, and any pharmaceutical dosage form known to those skilled in the art is within the scope of the present invention.
The inventor finds that the bulleyaconitine A can inhibit the conditional position preference induced by morphine, has obvious relieving effect on the heroin dependence induced jump promotion reaction, and can obviously reduce the enhancement effect of methamphetamine on the autonomous activity of mice. The bulleyaconitine A can be used for preparing drug-relief medicine.
Detailed Description
The invention discloses application of bulleyaconitine A in preparing a drug-breaking medicament, and the technical personnel in the field can appropriately improve process parameters by referring to the content. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of this invention without departing from the spirit and scope of the invention.
The bulleyaconitine A provided by the invention can be purchased from the market as raw materials and reagents in the application of preparing the drug-breaking medicine.
The invention is further illustrated by the following examples:
example 1 morphine conditional Place Preference test method (Conditioned Place Preference, CPP)
The component location preference is currently a globally accepted method of testing for addiction induction and relapse of drugs of abuse. The CPP box is mainly composed of two boxes with equal volumes, wherein one side is a black box (smooth floor), and the other side is a white box (rough floor). The imaging system is arranged in the box and connected with the computer, and the moving condition of the experimental animal in the box can be automatically recorded.
Test materials: bulleyaconitine A is produced by Yunnan Hao Pont pharmaceutical Co. Morphine, provided by the first civilian hospital of Kunming.
Experimental animals: kunming mouse, male and female half, weight 20 + -2 g, is provided by Kunming medical university experimental animal.
Statistical analysis software: SPSS 25.
The CPP experiment is divided into 3 stages, namely a pretesting stage and a training stage. In the pre-testing stage, the middle partition of the preference box is opened, and the animals (mice) are placed in the middle zone and allowed to freely run in the CPP box for 15min, 1 time per day for 3 consecutive days. On the third day, the average residence time of the animals in the white and black boxes was recorded and the natural preference tendencies of the animals were determined (black box). Rats were then trained with a non-natural preference box (white box) as a companion box. The black and white box channel is sealed by a partition plate in the training stage. In the morning of the first day, the animals were placed in a black box immediately after subcutaneous administration of physiological saline for 30 minutes; morphine was given subcutaneously in the afternoon and immediately placed in a white box for 30 minutes. Morphine was given the following morning and normal saline was given in the afternoon. The injection mode on the third and fifth days is the same as that on the first day, and the injection mode on the fourth day is the same as that on the second day. The animals in the non-matching group were injected with normal saline subcutaneously, and the training phase procedure was similar to that of the morphine group injected subcutaneously.
The change in the positional preference (match value) is indicated by calculating the difference in the time the animal stays in the drug match box (white box) after the training phase and after the pre-testing phase, and the time increase value indicates the preference of the animal for the drug match side.
The results of the study showed that on day six, the non-matched group (n-12) had an adjustment score of 13.48 ± 14.18 (mean ± sem), morphine was injected subcutaneously (7.5mg/kg) and gavage animals of the solvent-control group showed significant positional preference for the white-box matched values (224.58 ± 25.37, p <0.001, n-12, compared to the non-matched group). Animal matching values for the group subcutaneously injected with morphine (7.5mg/kg) and gavage administered to bulleyaconitine a (0.125mg/kg) were not significantly different from those for the control group subcutaneously injected with morphine plus gavage administered with solvent (170.06 ± 11.98, p > 0.005, n ═ 12, compared to the morphine plus solvent control group); the animal match values for the group injected subcutaneously with morphine (7.5mg/kg) and gavaged to bulleyaconitine a (0.25mg/kg) differed from the control group injected subcutaneously with morphine plus gavage to solvent (117.16 ± 21.25, p < 0.005, n ═ 12, compare to the morphine plus solvent control group); animals injected subcutaneously with morphine (7.5mg/kg) and gavaged with bulleyaconitine (0.5mg/kg) matched significantly different values from the control group administered subcutaneously with morphine plus gavage with solvent (93.80 ± 19.14, p <0.001, n-12, compared to the morphine plus solvent control group).
TABLE 1 summary of statistical analysis of the residence time of the saline group in the unnatural preference cassette
TABLE 2 summary of statistical analysis of the residence time of the morphine + saline group in the unnatural preference kit
TABLE 3 summary of statistical analysis of the residence time of the morphine +0.125mg/kg BLA group in the unnatural preference Box
TABLE 4 summary of statistical analysis of the residence time of the morphine +0.25mg/kg BLA group in the unnatural preference Box
TABLE 5 summary of statistical analysis of the residence time of the morphine +0.5mg/kg BLA group in the unnatural preference Box
The experimental results show that the group administered intragastrically with low dose bulleyaconitine A (0.125mg/kg) cannot suppress the conditioned place preference induced by morphine; intragastric administration with medium dose bulleyaconitine A (0.25mg/kg) and high dose bulleyaconitine A (0.5mg/kg) groups inhibited the conditional site preference induced by morphine (P < 0.01).
And (4) conclusion: bulleyaconitine A can inhibit morphine-induced conditioned place preference.
Example 2 experiment for inhibition of heroin dependent mouse skip response
Test materials: bulleyaconitine A is produced by Yunnan Hao Pont pharmaceutical Co. Heroin, provided by the public safety bureau of Kunming city, Yunnan province, with a purity of 91.2%. Naloxone hydrochloride, Beijing four-ring pharmaceutical factory.
Experimental animals: kunming mouse, male and female half, weight 20 + -2 g, is provided by Kunming medical university experimental animal.
Statistical analysis software: SPSS 25.
The experimental method comprises the following steps: randomly dividing mice into 5 groups, each group comprises 12 mice, injecting physiological saline subcutaneously into the physiological saline, injecting heroin addiction into the other groups subcutaneously, administering the mice with 6.25mg/kg twice a day, each time increasing by 3.75mg/kg, continuously administering for 5 days, 3 hours after the last injection, accelerating addiction with naloxone hydrochloride 5mg/kg, comparing with the physiological saline, having significant difference (P <0.001), proving success of modeling, continuing heroin addiction experiment, after 1 hour after the last injection, injecting the heroin into the physiological saline and the heroin groups, respectively administering the heroin to the stomach of the other groups
0.125mg/kg,0.25mg/kg and 0.5mg/kg bulleyaconitine A, which is administered for 1 hour after gastric lavage, i.e. 2 hours after the last injection of heroin, 20mg/kg addiction acceleration by intraperitoneal injection of naloxone hydrochloride, the mice were immediately placed in a measuring cylinder with the diameter of 10cm and the height of 40cm, and the jumping reaction of the mice within 10 minutes was observed, and the results are shown in Table 6.
TABLE 6 bulleyaconitine A effect on suppressing heroin dependent mouse skip reaction
The experimental results show that: the bulleyaconitine A low dose (0.125mg/kg) has obvious effect on reducing and relieving the heroin dependence induced jump reaction; the medium-dose (0.25mg/kg) group and high-dose (0.5mg/kg) group of bulleyaconitine A have significant relieving effect on the heroin dependence jump promotion reaction.
And (4) conclusion: the bulleyaconitine A with high dosage has obvious effect of relieving the heroin dependence induced jump reaction.
Example 3 Effect of bulleyaconitine A on Methylamphetamine (MA) -induced high Activity in mice
Behavioral sensitization is one of the main behavioral characteristics of animal addiction, and is widely used at present as a model for evaluating the potential of drug dependence on spirit. After repeated intermittent administration of the addictive drug, the activity of the experimental animal can be increased, and the behavior reaction which is increased along with the repeated administration is called behavior sensitization. Behavioral sensitization has an important relationship with drug addiction, and it has been demonstrated that addictive drug-induced behavioral sensitization has a significant effect on the development and maintenance of both drug-seeking and drug-relapse behavior.
Test materials: bulleyaconitine A is produced by Yunnan Hao Pont pharmaceutical Co. Methamphetamine, available from the public safety office of Kunming, Yunnan province.
Experimental animals: kunming mouse, male and female half, weight 20 + -2 g, is provided by Kunming medical university experimental animal.
Statistical analysis software: SPSS 25.
The mice are randomly divided into 5 groups, a normal saline group, a Methamphetamine (MA) group and three dose groups of the Methamphetamine (MA) and the bulleyaconitine A. The normal saline group is injected with 2mg/kg of normal saline in the abdominal cavity, and the Methamphetamine (MA) group is injected with 2mg/kg of Methamphetamine (MA) in the abdominal cavity; the administration group is respectively administered with bulleyaconitine A of 0.125mg/mg, 0.25mg/kg and 0.5mg/kg for 30 minutes by intragastric administration, and then 2mg/kg of Methamphetamine (MA) is intraperitoneally injected. Then, the mice were placed in a testing apparatus, and the autonomic activity of the mice was immediately measured, and the number of autonomic activities was recorded for 1 hour. The results are shown in Table 7.
TABLE 7 bulleyaconitine A vs. Methamphetamine (MA) induced mouse high activity statistical table
The result shows that the activity of the mice is obviously improved after 2mg/kg of methamphetamine is injected into the abdominal cavity of the mice. Before the methamphetamine is injected into the abdominal cavity, the autonomic activity count of the mice in the bulleyaconitine A group is reduced in a dose-dependent manner, and the reinforcing effect of the methamphetamine on the autonomic activity of the mice can be effectively reduced by intragastrically administering 0.125mg/kg of bulleyaconitine A (P is less than 0.05); the effect of the methamphetamine on the enhancement of the autonomic activity of the mice can be obviously reduced by administrating 0.25mg/kg and 0.5mg/kg of bulleyaconitine A through intragastric administration (P is less than 0.001).
And (4) conclusion: bulleyaconitine A can remarkably reduce the enhancement effect of methamphetamine on the autonomous activity of mice.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
1. Application of bulleyaconitine A in preparing medicine for inhibiting morphine-induced conditioned place preference is provided.
2. The use of claim 1, wherein the weight ratio of morphine to bulleyaconitine A is 7.5 (0.125-0.5).
3. Application of bulleyaconitine A in preparing medicine for relieving heroin dependence and promoting jump reaction is provided.
4. The use of claim 3, wherein the weight ratio of heroin to bulleyaconitine A is (6.25-40): 0.125-0.5.
5. Application of bulleyaconitine A in preparing medicine for reducing enhancement effect of methamphetamine on mouse autonomous activity is provided.
6. The use of claim 5, wherein the weight ratio of methamphetamine to bulleyaconitine A is 2 (0.125-0.5).
7. Application of bulleyaconitine A in preparing medicine for treating drug poisoning is provided.
8. The use of claim 7, wherein the drug comprises one or more of morphine, heroin or methamphetamine.
9. The use as claimed in any one of claims 1 to 8 wherein the effective dose of bulleyaconitine A is not less than 0.125mg/kg body weight of the mouse.
10. The use of any one of claims 1 to 8, wherein the effective amount of bulleyaconitine A is from 0.125mg/kg to 0.5mg/kg of mouse body weight.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110478350A (en) * | 2018-07-27 | 2019-11-22 | 上海品姗医药咨询有限公司 | The application of bulleyaconitine A and its derivative in the preparation inhibition addicted drug of drug |
| CN111135170A (en) * | 2020-01-23 | 2020-05-12 | 上海交通大学 | Use of bulleyaconitine A compound in treating psychological dependence of addictive substance |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110478350A (en) * | 2018-07-27 | 2019-11-22 | 上海品姗医药咨询有限公司 | The application of bulleyaconitine A and its derivative in the preparation inhibition addicted drug of drug |
| CN111135170A (en) * | 2020-01-23 | 2020-05-12 | 上海交通大学 | Use of bulleyaconitine A compound in treating psychological dependence of addictive substance |
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Application publication date: 20200605 |