CN1713911A - Medicament component of berberine for the use of prevention and treatment of psycological dependence on and analgesic tolerance to morphine - Google Patents
Medicament component of berberine for the use of prevention and treatment of psycological dependence on and analgesic tolerance to morphine Download PDFInfo
- Publication number
- CN1713911A CN1713911A CNA2003801022879A CN200380102287A CN1713911A CN 1713911 A CN1713911 A CN 1713911A CN A2003801022879 A CNA2003801022879 A CN A2003801022879A CN 200380102287 A CN200380102287 A CN 200380102287A CN 1713911 A CN1713911 A CN 1713911A
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- China
- Prior art keywords
- morphine
- berberine
- pharmaceutical composition
- analgesic
- addiction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- YBHILYKTIRIUTE-UHFFFAOYSA-N berberine Chemical compound C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 YBHILYKTIRIUTE-UHFFFAOYSA-N 0.000 title claims abstract description 62
- QISXPYZVZJBNDM-UHFFFAOYSA-N berberine Natural products COc1ccc2C=C3N(Cc2c1OC)C=Cc4cc5OCOc5cc34 QISXPYZVZJBNDM-UHFFFAOYSA-N 0.000 title claims abstract description 62
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Abstract
Disclosed is a pharmaceutical composition for preventing and treating addiction to morphine or preventing and inhibiting the development of tolerance to the analgesic effects of morphine, containing berberine as an effective ingredient, wherein the berberine has an inhibitory effect versus psychological dependence on abused drugs such as morphine and the increase of spontaneous locomotor activity upon administration of the drugs, The pharmaceutical composition and a Coptis japonica plant extract of the present invention, which contain berberine, are highly effective in inhibiting the aforementioned symptoms of morphine addiction, and are thus useful for prevention and treatment of addiction to abused drugs such as morphine. In addition, the pharmaceutical composition additionally containing a pharmaceutical acceptable carrier can be applied to prevent and inhibit morphine tolerance caused by repeated administration of morphine, while not affecting the analgesic effects of morphine upon a single administration.
Description
Technical field
Briefly say, the present invention relates to the pharmaceutical composition of the illeffects of a kind of prevention and treatment narcoticness analgesic.More specifically, the present invention relates to comprise the pharmaceutical composition of berberine as effective ingredient, wherein this pharmaceutical composition is inhibited to the SMA activity that the psychological dependence and the morphine of morphine causes.
Abuse addiction medicine person suffers from psychological dependence disease usually; i.e. glad effect because of the addiction medicine forces successive administration; although this medicine may produce harmful effect, and this medicine comprises morphine or derivatives thereof, cocaine and methamphetamine hydrochloride or derivatives thereof.
Morphine is a kind of narcoticness analgesic, and it has psychological excitation, though when prevailing symptom is to use relative high dose or hallucination and delirium during low prolonged and repeated use of dosage.This psychotoxicity incident strengthens because of using morphine repeatedly, and produces very high physiology and psychological dependence thus.In other words, the main character of the addiction medicine of abuse is to stimulate the central nervous system, and strengthens the psychology serious hope to continuous use.The addiction medicine of abuse strengthens the SMA activity by successive administration, and induces the psychological dependence to it.
The successive administration of the addiction medicine of abuse causes the exhaustion of dopamine, and reduces the activity of dopamine in nervous system.In order to compensate the dopamine activity of reduction, dopamine neuron is activated.Thereby it is very responsive that postsynaptic dopamine receptor becomes, and SMA is movable to be increased, and causes the development to the strong serious hope of continuous use.Because this effect that changes the mentality of morphine, the user that relies on morphine constantly increases.Because the abuse of this morphine causes serious social concern, so be badly in need of the medicament that exploitation is used for the treatment of and prevents morphine addiction.
Background technology
Korean Patent 10-0277481 discloses the isatinoxime derivant, and it serves as the antagonist of the neurotoxic effect of excited aminoacid, thereby can be used for treating excited amino acid-dependent disease, cerebrovascular, mental illness etc. among the central nervous system.Yet, at present still untappedly going out the medicine that increase movable to SMA and psychological dependence has obvious treatment and prevention effects, the increase of the movable and psychological dependence of described SMA causes because of abusing such as addiction medicine such as morphine.Thereby the problem of abuse addiction medicine is that it has deleterious side effect, as the development of active increase of SMA and psychological dependence.Especially, the abuse of addiction medicine and addiction have caused serious social concern.
On the other hand, analgesic is to suppress or alleviation acute pain medical treatment medicine commonly used.Analgesic is divided into narcoticness and non-narcotic two classes usually.Used the acute pain of narcoticness analgesic treatment patient with advanced cancer clinically, because they have excellent analgesic effect to visceral pain.Yet, as mentioned above, though, can make the habitual medication of analgesic and developed to the serious hope of analgesic when narcoticness analgesic during with the low prolonged and repeated administration of relative high dose administration or dosage.In addition, when user used the narcoticness analgesic of ormal weight repeatedly, its toleration to analgesic developed rapidly, caused the analgesic effect of analgesic to reduce.Thereby the narcoticness analgesic should use with the dosage that increases, so that obtain required analgesic effect.The increase of the dosage of this narcoticness analgesic causes different side effect, thereby the people is had serious toxicity.
As the representative example of narcoticness analgesic, known morphine is the highest analgesic of analgesic effect in the analgesic of being developed at present.Yet, can be caused its analgesic effect progressively to reduce with morphine repeatedly, and finally be caused tolerance development the morphine analgesic effect.Owing to these reasons, morphine is restricted in the application of clinical field, although it has excellent effect.Therefore, in order to utilize morphine as analgesic, it is very important keeping the initial analgesic effect of morphine not reduce its analgesic effect when reusing again.This purpose can realize by the tolerance development of inhibition to morphine.
Disclose among the korean patent application 1999-0036248 (application number 10-1998-0700916) and a kind ofly be used to prevent or suppress pharmaceutical composition as the tolerance development of the narcoticness analgesic of morphine, disclosed pharmaceutical composition is to the tolerance development of psychological dependence and/or narcoticness analgesic, inhibited, it comprises 2-(1-pyrrolidinyl) acetamide derivative as effective ingredient.Yet with regard to the component of compositions, aforementioned pharmaceutical compositions is different from the pharmaceutical composition that comprises berberine of the present invention.In addition, disclose a kind of pharmaceutical composition that contains berberine among the Korean Patent 10-0281003, it comprises proto-berberine compounds particularly as effective ingredient, and has antidepressant effect.Yet this compositions that can be used as antidepressant but be different from pharmaceutical composition of the present invention, and pharmaceutical composition of the present invention is inhibited to morphine tolerance because of the effect of berberine.
Summary of the invention
In order to realize the present invention, the inventor has carried out deeply and thorough research, to develop preventative or therapeutic medicament to abuse addiction drug dependence, found that, in the animal model of having induced psychological dependence, as the main component of Coptis japonica (Coptis japonica) and Cortex Phellodendri (Phellodendron amurense) plant, naturally occurring berberine has significant inhibitory effect to psychological dependence.
Therefore, the pharmaceutical composition that the purpose of this invention is to provide a kind of prevention and treatment morphine addiction.
In addition, the inventor also attempts developing a kind of pharmaceutical preparation, its to because of give repeatedly with morphine cause inhibited to the morphine toleration.This research causes following discovery: as the main component of Coptis japonica, Cortex Phellodendri and Korea Radix Berberidis Amurensis (Berberis koreana) plant, naturally occurring berberine has had strong inhibitory effects to the morphine toleration.
Therefore, another object of the present invention provides a kind of pharmaceutical composition that comprises berberine as effective ingredient, is used to prevent and suppress the morphine tolerance development.
Description of drawings
By detailed description below in conjunction with accompanying drawing, will more be expressly understood above-mentioned and other purpose of the present invention, feature and advantage, in the accompanying drawings:
Fig. 1 is the inhibiting figure that the mice psychological dependence that berberine causes morphine is shown;
Fig. 2 is the inhibiting figure that the active increase of mice autonomic movement that berberine causes morphine is shown;
Fig. 3 is when mice being shown giving with a morphine, and berberine is to the figure of the effect of morphine analgesic effect; And
Fig. 4 illustrates mice to give when using morphine repeatedly, and berberine is to the inhibiting figure of the toleration of morphine analgesic effect.
The specific embodiment
The invention provides a kind of new purposes and a kind of pharmaceutical composition that comprises berberine of berberine.More specifically, the invention provides a kind of pharmaceutical composition that comprises berberine as effective ingredient, be used to prevent and treat morphine addiction or prevent and suppress tolerance development the morphine analgesic effect.
An aspect of of the present present invention is to provide a kind of and is used to prevent and suppresses morphine addiction and to the pharmaceutical composition of the tolerance development of morphine analgesic effect, it also comprises pharmaceutically acceptable carrier except above-mentioned effective ingredient.
Another aspect of the present invention is to provide the purposes of berberine, is used to prepare prevent and suppress morphine addiction and to the pharmaceutical composition of the tolerance development of morphine analgesic effect.
In pharmaceutical composition of the present invention, effective ingredient berberine (7,8,13,13a-four dehydrogenations-9,10-dimethoxy-2,3-(methylene-dioxy) berbinium) belongs to isoquinoline alkaloid section, can extract from various plants, for example extract from the bark of the root of Coptis japonica and Cortex Phellodendri, wherein this two kind of plant belongs to Berberidaceae (Berberidaceae).Berberine is used for the painted of Pilus Caprae seu Ovis, silk, leather etc.That known present medical berberine has is antibiotic, intestinal is regulated and antiulcer action.On the books in the safe dose document of berberine, and the LD of known berberine in rat
50Value is 90mg/kg (peritoneal injection) (referring to Tang, W.and Eisenbrand, G, Chinese Drugs of Plant Origin, pp.362-371, SpringerVerlag, Berlin, Heidelberg, New York).Berberine used in the pharmaceutical composition of the present invention can obtain from commercial.
As the effective ingredient of pharmaceutical composition of the present invention, the daily dose of berberine can be determined according to patient's age, body weight and pathological state, and be generally 20～100mg (peritoneal injection) or 50～400mg (oral administration).In addition, the dosage of berberine can also suitably be determined according to those skilled in the art's experience.Berberine uses as medicine at present, and has known rare toxicity when it is applied to human body with common dosage.Therefore, those of ordinary skill in the art should be appreciated that comprise the effective dose berberine, be used to prevent and suppress morphine addiction and be safe, because it is with no harmful side-effects to the people the pharmaceutical composition of the tolerance development of morphine analgesic effect.
In the present invention, only by the morphine illustration in the above-mentioned part of description the narcoticness analgesic.Yet, if the toleration of narcoticness analgesic is caused that by single-dose or short-term or secular repeat administration the narcoticness analgesic is not limited to morphine.The non-limiting example of narcoticness analgesic comprises morphine and the semi-synthetic derivant thereof that comes from Opium, and the non-natural compound with similar morphinization, as Pethidine and salt thereof.More specifically, the example of narcoticness analgesic has alkaloid and semi-synthetic derivant such as the luxuriant and rich with fragrance class (for example, morphine, oxymorphone, Dilauid, codeine, dihydrocodeinone, heroin, thebaine and buprenorphine) that comes from Opium; Phenylpiperidine (for example, pethidine and fentanyl); Phenyl heptyl amine (for example, the methadone and the third oxygen sweet smell); Morphinan class (for example, Dromoran, the imitative and levolphan of America and Soviet Union); And benzo morphenol class (for example, phenazocine and pentazocine).
The pharmaceutical composition that comprises berberine of the present invention according to its dosage form, can further comprise pharmaceutically acceptable carrier commonly used in this area.Particularly, the pharmaceutical composition that comprises berberine of the present invention can the per os preparation or the form administration of ejection preparation.The per os examples of formulations can comprise tablet and gel capsule.The per os preparation except active component, can also comprise diluent (for example, lactose, glucose, sucrose, mannitol, sorbitol, cellulose and/or glycine), and lubricant (for example, Silicon stone, Talcum, stearic acid and magnesium salt thereof or calcium salt and/or Polyethylene Glycol).Preferred tablet (for example can also comprise binding agent, Magnesiumaluminumsilicate, gelatinized corn starch, gelatin, Tragacanth, methylcellulose, sodium carboxymethyl cellulose and/or polyvinyl pyrrolidone), and (for example can also comprise disintegrating agent when needed, starch, agar, alginic acid or its sodium salt, perhaps their mixture) and/or absorbent, coloring agent, flavoring agent and sweeting agent.Ejection preparation can be preferably isosmotic solution or suspension, and can be sterilized or comprise adjuvant (for example, antiseptic, stabilizing agent, wetting agent or emulsifying agent, permeability are regulated salt and/or buffer agent).In addition, described dosage form can also comprise upward useful material of other treatment.
Find that as the effective ingredient of pharmaceutical composition of the present invention, berberine does not influence the analgesic effect of morphine when individually dosed.In addition, find that also berberine has significant inhibitory effect to the tolerance development of morphine analgesic effect, keep the initial analgesic effect of morphine simultaneously, described tolerance development to the morphine analgesic effect causes because of repetitively administered.Therefore, pharmaceutical composition of the present invention can be used to prevent to morphine the time tolerance development to the morphine analgesic effect.Thereby pharmaceutical composition of the present invention can be used for preventing the purposes of morphine toleration development.In addition, pharmaceutical composition of the present invention has and suppresses or alleviate because of repeatedly to the effect to the toleration of morphine analgesic effect that causes with morphine.Thereby pharmaceutical composition of the present invention can be with the morphine administration, with the morphine toleration that suppresses before to have caused in treatment.
Now will be in conjunction with the accompanying drawings and with reference to the following examples, illustrate in greater detail the present invention.Yet the purpose that following embodiment is provided only is in order to demonstrate the invention, the invention is not restricted to these embodiment.
Embodiment
Method and material
By in the receptacle of control temperature and humidity, cultivating more than the week, the male ICR mouse of heavy 18～25g is shaked down.Every group is adopted 10～15 mices.(Inchon is Korea) with Sigma Company (USA) available from Keukdong Pharm Company respectively for morphine and berberine.
Embodiment 1: estimate the inhibitory action of berberine to the psychological dependence of morphine
By conditioned place preference, detect development to the psychological dependence of morphine.
(carry out in 15 * 15 * 15cm), each chest all has the front surface of being made by transparent polypropylene board to the chest that conditioned place preference equates two sizes.Make by the polypropylene board of white or black on three surfaces of other of each chest.(3 * 3 * 7.5cm) connect two chests, and this passage can be blocked with the extraction-type gate with grey chrominance channel.
In order to allow mice feel the texture on chest floor, white chest has coarse floor, and black box has slick floor.Mice is cultivated under the light intensity of 20Lux.
Step 1 (pretreatment stage)
At the 1st day, the gate of chest is opened, make mice freely detect two cabins 5 minutes.At the 2nd day, by mice being placed chest, mice is spent in two times in the chest carries out 15 minutes measurement with the 1st day identical mode, and should the time with comparing incubation period.
Step 2 (conditioning stage)
At the 3rd, 5,7 and 9 day, closed shutter.With the morphine of administration 5mg/kg in the mouse peritoneum, and it was placed 1 hour in having the white chest of hatred effect.At the 4th, 6,8 and 10 day, mice is used normal saline, and it was placed 1 hour in the black box with preference effect.Before the morphine administration 1 hour, with 1 or the berberine oral administration of 2mg/kg in mice.
Step 3 (experimental stage)
At the 9th day, after opening the sluices, mice is spent in two times in the chest carry out 15 minutes measurement, wherein said mice is not used any medicine, and compares with the time of measuring at the 2nd day.Deduct pretreatment time by test period, calculate the degree of psychological dependence development.As shown in Figure 1, the morphine matched group demonstrates significantly the psychological dependence of (p＜0.01).On the contrary, in the mice of using morphine and berberine, psychological dependence (p＜0.01) fully is suppressed in and the identical level of handling with normal saline of matched group.These results show that berberine has excellent inhibitory action to the psychological dependence of morphine.
Embodiment 2: the inhibitory action of estimating the active increase of SMA that berberine causes morphine
Utilize video frequency following system, (carry out the SMA movement test in 26 * 30 * 30cm) in the plastic chamber.At first, mice is used the morphine of 10mg/kg, once a day administration 6 days altogether.After the administration, immediately mice is placed the plastic chamber the last time, movable 30 minutes of record SMA, and utilize computer program that it is analyzed.Berberine preceding 1 hour in the morphine administration, with 1 and the amount oral administration of 2mg/kg in mice.The results are shown among Fig. 2.As shown in Figure 2, when only using morphine, mouse movement is movable significantly to be increased, and the step number of the forward foot in a step is 50242.On the contrary, when using 1 and during the berberine of 2mg/kg in advance, the motor activity of mice is respectively 19744 steps and 20027 and goes on foot.In other words, compare, find that berberine has suppressed the increase (p＜0.001) of 61% and 60% motor activity that is caused by morphine respectively significantly with the morphine matched group.
Embodiment 3: the effect of the morphine analgesic effect when estimating berberine to single-dose
By in the receptacle of control temperature and humidity, cultivating a week, the male ICR mouse of heavy 18～25g is shaked down.Every group is adopted 10 mices.(Inchon Korea) with Sigma Company (USA), and is dissolved in the distilled water before use available from Keukdong Pharm Company respectively for morphine and berberine (berberine Hemisulphate).
By hot plate test, mice is applied thermostimulation, and then estimate the effect of berberine the morphine analgesic effect.For hot plate test, every mice placed on 52 ℃ the hot plate, and the incubation period of observation when mice shows uncomfortable sign (rear solid end is patted or jumped) first.For fear of tissue injury, force maximum exposing to the sun the hot time (deadline) artificially, this time is 30 seconds.Also do not show behavior reaction if surpass 30 seconds, then mice is taken away from hot plate.With administration distilled water and 1 in the mouse peritoneum, 3 and the berberine of 10mg/kg.After 30 minutes, with the morphine of mouse subcutaneous injection distilled water and 5mg/kg.After injection 30,60 and 90 minutes, by with record identical method during incubation period, the measurement mice is to the beating or the hopping response of hot plate, maximum time is 30 seconds.The result is expressed as " maximum possible effect percent (%MPE) ", and it is to calculate according to following equation, and the intensity of morphine analgesic effect is expressed as " area under a curve (AUC) ".
MPE(％)＝(Tt-To)/(Tc-To)×100
Wherein, Tc is deadline, and Tt is for testing incubation period, and To is for contrasting incubation period.
As shown in Figure 3 (significant difference between matched group and the morphine processed group:
* *P＜0.001), compare with the matched group of handling with normal saline, the morphine processed group demonstrates the analgesic effect of obvious raising.In addition, in the pretreated group of employing 1,3 and 10mg/kg berberine, find that berberine seldom influences the analgesic effect of morphine.
Embodiment 4: estimate the effect of the morphine tolerance development that berberine causes repetitively administered
Estimate the effect of the morphine tolerance development that berberine causes repetitively administered.By peritoneal injection, with distilled water and 1,3 and the berberine of 10mg/kg mice is carried out pretreatment.After 30 minutes,, carried out altogether 6 days once a day the morphine of mouse subcutaneous injection normal saline and 10mg/kg.Next day, promptly the 7th day, according to embodiment 3 in identical hot plate test, the observation mice is to the behavior reaction of the thermostimulation of hot plate.To be expressed as AUC to the tolerance development of morphine analgesic effect, its be according to embodiment 3 in identical method calculate.
As shown in Figure 4 (significant difference between the morphine processed group of matched group and single-dose:
* *P＜0.01; Matched group and have significant difference between the morphine processed group of morphine toleration:
+P＜0.05; Have the group of morphine toleration and the significant difference between the berberine processed group:
++P＜0.01), when mice was used morphine repeatedly, the initial analgesic effect of morphine reduced widely, and this shows that morphine tolerance has developed.On the contrary, in the pretreated group of the berberine that adopts 10mg/kg, find that this morphine tolerance is subjected to significant inhibition.
Industrial applicibility
As previously mentioned, berberine almost completely makes morphinistic mouse return to normal mouse (physiology salt The water treatment group) level, this shows that the berberine morphine addicted has huge mitigation. In addition, Berberine suppresses significantly because repeatedly giving the increase of the spontaneity motion activity that causes with morphine. Therefore, Berberine can be used for prevention and treatment morphine addiction.
In addition, when preventing and suppress repeatedly to give with morphine to the development side of the tolerance of morphine analgesic effect Face, pharmaceutical composition of the present invention have excellent effect, do not affect again morphine when single-dose simultaneously Analgesic effect. Therefore, composition of the present invention is for the development right and wrong that prevent or alleviate morphine tolerance Chang Youyong's.
Claims (4)
1. a pharmaceutical composition is used for prevention or treatment morphine addiction, and it comprises psychological dependence and the inhibited berberine of the active increase of SMA.
2. according to the pharmaceutical composition of claim 1, wherein said composition comprises berberine as effective ingredient, and comprises pharmaceutically acceptable carrier.
3. pharmaceutical composition is used to prevent or suppresses tolerance development to the morphine analgesic effect, and it comprises berberine as effective ingredient.
4. according to the pharmaceutical composition of claim 3, also comprise pharmaceutically acceptable carrier.
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020020066029A KR20040037511A (en) | 2002-10-29 | 2002-10-29 | Medicament for treatment of morphine poisoning comprising berberine and coptis japonica extract |
| KR10-2002-0066029 | 2002-10-29 | ||
| KR1020020066029 | 2002-10-29 | ||
| KR10-2003-0060353A KR100496512B1 (en) | 2003-08-29 | 2003-08-29 | Medicament component of berberine for the use of preventing and treating of analgesic tolerance to morphine |
| KR10-2003-0060353 | 2003-08-29 | ||
| KR1020030060353 | 2003-08-29 | ||
| PCT/KR2003/002280 WO2004039372A1 (en) | 2002-10-29 | 2003-10-27 | Medicament component of berberine for the use of prevention and treatment of psycological dependence on and analgesic tolerance to morphine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1713911A true CN1713911A (en) | 2005-12-28 |
| CN1713911B CN1713911B (en) | 2010-05-05 |
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ID=35719195
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2003801022879A Expired - Lifetime CN1713911B (en) | 2002-10-29 | 2003-10-27 | Medicament component of berberine for the use of prevention and treatment of psycological dependence on and analgesic tolerance to morphine |
Country Status (2)
| Country | Link |
|---|---|
| KR (1) | KR20040037511A (en) |
| CN (1) | CN1713911B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108030780A (en) * | 2018-01-31 | 2018-05-15 | 苏州大学 | The application of 4-PBA |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR0132701B1 (en) * | 1994-09-22 | 1998-04-17 | 이명구 | Stress therapeutic agent extracted from coptis japonica rhizoma |
| KR100281003B1 (en) * | 1998-08-27 | 2001-02-01 | 이명구 | Antidepressant containing protoberberine alkaloid compound having monoamine oxidase inhibitory activity as an active ingredient |
| KR20030055632A (en) * | 2001-12-27 | 2003-07-04 | 학교법인 경희대학교 | Pharmaceutic composition for medical treatment and prevention of drug addiction using Coptidis rhizoma |
-
2002
- 2002-10-29 KR KR1020020066029A patent/KR20040037511A/en active Search and Examination
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- 2003-10-27 CN CN2003801022879A patent/CN1713911B/en not_active Expired - Lifetime
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108030780A (en) * | 2018-01-31 | 2018-05-15 | 苏州大学 | The application of 4-PBA |
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| Publication number | Publication date |
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| CN1713911B (en) | 2010-05-05 |
| KR20040037511A (en) | 2004-05-07 |
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