CN102008577A - Drug for preventing and curing dependence of amphetamine and opiate drugs - Google Patents
Drug for preventing and curing dependence of amphetamine and opiate drugs Download PDFInfo
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- CN102008577A CN102008577A CN 201010575253 CN201010575253A CN102008577A CN 102008577 A CN102008577 A CN 102008577A CN 201010575253 CN201010575253 CN 201010575253 CN 201010575253 A CN201010575253 A CN 201010575253A CN 102008577 A CN102008577 A CN 102008577A
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- medicine
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- rhomotoxine
- morphine
- fructus schisandrae
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Abstract
The invention relates to a medical preparation, in particular to a drug for preventing and curing dependence of amphetamine and opiate drugs. The drug comprises active ingredients and pharmaceutically acceptable auxiliary materials, and is characterized in that the active ingredients comprise the following bulk pharmaceutical chemicals in parts by weight: 20-80 parts of uncaria rhynchophylla total alkali and 10-60 parts of Schisandra chinensis total lignan, wherein the uncaria rhynchophylla total alkali is an uncaria rhynchophylla extract obtained by sequentially carrying out percolation extracting on uncaria rhynchophylla with ethanol and carrying out heating reflux extraction with diethyl ether; the total alkaloid content is 55-60%; the Schisandra chinensis total lignan is a Schisandra chinensis extract obtained by extracting the Schisandra chinensis with ethanol and petroleum ether and purifying with a silicagel column; and the Schisandra chinensis total lignan content is 40-45%.
Description
Technical field
The present invention relates to field of medicaments, be specifically related to a kind of medicinal preparation.
Technical background
Drug dependence, promptly addiction is meant long-term lasting use or periodically uses certain medicine or material, a kind of body adaptation state that is produced, and the behavior or other reaction that medicine are shown a kind of obsessive continuous or periodic this medicine of application.In case disconnected medicine, physiological function will get muddled, and a series of serious physiological reactions occur, is referred to as withdrawal symptom.Form dependent medicine and mainly contain medicine or materials such as barbiturates, amphetamine, opiates, Fructus Cannabis, cocaine and hallucinogen.Current, the drug issue of globalization has constituted significant threat to human existence and development.With the opiates be traditional narcotics of representative and with the amphetamine central stimulant (Amphetamine-type Stimulants is main drug abuse for the novel drug of representative ATS).Drug rehabilitation method commonly used both at home and abroad at present mainly is a Drug therapy.Mainly contain the alternative diminishing method of opiates preparation for the treatment of opioid addiction, as the methadone alternative medicine.Drug therapy for ATS abuse addict mostly is anti symptom treatment, as using tricyclic antidepressant, antipsychotic drug, sedative hypnotics etc.Because above chemical synthetic drug has tangible neurotoxic effect mostly, and some medicines itself have the dependency that the drug dependence potentiality maybe can strengthen some psychoactive drug substance, have therefore limited the application clinically of these medicines.
Compare with chemical synthetic drug, it is efficient that resource natural plants extensive medicine and effective ingredient have low toxicity, advantage safe in utilization.In recent years, the Chinese medicine against drug dependence preparation of domestic listing mostly is the compound recipe of being made up of several flavors or tens flavor Chinese medicines.Shortcomings such as most Chinese medicine against drug dependence products exist indication more, and therapeutic domain is wide, and curative effect is indeterminate, and specific aim is not strong.
Rhomotoxine is the main active site of Chinese medicine Ramulus Uncariae Cum Uncis, mainly is present in the Rubiaceae wild gambier plant.Rhomotoxine mainly contains Ramulus Uncariae cum Uncis alkali (rhynchophylline), isorhynchophylline (isorhynchophylline), corynoxeine (corynoxeine), isocorynoxeine (isocorynoxeine), ocrynoxine (corynoxine), corynoxine B (corynoxine B), hirsutine (hirsutine), dehydrogenation bristle Ramulus Uncariae cum Uncis alkali (hirsuteine) etc. based on indoles alkaloid.Effects such as the Ramulus Uncariae Cum Uncis alkaloid has blood pressure lowering, calmness, sleeps peacefully, spasmolytic, arrhythmia, Ramulus Uncariae cum Uncis alkali has the effect that anti-morphine relies on, anti-amphetamine central stimulant relies on.The inventor discovers, though the medicine that Ramulus Uncariae cum Uncis alkali or Rhomotoxine are made has the effect of control amphetamine and opioid drug dependence, but, the effect of using Ramulus Uncariae cum Uncis alkali or Rhomotoxine treatment opiates and amphetamines to rely on separately is still not very good, body rehabilitation aspect after especially cardio cerebral function infringement that causes for drugs and addiction are given up, the effect of Ramulus Uncariae cum Uncis alkali and Rhomotoxine is limited.
Summary of the invention
It is clear and definite that the technical problem to be solved in the present invention provides a kind of curative effect, with strong points, toxicity is little, there is not addicted anti-additive medicament, this medicine has the effect of the many target spots of Chinese medicine active chemical components group, multipath, multimachine system, show the whole structure of Chinese medicine, again can be fine the problems such as cardio cerebral function infringement of solution drugs due to relying on, promote the rehabilitation of body.
The technical scheme that the present invention solves the problems of the technologies described above is:
A kind of medicine of preventing and treating amphetamine and opioid drug dependence, this medicine is made up of effective ingredient and medically acceptable adjuvant, it is characterized in that described effective ingredient is made up of following bulk drugs: Rhomotoxine 20～80, Fructus Schisandrae Chinensis total lignanoid 10～60; Wherein,
Described Rhomotoxine is prepared by following method: hook taking rattan stem and branch with belt hook, be ground into coarse powder, and with 8～10 times of amount 75%～95% ethanol merceration 20～40h, percolation extracts in the seepage of packing into the tube; Collect percolate, concentrate behind the decompression recycling ethanol, extractum, 3% dissolve with hydrochloric acid solution, the filtration of doubly measuring with 2-4; Filtrate is transferred pH9～10 with ammonia, with the ether heating and refluxing extraction of 6～8 times of amounts 3～5 times, reclaims solvent, filters, and drying obtains total alkaloid content and be 55～60% Rhomotoxine;
Described Fructus Schisandrae Chinensis total lignanoid is prepared by following method: get schisandra chinensis medicinal material, drying is ground into coarse powder, adds 4～8 times of amount 80%～90% ethanol, and reflux, extract, 2～4h extracts 2～3 times, merges alcohol extract, and decompression recycling ethanol gets alcohol extract; 4～6 times of reuse amount petroleum ether extraction Chinese Magnoliavine Fruit alcohol extract, silicagel column on the extract use the eluent eluting, must lignanoid's content is 40～45% Fructus Schisandrae Chinensis total lignanoid; Wherein said eluent is that volume ratio is the n normal hexane: ethyl acetate: methanol: water=1: 0.9: 0.9: 1 mixed solution.
In the medicine of the present invention, the consumption of used crude drug is preferably Rhomotoxine 40～70 weight portions and Fructus Schisandrae Chinensis total lignanoid 25～45 weight portions, and the best is Rhomotoxine 65 weight portions and Fructus Schisandrae Chinensis total lignanoid 35 weight portions.
In the medicine of the present invention, described Ramulus Uncariae Cum Uncis is Rubiaceae wild gambier plant Ramulus Uncariae Cum Uncis Uncaria rhynchophylla (Miq.) Miq.Ex Havil., Uncaria sinensis (Oliv.) Havil. U.sinensis (Oliv.) Havil., Ramulus Uncariae macrophyllae U.macrophylla Wall., Ramulus Uncariae Cum Uncis U.hirsute Havil. or stockless fruit Ramulus Uncariae Cum Uncis U.sessilifructus Roxb.; Described Fructus Schisandrae Chinensis can be Schisandraceae Schizandra or Fructus Schisandrae Sphenantherae platymiscium Fructus Schisandrae Chinensis Schisandrachinensis (Turcz.) Baill., and perhaps schisandra chinensis S.sphenanthera Rehd.et Wils. also can be other congener.
In the medicine of the present invention, contain the adjusting axoneure in the described Ramulus Uncariae Cum Uncis, improve the natural activity alkaloid of central nervous system function, can act on cerebral cortex and subcortical center, the cerebral neuron that adjusting is snowed in, make it to recover normal excitement and inhibitory state, help the recovery of central nervous system function.The Rhomotoxine that proposes from Ramulus Uncariae Cum Uncis has significantly antiradiation drug dependence effect, and integrally-regulated effect has been played in the recovery of body function.Experimental results show that, Ramulus Uncariae cum Uncis alkali in the Rhomotoxine and hirsutine urge withdrawal symptom to have therapeutical effect to the drug dependence that morphine relies on large and small Mus, can suppress the withdrawal symptom that morphine relies on animal pattern, alleviate the weight loss that withdrawal symptom causes, promote the recovery of body; Ramulus Uncariae cum Uncis alkali and hirsutine have the obvious suppression effect to morphine, the inductive animal conditioned place preference of amphetamine central stimulant, alleviate the psychic dependence of animal pattern.
Effects such as in the medicine of the present invention, described Fructus Schisandrae Chinensis lignanoid has tangible antioxidation, regulates systema cariovasculare functional, protection cardio cerebral function can obviously improve the various untoward reaction that addiction is given up the back body.
The present invention share Ramulus Uncariae Cum Uncis alkaloid and Fructus Schisandrae Chinensis lignanoid can produce the obvious synergistic effect, the central nervous system all had tangible calmness, hypnosis, analgesia and angst resistance effect, significantly symptoms such as the pain of alleviation withdrawal symptom, insomnia, dysphoria, anxiety strengthen the prevention effect that addiction is given up.
In addition, medicine of the present invention itself do not have the characteristic of physical dependence, can induced animal produce the position preferences, do not have physical dependence, drug dependence begetting power and addiction yet; The present composition is made by natural plant active component, does not contain any chemosynthesis material, and life-time service does not have obvious adverse reaction and toxic and side effects, and is safe in utilization.
Advantages such as medicine of the present invention adopts the effective ingredient in Chinese compatibility, compares with Chinese medicine compound, and it is clear and definite to have curative effect, with strong points; Compare with compound monomer, the effective site collection all cpds monomer mutual reinforcement between mutual-assistance, the mutual coordination show the synergism of many target spots, multipath, multimachine system, and efficacy of drugs is brought into play to greatest extent; Simultaneously, mutual restriction and make the perform toxic attenuation of medicine again between all cpds monomer.
To further specify the antiradiation drug dependence effect and the technique effect of the present composition by zoopery below.Below respectively test the used reagent thing 1 that is subjected to and be the tablet of embodiment 2, be subjected to reagent thing 2 to be the oral liquid of embodiment 4, be subjected to reagent thing 3 to be the pill of embodiment 6; To respectively be subjected to be made into suitable concentration after the dissolving of reagent thing with distilled water before the experiment.
1. morphine-dependent mice is urged and is given up test
(1) animal grouping: get kunming mice, body weight 20-24g, male and female half and half are divided into 8 groups at random, i.e. blank group, the morphine model group, positive drug control group, is subjected to 1 group of reagent thing, is subjected to 2 groups of reagent things, is subjected to 3 groups of reagent things Ramulus Uncariae cum Uncis alkali group, schisandrin B group.Every group of 10 animals.
(2) model copy: except that the blank group, other each groups all adopt subcutaneous injection morphine, incremental dose method to make the mice morphine and rely on model.Give mice sc morphine every day, 2 times (8:30,16:30), the administration volume is 0.2ml/10g in administration every day.Dosage increases progressively day by day from 25mg/kg, increases to 150mg/kg in the 6th day, promptly makes the mouse model that morphine relies on.Carry out the naloxone urgency in the 7th day and give up test.
(3) Drug therapy: in experiment the 7th day, the morphine of stopping using, beginning drug treatment, successive administration 3 days.Each group gives different processing respectively: blank group and morphine model group give equal-volume normal saline (20ml/kg), positive controls gives buprenorphine (0.4mg/kg), the 60mg/kg administration according to dosage of Ramulus Uncariae cum Uncis alkali group, the 60mg/kg administration according to dosage of schisandrin B group is subjected to 1,2,3 groups of all 60mg/kg administrations according to dosage of reagent thing.Each group is irritates stomach (ig) administration.45min gave naloxone (6mg/kg, ip) urgency, the body weight change of mice behind number of skips that mice occurs in observation and the record 30min and the 1h after each organized the mice medicine.
(4) result:
The influence that A, medicine react mouse jump: adopt subcutaneous injection morphine, incremental dose method to make the mice morphine and rely on model.After using naloxone to urge addiction, tangible hopping response appears in morphine model group mice, and with weight loss, the normal saline control group mice is behind the ip naloxone, only idol has the disposable hopping response of indivedual mices, and model group is compared with the blank group, P＜0.01, significant differences is arranged, show that the animal model of this experiment is made successfully.Each medicine group mice is being irritated stomach Ramulus Uncariae cum Uncis alkali, schisandrin B or respectively is being subjected to the reagent thing to 30min before the naloxone respectively, the withdrawal symptom of addiction mice obviously alleviates, after showing that naloxone is urged, the number of skips of addiction mice all obviously reduces than model group, shows that medicine can alleviate the withdrawal symptom of morphine-dependent mice to a certain extent.See Table 1.
Table 1 morphine-dependent mice urge give up the hopping response number of times (
N=10)
*P＜0.05,
*Compare with the blank group P＜0.01.
#P＜0.05,
##Compare with the morphine model group P＜0.01.
B. medicine is to the influence of mice body weight: the blank group mice body weight that does not give morphine increases in time, and all than obviously increasing before the administration, there is significant difference P＜0.01 to the 7th, 8,9 day (d1 that promptly gives up, d2, d3) body weight of experiment.Each morphine-dependent mice is after naloxone is urged, and along with the appearance of withdrawal symptom, the mice body weight all obviously descends.The morphine model group and give the positive group mice body weight of buprenorphine and administration before relatively, no significant difference, P＞0.05.After giving Ramulus Uncariae cum Uncis alkali or respectively being subjected to the treatment of reagent thing, the mice body weight increases to some extent.D3 after giving up, the Ramulus Uncariae cum Uncis alkali group and be subjected to 1,2,3 groups of mice body weight of reagent thing and vertical administration before relatively, significant difference is arranged, P＜0.05.See Table 2.
Table 2 respectively organize mice body weight (g) result of variations (
N=10)
*P＜0.05,
*Compare with the blank group P＜0.01.
▲P＜0.05,
▲ ▲P＜0.01 is relatively preceding with administration.
2. morphine relies on the rat urgency and gives up test
(1) animal grouping: get the SD rat, body weight 200-240g, male and female half and half are divided into 7 groups at random, i.e. blank group, the morphine model group, positive drug control group, is subjected to 1,2,3 groups of reagent things at the Ramulus Uncariae cum Uncis alkali group.Every group of 10 animals.
(2) model copy: except that the blank group, other each groups all adopt lumbar injection morphine, incremental dose method to duplicate the rat morphine and rely on model.Inject morphine every day 2 times (8:00,20:00), dosage is incremented to 90mg/kg successively from each 5mg/kg, and continuous using to the 10th day promptly made the rat model that morphine relies on.Carry out the naloxone urgency in the 11st day and give up test.
(3) Drug therapy: in experiment the 11st day, the morphine of stopping using, beginning drug treatment.Each group gives different processing respectively: blank group and morphine model group give the equal-volume normal saline, positive controls give buprenorphine (0.2mg/kg, ip), Ramulus Uncariae cum Uncis alkali group and be subjected to 1,2,3 groups of all 30mg/kg administrations according to dosage of reagent thing.Each group is irritates stomach (ig) administration.Successive administration 5 days.Rat drinking-water, feed freedom.(4.0mg/kg ip) urges addiction, observes withdrawal symptom and the urgency of rat in the 30min and gives up the body weight change situation of back 1h rat to give naloxone behind treatment d1, d3, d5 administration 1h.
(4) result:
A. medicine relies on the influence that rat is urged withdrawal symptom to morphine: after the blank group gave naloxone, rat did not have obvious withdrawal symptom.Each is organized morphine and relies on rat, tangible withdrawal symptom all occurs after naloxone is urged, and compares with the blank group, significant difference is arranged, P＜0.01.Show that morphine relies on rat model and duplicates successfully.After morphine dependence rat was stood 1,2,3 treatments of reagent thing, the withdrawal symptom score value all had reduction in various degree.The withdrawal symptom score value of each administration group and morphine model group relatively all have significant difference, P＜0.05 or P＜0.01.Ramulus Uncariae cum Uncis alkali group rat d3 and d5 give up score value and morphine model group relatively, and significant difference is arranged, P＜0.05, but d1 give up score value and the comparison of morphine model group, there was no significant difference, P＞0.05.See Table 3.
Table 3 morphine dependence rat urgency withdrawal symptom score value (
N=10)
*P＜0.05,
*Compare with the blank group P＜0.01.
#P＜0.05,
##Compare with the morphine model group P＜0.01.
B. medicine relies on rat to morphine and urges the influence of giving up body weight change: the result shows, the blank group rat body weight that does not give morphine increases in time, the the 11st, 13,15 day (d1 that promptly gives up, d3, d5) body weight of experiment is all than obviously increasing before the administration, there is significant difference P＜0.05.Each morphine relies on rat after naloxone is urged, and along with the appearance of withdrawal symptom, rat body weight all obviously descends.After giving respectively to be subjected to the treatment of reagent thing, rat body weight increases to some extent.At the d1 that gives up, d3 and d5, each drug treatment group rat body weight and morphine model group relatively have significant difference, P＜0.05 or P＜0.01.Table 4.
Each group of table 4 urge give up rat body weight (g) result of variations (
N=10)
*P＜0.05,
*Compare with the blank group P＜0.01.
#P＜0.05,
##Compare with the morphine model group P＜0.01.
▲P＜0.05,
▲ ▲P＜0.01 is relatively preceding with administration.
3. amfetamine inducing mouse conditioned place preference
(1) animal grouping: the natural place of learning from else's experience preference is measured qualified Kunming mouse, body weight 20-24g, male and female half and half, be divided into 7 groups at random, i.e. blank group, amfetamine model group, the Ramulus Uncariae cum Uncis alkali group, the deoxyschizandrin group is subjected to 1 group of reagent thing, is subjected to 2 groups of reagent things and is subjected to 3 groups of reagent things.Every group of 10 animals.
(2) model copy: except that the blank group, other each groups all adopt black and white position preference case tendentiousness training program to duplicate amfetamine inducing mouse position preference model.Immediately mice is placed white box 60min behind the odd number sky morning (8:00) lumbar injection (ip) amfetamine (4mg/kg).The even number sky morning (8:00) lumbar injection (ip) equal-volume normal saline places mice black box 60min immediately.Later 6d is operation as stated above all, trains altogether 8 days.8:00 carried out position preference detection in the 9th day morning, and by the Animal Behavior Science analytical system, the time of stop in the inherent white box of mice 15min (companion's medicine-chest) also analyzed in record.
(3) Drug therapy: each medication therapy groups is in beginning administration in the 6th day of experiment, and every afternoon, 16:00 was respectively by the corresponding dosage administration.Blank group and morphine model group give the equal-volume normal saline, the 60mg/kg administration according to dosage of Ramulus Uncariae cum Uncis alkali group, and the deoxyschizandrin group is pressed the 60mg/kg administration, is subjected to 1,2,3 groups of all 60mg/kg administrations according to dosage of reagent thing.Each group is irritates stomach (ig) administration.Continued medication 3 days, the experimental session mice freely drinks water and takes food.
(4) result: no significant difference (P＞0.05) before time that in white casing, stops behind the blank group mice medicine and the medicine.Amfetamine model group and blank group relatively, the time significant prolongation (P＜0.01) that mice stops at white box and is compared before the administration, the time that mice stops in white box is significant prolongation (P＜0.01) also, shows that mice has produced the visibility point CPP effect.Each administration group successive administration 3 days, Ramulus Uncariae cum Uncis alkali group (60mg/kg), and compared with the amfetamine model group by reagent thing 1,2,3 groups (60mg/k), the time that mice stops in white box significantly shortens, (P＜0.05 or P＜0.01), with relatively reach before the administration and the blank group relatively, the time that mice stops in white box is not seen obvious prolongation (P＞0.05).Table 5.
Table 5 medicine to the influence of amfetamine inducing mouse position CPP effect (
N=10)
*P＜0.05,
*Compare with the blank group P＜0.01;
#P＜0.05,
##Compare with the amfetamine model group P＜0.01;
△P＜0.05,
△ △P＜0.01 is with comparison before the administration.
4. methamphetamine is induced the rat conditioned place preference
(1) animal grouping: the natural place of learning from else's experience preference is measured qualified SD rat, and body weight 200-240g is male, is divided into 6 groups at random, i.e. blank group, and model group, is subjected to 1,2,3 groups of reagent things at the Ramulus Uncariae cum Uncis alkali group.Every group of 10 animals.
(2) model copy: except that the blank group, other each groups all adopt black and white position preference case tendentiousness training program to duplicate methamphetamine and induce rat position preference model.The odd number sky morning (8:00) lumbar injection (ip) methamphetamine (2mg/kg) places white box with rat then immediately.The even number sky morning (8:00) lumbar injection (ip) equal-volume normal saline places black box with rat immediately.Be 1h standing time.Later 6d is operation as stated above all, trains altogether 8 days.8:00 carried out position preference detection in the 9th day morning, by the Animal Behavior Science analytical system, and the time that stops in the inherent white box of record and analyzing rat 15min.
(3) Drug therapy: each medication therapy groups is in beginning administration in the 4th day of experiment, and every afternoon, 16:00 was respectively by the corresponding dosage administration.Blank group and morphine model group give the equal-volume normal saline, the 30mg/kg administration according to dosage of Ramulus Uncariae cum Uncis alkali group, and being subjected to 1,2,3 groups of dosages of reagent thing is 30mg/kg.Each group is irritates stomach (ig) administration.Continued medication 5 days, the experimental session rat freely drinks water and takes food.
(4) result: no significant difference (P＞0.05) before time that in white casing, stops behind the blank group rat medicine and the medicine.Methamphetamine model group and blank group are relatively, the time significant prolongation (P＜0.01) that rat stops at white box, with compare before the administration, the time that rat stops in white box is significant prolongation (P＜0.01) also, expression rat p-Methylamphetamine has produced the visibility point CPP effect.Each administration group successive administration 5 days, Ramulus Uncariae cum Uncis alkali group (30mg/kg), be subjected to reagent thing 1,2,3 groups (30mg/k) and mephentermine model group relatively, the time that rat stops in white box significantly shortens, (P＜0.05 or P＜0.01), with relatively reach before the administration and the blank group relatively, the time that rat stops in white box is not seen obvious prolongation (P＞0.05).Table 6.
Table 6 medicine p-Methylamphetamine induce rat position CPP effect influence (
N=10)
*P＜0.05,
*Compare with the blank group P＜0.01;
#P＜0.05,
##Compare with the methamphetamine model group P＜0.01;
△P＜0.05,
△ △P＜0.01 is with comparison before the administration.
5. the physical dependence evaluation test of the present composition
Get 50 of SPF level SD rats, male and female half and half are divided into 3 groups at random, i.e. negative control group, is subjected to 1 group of reagent thing, every group of 10 animals at the morphine matched group.Morphine matched group, compositions group all adopt and increase progressively dose regimen, and morphine matched group subcutaneous injection (sc) morphine hydrochloride is subjected to 1 group of gastric infusion of reagent thing, and (8:00am 8:00pm) was administered once in per 12 hours.According to dosage increase progressively principle, the dosage of morphine all from each 5mg/kg, increases progressively successively, to each 60mg/kg, and continuous using to the 9th day.The dosage that is subjected to 1 group of reagent thing increases progressively successively from 10mg/kg, to each 100mg/kg, and continuous using to the 9th day.Negative control group is irritated stomach with the capacity normal saline every day, and administration time and number of times are with the administration group.Respectively organized rat 60min after the 8:00 administration on the 9th day, (4mg/kg ip) urges to give naloxone.Observation is urged the withdrawal symptom of giving up rat in the 1h of back and is urged front and back body weight situation of change.Withdrawal symptom to rat is marked, and each group rat body weight variation percentage rate is carried out statistical disposition.[rat body weight changes percentage rate=(give up body weight-give up preceding body weight)/give up back body weight * 100%]
Experimental result shows that the morphine control rats is after naloxone is urged, and the withdrawal symptom score value of animal subject and weight loss percentage rate show that all apparently higher than cloudy matched group (P＜0.01) morphine group rat has formed tangible physical dependence.Originally be subjected to 1 group of rat of reagent thing incremental method successive administration 9 days according to dosage, urge through naloxone, do not show tangible withdrawal symptom, score value of rat and weight loss percentage rate and negative control group more all do not have significant difference (P＞0.05); With the morphine matched group highly significant difference is arranged then, P＜0.01.Show that being subjected to not form physical dependence after 1 group of rat medication of reagent thing reacts.See Table 7.
Table 7 respectively organize rat urge withdrawal symptom score value and body weight change percentage rate (
N=10)
*Compare with the blank group P＜0.01;
##Compare with the morphine group P＜0.01.
6. the psychic dependence Potential Evaluation of present composition test
The natural place of learning from else's experience preference is measured 50 of qualified SPF level Kunming mouses, male and female half and half, be divided into negative control group (with the volume normal saline) at random, morphine matched group (9mg/kg), be subjected to reagent thing 1 group (60mg/kg), be subjected to reagent thing 2 groups (60mg/kg), be subjected to 3 groups of reagent things (60mg/kg).Every group of 10 animals.Each treated animal is administered twice every day, and twice dosing interval 8h (8:00,16:00).Twice equal ip normal saline of negative control group, morphine group sc morphine hydrochloride and normal saline each once, be subjected to 1,2,3 groups of reagent things according to dosage irritate respectively the corresponding medicinal liquid of stomach and normal saline each once.Each administration group gives medicine the equal morning, gives normal saline afternoon.The mice administration is placed on non-preference side white casing, gives normal saline and is placed on preference side black casing.Mice standing time in case is 40min.Train 6d altogether.Detect in the laggard line position preference of last administration 24h.To have a preference for separator for container and extract out, mice by only putting in the middle of the casing, will be observed 15min, be as the criterion the time of staying of record mice at companion's medicine box with the head of mice.
Experimental result shows, behind the morphine control group mice medication 6d, animal subject prolongs (P＜0.01) in residence time of companion's medicine box before obviously than administration, also obviously is longer than negative control group (P＜0.05).Show that the morphine induction mice has produced the visibility point CPP effect.After being subjected to 1,2,3 groups of mice medication 6d of reagent thing, mice does not all have obvious prolongation in the residence time of companion's medicine box, with compare before the administration, no significant difference (P＞0.05), with the negative control group ratio, also do not have significant difference (P＞0.05), with the morphine matched group highly significant difference is arranged then, P＜0.05 or P＜0.01.Show that mice does not produce rewarding effect or detests effect the present composition.See Table 8.
Table 8 respectively organize mice conditioned place preference effect (
N=10)
*Compare with the blank group P＜0.05;
#P＜0.05,
##Compare with the morphine group P＜0.01.
△ △P＜0.01 is with comparison before the administration.
Above-mentioned experimental result shows that the present composition urges withdrawal symptom to have therapeutical effect to the drug dependence that morphine relies on large and small Mus, can suppress the withdrawal symptom that morphine relies on animal pattern, alleviates the weight loss that withdrawal symptom causes, promotes the recovery of body.The conditioned place preference experiment is to grow up abroad the eighties to be used to estimate a kind of newer method of medicine drug dependence begetting power.Above-mentioned experimental result shows that this compositions has the obvious suppression effect to the inductive conditioned place preference of amphetamine central stimulant.By the effect of compositions, alleviated the psychic dependence of large and small Mus.
Above-mentioned experimental data displaying monomer composition deoxyschizandrin and schisandrin B use withdrawal symptom and the inductive conditioned place preference of amfetamine to morphine-dependent mice not to have obvious influence separately, and after the compositions administration of same dose, the obvious suppression effect that all shows is had a preference in the withdrawal symptom and the position of animal subject.The effect that is subjected to the reagent thing is with obvious than the effect of Ramulus Uncariae cum Uncis alkali group.Show performance synergism to a certain degree between each composition of compositions, its effect is remarkable than the effect of single component.
Above-mentioned experiment has proved that simultaneously the present composition itself does not have the characteristic of physical dependence, can not induced animal produces the position preferences, shows that compositions do not have physical dependence and drug dependence begetting power.The present invention experimental results show that by pharmacological experiment and drug dependence the present composition has anti-opioid and the amphetamine central stimulant relies on, the effect of control withdrawal symptom, and compositions itself does not have physical dependence and psychic dependence, no addiction.For clinical application provides scientific basis.
The specific embodiment
Embodiment 1 (capsule)
Prescription: Rhomotoxine 750 grams, Fructus Schisandrae Chinensis total lignanoid 250 grams, micropowder silica gel 30 grams, starch 70 grams, magnesium stearate 10 grams.
Preparation:
Handle medical material at first by the following method, prepare each crude drug:
(1) hook taking rattan stem and branch with belt hook is ground into coarse powder, and with 10 times of amount 75% ethanol merceration 24h, percolation extracts in the seepage of packing into the tube.Collect percolate, concentrate behind the decompression recycling ethanol, get extractum, with 3 times of amount 3% dissolve with hydrochloric acid solutions, filtration.Filtrate is alkalized with ammonia, transfers pH to 9, with 6 times of amount ether heating and refluxing extraction 5 times, reclaims solvent, filtration, and drying obtains Rhomotoxine.
The Rhomotoxine Determination on content adopts ultraviolet spectrophotometry, and the method is for detecting the conventional method of total alkaloids.This research reference literature reported method [Zhong Yun, Feng Ruizhi. the ultraviolet spectrometry of Ramulus Uncariae Cum Uncis and congener alkaloid thereof, HPLC measure. Chinese herbal medicine, 1993,24 (9): 462; Yang Jiaqiang, etc. the component analysis of Ramulus Uncariae cum Uncis alkali in the Ramulus Uncariae Cum Uncis. modern medicine health, 2007,23 (16): 2378-2379], specific as follows:
Reference substance: Ramulus Uncariae cum Uncis alkali (purity 99.67%), by Japanese Wako Pure Chemical Industries, Ltd. provides.Detecting instrument: UV-2401 ultraviolet spectrophotometer (day island proper Tianjin company product), detect wavelength: 242nm.Detecting the reference substance of degree of passing concentration earlier, is abscissa with concentration (C), and absorbance (A) is a vertical coordinate, and the drawing standard curve gets regression equation A=0.0573C-0.0401, correlation coefficient r=0.9989.Sample solution is that the 242nm place surveys its absorbance A value detecting wavelength after the methanol dilution, and the above-mentioned standard curve of A value substitution is calculated total alkaloids concentration.Rhomotoxine content was 57.8% during the result was extract obtained.
(2) get schisandra chinensis medicinal material, drying is ground into coarse powder, adds 5 times of amount 90% ethanol, and reflux, extract, 4h extracts 3 times, merges alcohol extract, and decompression recycling ethanol gets alcohol extract.6 times of amounts of reuse petroleum ether extraction Chinese Magnoliavine Fruit alcohol extract, silicagel column on the extract, usefulness n normal hexane-ethyl acetate-methanol-water (1: 0.9: 0.9: 1, v/v) eluting gets Fructus Schisandrae Chinensis total lignanoid.
The Fructus Schisandrae Chinensis total lignanoid assay adopts high performance liquid chromatogram (HPLC) method.The method is for detecting the conventional using method of lignan component.This research reference " Chinese pharmacopoeia and pertinent literature reported method [Chinese Pharmacopoeia Commission. Pharmacopoeia of People's Republic of China (version in 2010, an one). Beijing: Chinese Medicine science and technology publishing house, 2010:61-62; Tian Zhenkun, etc. the extraction process of the preferred Fructus Schisandrae Chinensis extractum of high performance liquid chromatography. Chinese medicine journal, 2009,37 (2): 43-45], specific as follows:
Reference substance: schisandrin, schisantherin B, schisantherin A, deoxyschizandrin, schisandrin B reference substance provide by Nat'l Pharmaceutical ﹠ Biological Products Control Institute.Chromatographic condition: chromatographic column: Hypersil-C18 (250mm * 416mm, 5 μ L), mobile phase methanol-water (V/V), gradient elution, 0～36min (60: 40～66: 34), 36～65min (66: 34～80: 20), 65～70min (80: 20), 70～75min (80: 20～100: 0); Flow velocity 0.5mL/min; Detect wavelength 254; Column temperature: room temperature; Sample size 20 μ L. measure according to above-mentioned chromatographic condition, and each composition number of theoretical plate of Fructus Schisandrae Chinensis is not less than 3000.Detect through HPLC, schisandrin, schisantherin B, schisantherin A, deoxyschizandrin, schisandrin B content (%) are respectively 41.3%, 6.2%, 7.7%, 6.0%, 9.5% in the extract.Total lignans content was 43.7% during the result was extract obtained.
With Rhomotoxine and Fructus Schisandrae Chinensis total lignanoid mix homogeneously, add micropowder silica gel, starch and magnesium stearate and granulate, drying, granulate, mixing, encapsulated, make capsule.
Instructions of taking: oral, one time 3,3-4 time on the one.
Embodiment 2 (tablet)
Prescription: Rhomotoxine 650 grams, Fructus Schisandrae Chinensis total lignanoid 350 grams, dextrin 50 grams, micropowder silica gel 30 grams, starch 100 grams.
Preparation:
Hook taking rattan stem and branch with belt hook is ground into coarse powder, and with 9 times of amount 85% ethanol merceration 24h, percolation extracts in the seepage of packing into the tube.Collect percolate, concentrate behind the decompression recycling ethanol, get extractum, with 3% dissolve with hydrochloric acid solution, the filtration of 2 times of amounts.Filtrate is transferred pH10 with ammonia, with the ether heating and refluxing extraction of 8 times of amounts 4 times, reclaims solvent, filters, and drying obtains Rhomotoxine.Recording total alkaloid content by the ultraviolet spectrophotometry among the embodiment 1 is 59.1%.
Get schisandra chinensis medicinal material, drying is ground into coarse powder, adds 8 times of amount 85% ethanol, and reflux, extract, 2h extracts 2 times, merges alcohol extract, and decompression recycling ethanol gets alcohol extract.5 times of amounts of reuse petroleum ether extraction Chinese Magnoliavine Fruit alcohol extract, silicagel column on the extract, usefulness n normal hexane-ethyl acetate-methanol-water (1: 0.9: 0.9: 1, v/v) eluting gets Fructus Schisandrae Chinensis total lignanoid.Recording lignanoid's content by the PHLC method among the embodiment 1 is 42.5%.
Ramulus Uncariae Cum Uncis total alkaloids and Fructus Schisandrae Chinensis total lignanoid are mixed, add microcrystalline Cellulose, starch and micropowder silica gel, fully cross 100 mesh sieves behind the mixing, granulate, cold drying, granulate, tabletting, the bag film-coat is made Film coated tablets.
Instructions of taking: oral, one time 3,3-4 time on the one.
Embodiment 3 (drop pill)
Prescription: Rhomotoxine 400 grams, Fructus Schisandrae Chinensis total lignanoid 600 grams, PEG 800 grams.
Preparation:
Hook taking rattan stem and branch with belt hook is ground into coarse powder, and with 10 times of amount 80% ethanol merceration 24h, percolation extracts in the seepage of packing into the tube.Collect percolate, concentrate behind the decompression recycling ethanol, get extractum, with 3% dissolve with hydrochloric acid solution, the filtration of 4 times of amounts.Filtrate is transferred pH10 with ammonia, with the ether heating and refluxing extraction of 8 times of amounts 5 times, reclaims solvent, filters, and drying obtains Rhomotoxine.Recording total alkaloid content by the ultraviolet spectrophotometry of embodiment 1 is 60%.
Get schisandra chinensis medicinal material, drying is ground into coarse powder, adds 4 times of amount 95% ethanol, and reflux, extract, 2h extracts 2 times, merges alcohol extract, and decompression recycling ethanol gets alcohol extract.4 times of amounts of reuse petroleum ether extraction Chinese Magnoliavine Fruit alcohol extract, silicagel column on the extract, usefulness n normal hexane-ethyl acetate-methanol-water (1: 0.9: 0.9: 1, v/v) eluting gets Fructus Schisandrae Chinensis total lignanoid.Recording lignanoid's content by the PHLC method of embodiment 1 is 40.8%.
Ramulus Uncariae Cum Uncis alkaloid and Fructus Schisandrae Chinensis lignanoid are mixed, and cold drying is pulverized, and adds among the PEG that has melted, stirs, wait medicine to be dispersed in the liquid carrier fully after, put in the drilling pill device, splash into liquid paraffin, drip and make piller.
Instructions of taking: oral, one time 4,4 times on the one.
Embodiment 4 (oral liquid)
Prescription: Rhomotoxine 200 grams, Fructus Schisandrae Chinensis total lignanoid 600 grams, sucrose 400 grams, ethyl hydroxybenzoate 0.3 gram.
Preparation:
Hook taking rattan stem and branch with belt hook is ground into coarse powder, and with 8 times of amount 95% ethanol merceration 24h, percolation extracts in the seepage of packing into the tube.Collect percolate, concentrate behind the decompression recycling ethanol, get extractum, with 3% dissolve with hydrochloric acid solution, the filtration of 3 times of amounts.Filtrate is transferred pH10 with ammonia, with the ether heating and refluxing extraction of 7 times of amounts 4 times, reclaims solvent, filters, and drying obtains Rhomotoxine.Recording total alkaloid content by the ultraviolet spectrophotometry of embodiment 1 is 59.5%.
Get schisandra chinensis medicinal material, drying is ground into coarse powder, adds 7 times of amount 90% ethanol, and reflux, extract, 4h extracts 3 times, merges alcohol extract, and decompression recycling ethanol gets alcohol extract.6 times of amounts of reuse petroleum ether extraction Chinese Magnoliavine Fruit alcohol extract, silicagel column on the extract, usefulness n normal hexane-ethyl acetate-methanol-water (1: 0.9: 0.9: 1, v/v) eluting gets Fructus Schisandrae Chinensis total lignanoid.Recording lignanoid's content by the PHLC method of embodiment 1 is 44.0%.
Ramulus Uncariae Cum Uncis alkaloid and Fructus Schisandrae Chinensis lignans extract are mixed.Get 400g sucrose and add the 1000ml water dissolution and boil, add the 0.3g ethyl hydroxybenzoate, the stirring and dissolving after-filtration adds above-mentioned two kinds of extracts then, and stirring and dissolving is filtered, fill, and sterilization promptly gets present composition oral liquid.
Instructions of taking: oral, a 10ml, 3-4 time on the one.
Embodiment 5 (soft capsule)
Prescription: Rhomotoxine 500 grams, Fructus Schisandrae Chinensis total lignanoid 500 grams.Edible vegetable oil 500 grams, gelatin 50 grams, glycerol 50 grams.
Preparation:
Hook taking rattan stem and branch with belt hook is ground into coarse powder, and with 8 times of amount 90% ethanol merceration 24h, percolation extracts in the seepage of packing into the tube.Collect percolate, concentrate behind the decompression recycling ethanol, get extractum, with 3% dissolve with hydrochloric acid solution, the filtration of 4 times of amounts.Filtrate is transferred pH9.5 with ammonia, with the ether heating and refluxing extraction of 6 times of amounts 5 times, reclaims solvent, filters, and drying obtains Rhomotoxine.Recording total alkaloid content by the ultraviolet spectrophotometry of embodiment 1 is 56%.
Get schisandra chinensis medicinal material, drying is ground into coarse powder, adds 8 times of amount 80% ethanol, and reflux, extract, 3h extracts 3 times, merges alcohol extract, and decompression recycling ethanol gets alcohol extract.5 times of amounts of reuse petroleum ether extraction Chinese Magnoliavine Fruit alcohol extract, silicagel column on the extract, usefulness n normal hexane-ethyl acetate-methanol-water (1: 0.9: 0.9: 1, v/v) eluting gets Fructus Schisandrae Chinensis total lignanoid.Recording lignanoid's content by the PHLC method of embodiment 1 is 45%.
Handle medical material according to the method among the embodiment 1, preparation crude drug Ramulus Uncariae Cum Uncis total alkaloids and Fructus Schisandrae Chinensis total lignanoid.With the alkaloid that extracts and lignanoid mix, dry, pulverize, mix then with through heat sterilization, clarifying food plant, stir, put into liquor tank, gelatin, the blended gelatin solution of G ﹠ W are placed the gelatin solution storage tank, be processed into soft capsule.
Instructions of taking: oral, one time 3,4 times on the one.
Embodiment 6 (pill)
Prescription: Rhomotoxine 800 grams, Fructus Schisandrae Chinensis total lignanoid 100 grams.
Preparation:
Hook taking rattan stem and branch with belt hook is ground into coarse powder, and with 9 times of amount 75% ethanol merceration 24h, percolation extracts in the seepage of packing into the tube.Collect percolate, concentrate behind the decompression recycling ethanol, get extractum, with 3% dissolve with hydrochloric acid solution, the filtration of 2 times of amounts.Filtrate is transferred pH9 with ammonia, with the ether heating and refluxing extraction of 6 times of amounts 3 times, reclaims solvent, filters, and drying obtains Rhomotoxine.Recording total alkaloid content by the ultraviolet spectrophotometry of embodiment 1 is 55%.
Get schisandra chinensis medicinal material, drying is ground into coarse powder, adds 6 times of amount 90% ethanol, and reflux, extract, 4h extracts 3 times, merges alcohol extract, and decompression recycling ethanol gets alcohol extract.6 times of amounts of reuse petroleum ether extraction Chinese Magnoliavine Fruit alcohol extract, silicagel column on the extract, usefulness n normal hexane-ethyl acetate-methanol-water (1: 0.9: 0.9: 1, v/v) eluting gets Fructus Schisandrae Chinensis total lignanoid.Recording lignanoid's content by the PHLC method of embodiment 1 is 45%.
With above two kinds of crude drug mixing, dry, pulverizing, cross 100 mesh sieves and get fine powder, use water pill then, drying gets pill, and per 100 balls nearly weigh 1g, promptly.
Instructions of taking: oral, a 3g, 3-4 time on the one.
Embodiment 7 (pellet)
Prescription: Rhomotoxine 700 grams, Fructus Schisandrae Chinensis total lignanoid 250 grams, microcrystalline Cellulose 50 grams, magnesium stearate 10 grams.
Preparation:
Hook taking rattan stem and branch with belt hook is ground into coarse powder, and with 9 times of amount 90% ethanol merceration 24h, percolation extracts in the seepage of packing into the tube.Collect percolate, concentrate behind the decompression recycling ethanol, get extractum, with 3% dissolve with hydrochloric acid solution, the filtration of 4 times of amounts.Filtrate is transferred pH9 with ammonia, with the ether heating and refluxing extraction of 7 times of amounts 4 times, reclaims solvent, filters, and drying obtains Rhomotoxine.Recording total alkaloid content by the ultraviolet spectrophotometry of embodiment 1 is 59.4%.
Get schisandra chinensis medicinal material, drying is ground into coarse powder, adds 4 times of amount 95% ethanol, and reflux, extract, 4h extracts 3 times, merges alcohol extract, and decompression recycling ethanol gets alcohol extract.4 times of amounts of reuse petroleum ether extraction Chinese Magnoliavine Fruit alcohol extract, silicagel column on the extract, usefulness n normal hexane-ethyl acetate-methanol-water (1: 0.9: 0.9: 1, v/v) eluting gets Fructus Schisandrae Chinensis total lignanoid.Recording lignanoid's content by the PHLC method of embodiment 1 is 44.6%.
With two kinds of extracts mixing, dry, pulverizing, cross 100 mesh sieves and get fine powder, add microcrystalline Cellulose and magnesium stearate, prepare micropill, be dried promptly.The micropill that makes can directly take or the capsulae vacuus of packing in use.
Instructions of taking: oral, a 3g, 3-4 time on the one.
Claims (4)
1. prevent and treat the medicine that amphetamine and opioid drug rely on for one kind, this medicine is made up of effective ingredient and medically acceptable adjuvant, it is characterized in that described effective ingredient is made up of following bulk drugs: Rhomotoxine 20～80, Fructus Schisandrae Chinensis total lignanoid 10～60; Wherein, described Rhomotoxine is prepared by following method: hook taking rattan stem and branch with belt hook, be ground into coarse powder, and with 8～10 times of amount 75%～95% pure merceration 20～40h, percolation extracts in the seepage of packing into the tube; Collect percolate, concentrate behind the decompression recycling ethanol, extractum, 3% dissolve with hydrochloric acid solution, the filtration of doubly measuring with 2-4; Filtrate is transferred pH9～10 with ammonia, with the ether heating and refluxing extraction of 6～8 times of amounts 3～5 times, reclaims solvent, filters, and drying obtains total alkaloid content and be 55～60% Rhomotoxine;
Described Fructus Schisandrae Chinensis total lignanoid is prepared by following method: get schisandra chinensis medicinal material, drying is ground into coarse powder, adds 4～8 times of amount 80%～90% ethanol, and reflux, extract, 2～4h extracts 2～3 times, merges alcohol extract, and decompression recycling ethanol gets alcohol extract; 4～6 times of reuse amount petroleum ether extraction Chinese Magnoliavine Fruit alcohol extract, silicagel column on the extract use the eluent eluting, must lignanoid's content is 40～45% Fructus Schisandrae Chinensis total lignanoid; Wherein said eluent is that volume ratio is the n normal hexane: ethyl acetate: methanol: water=1: 0.9: 0.9: 1 mixed solution.
2. a kind of medicine that amphetamine and opioid drug rely on of preventing and treating according to claim 1 is characterized in that described effective ingredient is made up of following bulk drugs: Rhomotoxine 40～70, Fructus Schisandrae Chinensis total lignanoid 25～45.
3. a kind of medicine that amphetamine and opioid drug rely on of preventing and treating according to claim 1 is characterized in that described effective ingredient is made up of following bulk drugs: Rhomotoxine 65, Fructus Schisandrae Chinensis total lignanoid 35.
4. according to the described a kind of medicine of preventing and treating amphetamine and opioid drug dependence of one of claim 1-3, it is characterized in that this medicine is medically acceptable oral formulations.
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| CN110882247A (en) * | 2019-11-16 | 2020-03-17 | 南方医科大学 | Use of isorhynchophylline in preparing drug-relief medicine |
| CN113604420A (en) * | 2021-07-07 | 2021-11-05 | 南方医科大学珠江医院 | Method for inducing human placental mesenchymal stem cells to differentiate into liver cells in vitro and composition containing schisandrin B |
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| CN110882247A (en) * | 2019-11-16 | 2020-03-17 | 南方医科大学 | Use of isorhynchophylline in preparing drug-relief medicine |
| CN113604420A (en) * | 2021-07-07 | 2021-11-05 | 南方医科大学珠江医院 | Method for inducing human placental mesenchymal stem cells to differentiate into liver cells in vitro and composition containing schisandrin B |
| CN113604420B (en) * | 2021-07-07 | 2022-07-08 | 南方医科大学珠江医院 | Method for inducing human placental mesenchymal stem cells to differentiate into liver cells in vitro and composition containing schisandrin B |
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