CN101229351B - Medicine compounds with detoxication uses - Google Patents

Medicine compounds with detoxication uses Download PDF

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CN101229351B
CN101229351B CN2008100453025A CN200810045302A CN101229351B CN 101229351 B CN101229351 B CN 101229351B CN 2008100453025 A CN2008100453025 A CN 2008100453025A CN 200810045302 A CN200810045302 A CN 200810045302A CN 101229351 B CN101229351 B CN 101229351B
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radix
detoxication
medicine
group
composition
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CN101229351A (en
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王建生
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Chengdu Zhizhi Pharmaceutical Co ltd
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CHENGDU ZHIZHI PHARMACY GROUP Co Ltd
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Abstract

The invention relates to a medicament combination with efficacy of detoxification. The raw materials of natural drugs such as radix aconiti praeparata, calculus bovis factitious, datura flower, uncaria pearl, ginseng, radix curcumae, aloe and liquoric root are adopted as effective ingredients which are combined with acceptable auxiliary ingredients in pharmacy to prepare oral medicinal preparation. The effective medicinal ingredients are calculated in portions by weight of the natural drugs: 500-700 portions of the radix aconiti praeparata, 10-90 portions of the calculus bovis factitious, 5-30 portions of the datura flower, 60-140 portions of the uncaria, 10-90 portions of the pearl, 20-100 portions of the ginseng, 60-140 portions of the radix curcumae, 60-140 portions of the aloe and 20-100 portions of the liquoric root. Experiment results demonstrate that the medicament combination of the invention has positive and absolute healing efficacy to the detoxification of the dependency of morphine.

Description

Pharmaceutical composition with detoxication uses
Technical field
The present invention relates to a kind of pharmaceutical composition, particularly with the pharmaceutical composition with detoxication uses of natural drug material composition as the active drug composition with detoxication uses.
Background technology
Drug issue is a kind of international public hazards, except that the infringement of drugs to person health and human nature itself, still is as the important route of transmission of other many serious diseases such as acquired immune deficiency syndrome (AIDS).
In the Drug therapy withdrawal symptom of detoxification phase I as a whole, both at home and abroad at present medicines that adopt have two classes more: as the replacement therapy of opioid receptor agonists such as methadone, and the verification treatment of non-opioid receptor agonist such as clonidine.But, thereby also have and run off and become the possibility of opium succedaneum because methadone etc. self promptly has dependency.Medicines such as clonidine only can partly be controlled acute withdrawal symptom, and can cause untoward reaction such as postural hypotension.Then both are all invalid for protracted abstinence symptom (psa), and both are also all unhelpful for the correction of addiction caused organismic internal environment dysequilibrium.And have a sleepless night, protracted abstinence symptom (psa)s such as anxiety, pain are to cause the main cause of reverting to take drugs, also be simultaneously at present with adopt the chemicals mode quit drug abuse in a still scabrous so far problem.
Summary of the invention
At above-mentioned situation, the present invention will provide a kind of pharmaceutical composition with detoxication uses, be the active drug composition with the natural drug raw material particularly and have a detoxification pharmaceutical composition through what evidence can have a promising result.
Chinese medicine and pharmacy can have the impaired theory of qi-blood-body fluid to the understanding and the theory of opiate addiction and drug rehabilitation, and the vital organs of the human body are inveterate to be said, three warmers are subjected to that addiction is said etc., thinks because the evil poison of opium lies prostrate internal organs deeply, damage body healthy energy steam, the pathological reaction of visceral dysfunction, evil malicious glue is difficult to resolve admittedly, the function disorder.And further deeply point out, because the bitter temperature of Opium is poisonous, go into lung, kidney and large intestine channel.Hold back wetly because of bitter temperature, inhale the clothes addiction and then lie prostrate internal organs admittedly deeply for malicious evil glue, consumption is hindered body steam, upsets function, its yang-energy collapse, and conscience is excited, and empty sun is outer to be taken off with the conscience yang hyperactivity and deposits, and deficiency syndrome are double mutually with excess syndrome.Yang-energy is the active motive power of human-body viscera function, and deficient and weak YANG QI takes off outward, and patient then shows as lethargy, sheds streams of tears and to snivel, gape sneeze, aversion to cold cold extremities.Dripping cold sweat, shed streams of tears and to snivel that to be that empty sun is outer take off, gas does not soak admittedly; Body fluid leaks, and gape sneeze is not warming the lung of sun, and lung is not declared logical, and aversion to cold cold extremities, headache general pain are that the sun mistake is warm, the sluggish event of passages through which vital energy circulates.The heart controls mental activities, main thinking activities, and the heart matches fire is dirty, and heart-fire is the easiest burns vehemently, and hyperactivity of heart-fire upsets that the mind is then fainted from fear, agitation, anxiety, insomnia, and the mind can not be autonomous; Liver is reported the property of wind wood then for just dirty, and high positive wind-transformation is susceptible to lose temper due to restlessness then, even the scream of twitching.
At above-mentioned analysis and understanding, what medicine of the present invention was established is that arresting convulsion is calmed the nerves with the recuperating depleted YANG QI invigorating, analgesia relieving convulsion, the principle of detoxifcation withdrawal.For this reason; the present invention has the pharmaceutical composition of detoxication uses; employing is the active drug composition with natural drug raw material Radix Aconiti Lateralis Preparata, artificial Calculus Bovis, Flos Daturae, Ramulus Uncariae Cum Uncis Margarita, Radix Ginseng, Radix Curcumae, Aloe and Radix Glycyrrhizae; become oral type pharmaceutical preparation with acceptable auxiliary element mutual group in the pharmacy, wherein be preferably capsule-type pharmaceutical preparation.Active drug composition in the material medicine weight portion consists of:
Radix Aconiti Lateralis Preparata 500-700, artificial Calculus Bovis 10-90, Flos Daturae 5-30, Ramulus Uncariae Cum Uncis 60-140,
Margarita 10-90, Radix Ginseng 20-100, Radix Curcumae 60-140, Aloe 60-140, Radix Glycyrrhizae 20-100.
Further preferred composition form in the active drug composition of material medicine weight portion in the aforementioned pharmaceutical compositions of the present invention is:
Radix Aconiti Lateralis Preparata 600, the artificial Calculus Bovis 50, Flos Daturae 20, Ramulus Uncariae Cum Uncis 100, Margarita 50,
Radix Ginseng 60, Radix Curcumae 100, Aloe 100, Radix Glycyrrhizae 60.
According to Chinese medical theory, the Radix Aconiti Lateralis Preparata in the above-mentioned active drug composition is a monarch drug, and is hot poisonous, and the supporing yang merit of fire is mended in the tool recuperating depleted YANG and rescuing the patient from collapse; Radix Ginseng is a ministerial drug, sweet flat little hardship, and strongly invigorating primordial QI, multiple arteries and veins takes off admittedly, and the two compatibility is established for collapsing at yang-energy, controls dripping cold sweat, aversion to cold acroesthesia, and lethargy is shed streams of tears and to snivel, the disease of YANG-depletion QI prostration such as faint pulse.
Modern medicine study proves, the chemical constituent of Radix Aconiti Lateralis Preparata mainly contains aconitine, rod chapter alkali, benzoyl mesaconitine, nor-aconitine, Salsolinol, methyldopa amine hydrochlorate etc., can have analgesia, heart tonifying, coronary dilating, arrhythmia, shock, and improve multiple pharmacological effect such as immunologic function, antiinflammatory, cold resistance.
Radix Ginseng is the key medicine of QI invigorating emergency treatment of collapse, and it is only that serious disease, prolonged illness, shortness of breath and tired spirit, faint pulse being about to disappear, fictitious pole are desired the non-Radix Ginseng of disease that takes off.Radix Aconiti Lateralis Preparata is dispersing cold for relieving pain again, but promoting the flow of QI-blood by warming the meridian stagnate with analgesia, can treat pain diseases such as headache in the withdrawal symptom, general pain, abdominal pain.Modern study proves; its contained ginsenoside can have many-sided pharmacological action, if can block the generation of hydromorphone effectively, improves the level of glutathion in the liver; the contact morphine is to the inhibition of release neurotransmitters in the brain; alleviate withdrawal symptom, also can have two-ways regulation again simultaneously, improve resistance infecting to blood pressure; has the anti-liver injury effect; body there is significant protective effect, improves anti-hypoxia, resisting fatigue, anti-stress and mutation ability, the adaptability of enhancing body.
The artificial Calculus Bovis also is a monarch drug; the conscience warp is gone in bitter cold; the tool heat-clearing and toxic substances removing; cherish the wind relieving convulsion; the waking up the patient from unconsciousness by dissipating phlegm effect; removing summer-heat lies prostrate in conscience deeply through opium temperature poison, the positive pathogenic heat fire that cool removing pathogen in the heart liver is excited, and treatment faints from fear, twitches, irritated spiritual excited symptom not according to hyperactive liver-YANG causing syndrome of liver-wind such as, anxiety insomnia, the heart disturbed by phlegm-fire.Modern study proves, gas can have calmness, convulsion, analgesic, antitussive and analgesic effect to the central nervous system; The contained artificial Calculus Bovis's acid of gas can suppress neurotransmitter stimulates the norepinephrine and the acetylcholine that cause to discharge, and regulation and control GABA release, regulates the content of acetylcholine, dopamine, GABA and glutamic acid in the brain, has the hepatic cholagogic effect.
Margarita is a ministerial drug, and salty in the mouth is cold in nature, has the arresting convulsion of taking shelter effect, but tranquilizing mind will, and suppressing the hyperactive liver arresting convulsion wind is strengthened the flat excited sun of liver with great concentration of artificial Calculus Bovis.Flos Daturae pain relieving spasmolytic, Xin Wen is poisonous, and " narcotic analgesic " is longer than in its pain relieving especially, assists Radix Aconiti Lateralis Preparata treatment headache, general pain, abdominal pain, and can assist and strengthen artificial Calculus Bovis's spasmolytic, the effect of endogenous wind stopping relieving convulsion.Modern study proves, the main medicinal ingredient of Flos Daturae is an alkaloid, wherein scopolamine accounts for more than 85%, hyoscyamine and atropine account for 15% altogether, the gas pharmacological action can comprise with M-nachr antagonist form has inhibitory action to cerebral cortex and maincenter network structure ascending activating system, significant calmness is arranged and contact excited effect.Brain microdialysis method proof gas can make the DOPAMINE CONTENT IN RABBIT of brain stem and midbrain significantly improve, and 5-hydroxy tryptamine content descends in the brain stem; The electricity Physiological Experiment shows that scopolamine can resist the acetylcholine sample effect of opiate addiction, and microcirculation improvement, shock have blood circulation promoting and blood stasis dispelling and promote blood circulation, and removes vasospasm, the worldwide discharge of opiates metabolism toxic product in the body.
Ramulus Uncariae Cum Uncis is an adjuvant drug, sweet in the mouth, is slightly cold, and returns liver, pericardium channel, and the endogenous wind stopping relieving convulsion is arranged, the heat clearing away suppressing the hyperactive liver, and the fire of liver heat removing and pericardium two warps has good Xian wind relieving convulsion effect.Modern study confirms that gas can have blood pressure lowering, relieving asthma and calm, anticonvulsant action.
Radix Curcumae acrid in the mouth, bitter cold, promoting QI circulation for relieving depression, the good serum heart is separated stagnation of liver-QI and regulation of mental activities will clears away heart-fire heat and the will of calming the nerves.The Aloe bitter in the mouth, beg coldly, rush down down, liver heat removing.Can treat constipation under rushing down, the constipation of withdrawal symptom is to be hindered due to intestinal Tianjin by opium temperature poison consumption, and the Aloe relieving constipation by purgation is longer than the hot body fluid deficiency constipation for the treatment of the liver, and is mutually suitable with the symptom pathogenesis.
Radix Glycyrrhizae is a messenger drug, and particularly the Radix Glycyrrhizae sweet in the mouth is alleviated poison, and the mediation property of medicine can be alleviated the toxicity of Radix Aconiti Lateralis Preparata, Flos Daturae, and relaxes the high property of gas.Glucocorticoid that it had and mineralocorticoid effect can have relieving cough and expelling phlegm, effect for reducing blood fat, and Immune Effects is arranged.
Therefore, with above-mentioned all kinds of medicine as the active drug composition, can play recuperating depleted YANG QI invigorating, arresting convulsion calm the nerves, the ease pain merit of relieving convulsion, the withdrawal of detoxifying altogether, embodied many internal organs such as kidney, spleen, conscience have been adjusted, the treatment thought that empty (yang-energy collapse), real (liver-yang, heart-fire), poison (the opium poison of the internal organs of hiding) are ruled together.Control the kidney spleen in temperature compensation recuperating depleted YANG QI invigorating, treating the liver is controlled the heart and is calmed the nerves in arresting convulsion at the endogenous wind stopping relieving convulsion, and toxin expelling will reside in one with rushing down down by separating conscience dysentery, and medical treatment comprehensively in the withdrawal symptom of opiate addiction, belongs to the yang-energy collapse; The excited person's effect of conscience is ideal.
The acceptable auxiliary element can be tablet in the said pharmacy, granule, adjunct ingredient commonly used in the oral type pharmaceutical preparatioies such as capsule, as corresponding disintegrating agent, excipient, lubricant, binding agent, auxiliary adding ingredient, for example cross-linking sodium carboxymethyl cellulose commonly used such as filler, polyvinylpolypyrrolidone, carboxymethyl starch sodium, hydroxypropyl starch, the low-substituted hydroxypropyl cellulose citric acid, tartaric acid, anhydride, sodium bicarbonate, sodium carbonate, starch, dextrin, Icing Sugar, pregelatinized Starch, lactose, glucose, microcrystalline Cellulose, calcium carbonate, calcium sulfate, calcium bicarbonate, hypromellose, polyvidone, starch slurry, the dextrin slurry, syrup, rubber cement, sodium alginate, Polyethylene Glycol, Resina persicae, arabic gum, magnesium stearate
(sodium), Pulvis Talci, micropowder silica gel, liquid paraffin, Polyethylene Glycol etc.
In aforementioned pharmaceutical compositions of the present invention, the type of service of each effective medicinal ingredient can be with reference to traditional pharmacy custom.For example; to the valuable medicinals such as Radix Ginseng, Margarita, artificial Calculus Bovis and Aloe in forming; can distinguish the powder that directly uses its relative medicine raw material; mix mutually with the water extract or the ethanol extraction of other raw materials such as Radix Aconiti Lateralis Preparata, Flos Daturae, Ramulus Uncariae Cum Uncis, Radix Curcumae, Radix Glycyrrhizae, form the active drug composition jointly.
The specific embodiment below in conjunction with embodiment is described in further detail foregoing of the present invention again.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example.Do not breaking away under the above-mentioned technological thought situation of the present invention, various replacements or change according to ordinary skill knowledge and customary means are made all should comprise within the scope of the invention.
The specific embodiment
Embodiment 1
One-tenth is grouped into: Radix Aconiti Lateralis Preparata 500g, and artificial Calculus Bovis 90g, Flos Daturae 15g, Ramulus Uncariae Cum Uncis 60g, Margarita 10g,
Radix Ginseng 100g, Radix Curcumae 60g, Aloe 80g, Radix Glycyrrhizae 20g
Preparation method:
More than in the nine herbal medicine raw materials, get Radix Ginseng, Margarita, Aloe pulverize separately and become fine powder, standby.Get Radix Aconiti Lateralis Preparata, Flos Daturae, Ramulus Uncariae Cum Uncis, Radix Curcumae, Radix Glycyrrhizae with 90% soak with ethanol 1 hour; reflux, extract, 3 times each 1 hour, adds amount of alcohol and is respectively heavy 7 times, 5 times, 5 times of medical material; merge extractive liquid; reclaim ethanol, being concentrated into relative density is 1.32-1.36 (90-95 ℃), adds Radix Ginseng powder and appropriate amount of starch; mixing. drying under reduced pressure; pulverizing and artificial Calculus Bovis, Margarita powder, Aloe powder mixing, granulation, the dry 400g granule that gets, filling becomes 1000 capsules (0.4g/ grain).
Embodiment 2
One-tenth is grouped into: Radix Aconiti Lateralis Preparata 700g, and artificial Calculus Bovis 10g, Flos Daturae 30g, Ramulus Uncariae Cum Uncis 140g, Margarita 80g,
Radix Ginseng 40g, Radix Curcumae 120g, Aloe 60g, Radix Glycyrrhizae 50g
Preparation method:
More than in the nine herbal medicine raw materials, get Radix Ginseng, Margarita, Aloe pulverize separately and become fine powder, standby.Get Radix Aconiti Lateralis Preparata, Flos Daturae, Ramulus Uncariae Cum Uncis, Radix Curcumae, Radix Glycyrrhizae and be soaked in water reflux, extract, 2 times, each 2 hours 1.5 hours; amount of water is respectively heavy 7 times, 7 times of medical material; merge extractive liquid,, being concentrated into relative density is 1.32-1.36 (90-95 ℃), adds Radix Ginseng powder and appropriate amount of starch; mixing; drying under reduced pressure, pulverizing and artificial Calculus Bovis, Margarita powder, Aloe powder mixing, granulation, the dry 400g granule that gets; the dress aluminium plastic bag gets granule.
Embodiment 3
One-tenth is grouped into: Radix Aconiti Lateralis Preparata 550g, and artificial Calculus Bovis 70g, Flos Daturae 5g, Ramulus Uncariae Cum Uncis 80g, Margarita 15g,
Radix Ginseng 20g, Radix Curcumae 90g, Aloe 140g, Radix Glycyrrhizae 100g
Preparation method:
More than in the nine herbal medicine raw materials, get Radix Ginseng, Margarita, Aloe pulverize separately and become fine powder, standby.Get Radix Aconiti Lateralis Preparata, Flos Daturae, Ramulus Uncariae Cum Uncis, Radix Curcumae, Radix Glycyrrhizae with 90% soak with ethanol 1 hour, reflux, extract, 3 times, each 1 hour; amount of alcohol is respectively heavy 7 times, 5 times, 5 times of medical material; merge extractive liquid, reclaims ethanol, is concentrated into relative density 1.32-1.36 (90-95 ℃), adds Radix Ginseng powder and appropriate amount of starch; mixing; drying under reduced pressure, pulverizing and artificial Calculus Bovis, Margarita powder, Aloe powder mixing, granulation, the dry 400g granule that gets; the dress aluminium plastic bag gets granule.
Embodiment 4
One-tenth is grouped into: Radix Aconiti Lateralis Preparata 600g, and artificial Calculus Bovis 50g, Flos Daturae 20g, Ramulus Uncariae Cum Uncis 100g, Margarita 50g,
Radix Ginseng 60g, Radix Curcumae 100g, Aloe 100g, Radix Glycyrrhizae 60g
Preparation method:
More than in the nine herbal medicine raw materials, get Radix Ginseng, Margarita, Aloe pulverize separately and become fine powder, standby.Get Radix Aconiti Lateralis Preparata, Flos Daturae, Ramulus Uncariae Cum Uncis, Radix Curcumae, Radix Glycyrrhizae with 90% soak with ethanol 1 hour; reflux, extract, 3 times, each 1 hour, amount of alcohol was respectively heavy 7 times, 5 times, 5 times of medical material; merge extractive liquid, reclaims ethanol; be concentrated into relative density 1.32-1.36 (90-95 ℃), add Radix Ginseng powder and appropriate amount of starch, mixing; drying under reduced pressure; pulverizing and artificial Calculus Bovis, Margarita powder, Aloe powder mixing, granulation, the dry 400g granule that gets, filling becomes 1000 capsules (0.4g/ grain).
Embodiment 5
One-tenth is grouped into: Radix Aconiti Lateralis Preparata 650g, and artificial Calculus Bovis 20g, Flos Daturae 10g, Ramulus Uncariae Cum Uncis 70g, Margarita 90g,
Radix Ginseng 55g, Radix Curcumae 75g, Aloe 95g, Radix Glycyrrhizae 40g
Preparation method:
More than in the nine herbal medicine raw materials, get Radix Ginseng, Margarita, Aloe pulverize separately and become fine powder, standby.Getting Radix Aconiti Lateralis Preparata, Flos Daturae, Ramulus Uncariae Cum Uncis, Radix Curcumae, Radix Glycyrrhizae was soaked in water 1.5 hours; reflux, extract, 2 times, each 2 hours, amount of water was respectively heavy 7 times, 7 times of medical material; merge extractive liquid; being concentrated into relative density is 1.32-1.36 (90-95 ℃), adds Radix Ginseng powder and appropriate amount of starch, mixing; drying under reduced pressure; pulverizing and artificial Calculus Bovis, Margarita powder, Aloe powder mixing, granulation, the dry 400g granule that gets is pressed into 1000 (0.4g/ sheets).
With the medicine of the foregoing description 4 composition forms experiment medicine, carried out following related experiment as of the present invention group.The trial drug employing is used after capsule 's content is made into the suspension of testing used concentration with distilled water or normal saline.
One, animal toxicity test
1. acute toxicity test
The kunming mice that with the body weight is 18-23 gram, male and female half and half respectively is an experimental animal, filling stomach mode is divided into single administration and three administrations two groups respectively, with body weight be that the Wistar rat of 190-230 gram is a laboratory animal, employing is by the above-mentioned trial drug of normal saline preparation, and the stomach mode is divided into respectively once to irritate, secondary and three administrations three groups.The dosage of mice single administration group is 4.6g/kg, and the dosage of three administrations (4-6 hour at interval) group is 13.8g/kg, and the dosage of rat single administration administration group is 6.0g/kg, observes a week behind the gastric infusion, is the discovery animal dead; The dosage of rat secondary administration group (4-6 hour at interval) is 8.0g/kg, the dosage of three administration groups (4-6 hour at interval) is that toxic reaction then occurred in a week for two groups of 12.0g/kg, 10% and 20% animal dead is arranged respectively, and animal dead mostly occurred after administration in 24-48 hour.All the other animals generally recovered normal gradually after 48-72 hour.Dead animal is become celestial, and perusal is not found any unusual.Result of the test shows that mice is 13.8g (crude drug)/kg to the maximum tolerated dose of trial drug, is equivalent to 276 times of clinical human daily dose; Rat is 12.0g (crude drug)/kg to the trial drug maximum tolerated dose, is equivalent to 240 times of clinical human daily dose.
2. long term toxicity test
Using by the above-mentioned trial drug of distilled water preparation, is that laboratory animal is tested with rat and Canis familiaris L. respectively.
(1) the Wistar rat is divided into three dosage groups of 1.2g/kg, 0.6g/kg and 0.2g/kg (be equivalent to approximately respectively clinical human dosage 70,35 and 12 times), every day with once<the amount gastric infusion of 3ml, and establish the matched group of giving the equivalent normal saline.Successive administration 2 months is clinical 4-6 times of using the administration phase.After the administration 1 month, high dose group and matched group are put to death 1/3 animal respectively, measure every index; After the administration 2 months, each dosage group is except that staying 1/3 animal to do the convalescent period observation respectively, and all the other are all put to death, and measure every index.Observe and the mensuration project comprises as outward appearance Signs and behavioral activity, secretions, feces character; The conventional index of blood and biochemical indicator; Contents such as system's postmortem and organ coefficient and histological examination.
Result of the test shows that behind the long-term gastric infusion continuously of rat, administration group rat occurs quiet, body weight obviously alleviates, and alanine aminotransferase and blood urea nitrogen raise, and the neutrophilic leukocyte ratio increases, the organ coefficient of lung, liver, kidney, the heart, brain increases, and the organ coefficient of thymus diminishes.The case history resistance checks that lung, liver, kidney resistance have the inflammatory kitchen range, and wherein pulmonary lesion is particularly outstanding.These pathological changes immune system that may be drug influence and secondary.Quadrant diminishes and lymphopenia all is the beneath performances of immunologic function.Therefore medicine of the present invention mainly is lung, liver and kidney to the toxic reaction target organ of rat.
3/20 animal dead is arranged in the rat high dose group, though middle dosage group does not have death, worry 2/20 has the lung tissue pathological changes.Low dose group does not all occur dead in experimental period and convalescent period, but the situation that still has the blood urea nitrogen index not recover fully illustrates and take certain reaction of accumulating for a long time that toxic reaction alleviates disappearance after the drug withdrawal.The result shows that rat is 4g (crude drug)/kg to the non-toxic of above-mentioned trial drug, and toxic dose is 12-24g (crude drug)/kg.
(2) Canis familiaris L. of body weight 9-12kg male and female half and half is divided into 0.6g/kg, 0.3g/kg and three dosage groups of 0.1g/kg (be equivalent to respectively clinical human dosage 35,18 and 6 times) and a negative control group, once a day with the amount gastric infusion of<100ml, successive administration 2 months, for the 4-6 of clinical administration phase doubly.Each dosage group stays 1/2 animal to continue to observe 14 days behind experimental period, and all the other are all lived and kill, and check every index, understands the degree of reversibility of toxic reaction and the retardance toxic reaction that may occur.Observe identical with above-mentioned rat test with the index content that detects.
Result of the test shows that high dose group has 1/4 animal vomiting to occur at the administration initial stage, and administration 2 all thick high dose group have 1 death, and dead preceding symptom mainly shows as asthma, cough, do not eat food off color.Animal dead does not appear in middle dosage and low dose group.Body weight gain of Canis familiaris L. and hematology, blood biochemical, routine urinalysis and detecting ECG are all with matched group no significant difference (P>0.05).The main pathological change of dead Canis familiaris L. is a pneumonia, has 1 to have only interstitial lung to thicken and other Canis familiaris L. no abnormality seen pathological changes is arranged the fibroplasia in the survival Canis familiaris L. in high dose group.After the drug withdrawal, each dosage treated animal does not all have death, the retardance toxic reaction do not occur yet.
This results suggest, trial drug is lighter than rat to the toxic reaction of Canis familiaris L., and the immediate cause of dead Canis familiaris L. is because pneumonia causes, so the main site of action of its toxicity may be a lung.The Canis familiaris L. that survives in the high dose group and in, the every index of Canis familiaris L. of low dose group all compares normally, dead and retardance toxic reaction also appear in convalescent period.Result of the test shows that the non-toxic of Canis familiaris L. is 1.5g (crude drug)/kg, and toxic dose is 3.0g (crude drug)/kg.
Two, analgesic effect test
Prepare above-mentioned trial drug with distilled water, test with the mice hot plate method.Female Kunming mouse with body weight 18-22 gram is a laboratory animal, the dosage that is set to give trial drug respectively is 0.4g/kg (heavy dose), (0.2g/kg middle dosage group) and 0.1g/kg (small dose group), and give the positive controls of tramadol 0.1ml/10g and the blank group of giving the equal-volume distilled water, all with the amount gastric infusion of 0.2ml/kg.Before administration and administration after 30 minutes and 60 minutes, on 55 ℃ metallic plate mensuration mice pain threshold.
Result of the test shows, the mice pain threshold of 30 minutes and 60 minutes improves percentage rate and is 90% after the heavy dose group administration of trial drug of the present invention, the raising rate of middle dosage group is respectively 90% and 75%, with the blank group significant difference (being respectively P<0.01 and P<0.05) is arranged relatively, show that it has significant analgesia role, and its analgesic activity there is certain amount-result relation.The mice pain threshold of 30 minutes and 60 minutes improves percentage rate and is respectively 90% and 81% after the administration of tramadol matched group, proves that the analgesia intensity and the tramadol of medicine of the present invention is suitable.
Three, detoxification drug effect is really tested
Prepare above-mentioned trial drug with normal saline, be experimental animal with the Wistar kind rat of body weight 180-220 gram male and female half and half and the male Guangxi monkey (Rhesus Macacus subspecies) of body weight 3-5.5kg respectively, carried out: morphine relies on rat and urges withdrawal and treatment test, morphine dependence rat natural withdrawal therapeutic test and morphine to rely on the therapeutic test of monkey natural withdrawal.
1. morphine relies on rat and urges the withdrawal and treatment test
Form the rat morphine with incremental dose method and rely on model: sc every day (subcutaneous injection) morphine 3 times, dosage are 5mg/kg and 10mg/kg each 4 days, 15mg/kg and 20mg/kg each 3 days, and injection volume is 0.1ml/100g.At the 15th day rat is divided into 5 groups at random, every group of 10-11 only, be divided into the negative control group of giving to wait capacity normal saline (NS), the treatment group of giving the positive controls of 0.2mg/kg clonidine and giving the above-mentioned experiment medicine of the present invention respectively, according to dosage be made as 0.05g/kg (low dose), 0.10g/kg (middle dosage) and three dosage groups of 0.15g/kg (heavy dose) in the medicine group wherein of the present invention respectively.With gastric infusion, administration was urged with naloxone (i.p 4mg/kg) after 2 hours respectively, observe, write down the withdrawal symptom of rat in 1 hour immediately, and, press the withdrawal symptom scoring, and compare with positive controls and NS group in 30 minutes and 60 minutes weighing rat body weights.The result is as shown in table 1.
The inhibitory action result of withdrawal symptom and weight loss when table 1 pair morphine dependence rat urgency is given up
Group Number of animals (only) The withdrawal symptom branch (X ± SD) Body weight change (%) (X ± SD)
Blank 10 6.00±2.64 -5.16±1.49
Positive control 11 2.91±1.26 ** -4.66±1.46
Medicine low dose of the present invention 10 6.60±3.00 -3.30±1.34 **#
Dosage in the medicine of the present invention 11 5.82±4.42 -2.22±1.89 **##
Medicine heavy dose of the present invention 10 3.00±2.97 * -2.30±1.55 **#
Annotate: compare with the NS group: *: P<0.05, *: P<0.01; Compare with positive controls: #:P<0.05, ##<0.01.
Above-mentioned result of the test shows that 3 dosage groups of trial drug of the present invention all can obviously suppress morphine dependence rat and urge weight loss (P<0.01) when giving up, and control well than positive control medicine clonidine.Aspect the control of withdrawal symptom, have only the heavy dose of group of medicine of the present invention to show obvious treatment effect (P<0.05), and suitable with the effect of clonidine, but in, small dose group is not as clonidine group.
2. morphine relies on the therapeutic test of rat natural withdrawal
Form the rat morphine with incremental dose method and rely on model: rat skin lower injection dose of morphine the last fortnight is identical with above-mentioned urgency test, and the 3rd, 4 liang is respectively 30mg/kg and 40mg/kg week, and the administration capacity is 0.1ml/100g.At random be divided into 5 group with rat the 29th day morning, be respectively etc. capacity NS negative control group, clonidine 0.1mg/kg positive controls, trial drug of the present invention little, in, heavy dose of group (0.015,0.030,0.045g/kg/ time), every day 3 times (minor tick 6 hours), in a continuous week of i.g administration, the administration capacity is 0.1ml/100g.During treatment the previous day and the treatment, before administration every day, claim rat body weight, observe the inhibitory action that medicine descends to the natural withdrawal rat body weight.Result of the test is as shown in table 2.
Table 2 medicine relies on the result that influences of weight loss during the rat natural withdrawal to morphine
Figure G2008100453025D00081
Above-mentioned result of the test shows that three dosage groups of trial drug of the present invention had control action at first day to weight loss, but the decline of body weight all and can control morphine and rely on the rat natural withdrawal time in afterwards six days.The positive drug clonidine does not have therapeutical effect too.
3. monkey natural withdrawal therapeutic test
Form the monkey morphine with incremental dose method and rely on model: sc morphine every day 3 times (minor tick 6 hours), 1-4 week weekly dosage be respectively 3,6,9 and 12mg/kg, the 5th week was played 15mg/kg, was maintained until 3 months.Observe, be familiar with the behavior characteristics of every monkey before stopping morphine, record stops three (minor tick 6 hours) body weight and the behavior performance of preceding 1 day every monkey of morphine.With morphine rely on monkey be divided at random negative control group (waiting capacity NS), positive controls (clonidine 0.02mg/kg) and trial drug of the present invention little, in, heavy dose of group (0.025g/kg, 0.1g/kg, 0.15g/kg).Stop beginning above-mentioned treatment administration after the morphine.Before each administration, weigh, observe the various withdrawal symptoms of monkey, and calculate the body weight change percentage rate.Result of the test is respectively shown in table 3, table 4 and table 5.
The inhibitory action of withdrawal symptom during the table 3 pair morphine dependence monkey natural withdrawal (X ± SD)
Figure G2008100453025D00091
Annotate: compare with the NS group: #:0.01<P<0.05: *: P<0.05, *: P<0.01
The inhibitory action of weight loss during the table 4 pair morphine dependence monkey natural withdrawal (X ± SD)
Figure G2008100453025D00092
Annotate: compare with NS group and positive drug group: #:0.01<P<0.05; *: P<0.01
Above-mentioned result of the test shows, stop morphine after each treated animal the different withdrawal symptom of degree appears successively, invite, restlessness, fight, sting chain, appetite decline, intentional tremor, paroxysmal and twitch, embrace abdomen, unable couch etc. as easy Ji.It is dead that the NS group has indivedual monkeys to occur.Compare with the NS matched group, aspect the control withdrawal symptom, 3 dosage groups of trial drug of the present invention all are lower than the NS group, and certain amount-result relation is arranged.Wherein low dose of and middle dosage group first three day withdrawal symptom grand average is starkly lower than NS group (0.01<P<0.05); When treatment finished in 7 days, the withdrawal symptom grand average of low dose of and middle dosage group was starkly lower than the NS group, and statistical disposition has significant difference (P<0.01 and P<0.05), and curative effect is like reserving than positive drug cola.
Frequency that the various withdrawal symptoms of each test group of table 5 on average occur and inhibition percentage rate (NS group relatively)
Figure G2008100453025D00101
Aspect controlling body weight decline, 3 dosage groups of trial drug of the present invention all are lower than the NS group, and wherein preceding 3 days body weight decline percentage rate after the treatment of small dose group have significant difference (0.01<P<0.05) with NS group and positive controls ratio; Body weight decline percentage rate meansigma methods also was starkly lower than NS group and clonidine group (P<0.01) in 7 days.
Aspect the suppression ratio of various withdrawal symptoms, 3 dosage groups of trial drug of the present invention all have certain inhibitory action to most of withdrawal symptom, wherein, middle dosage and heavy dose of group to the suppression ratio of most of withdrawal symptom basically all between 50%~95%.And no matter small dose group is that still the curative effect aspect controlling body weight decline is seemingly all reserved than positive drug cola aspect the control withdrawal symptom.
Four, clinical detoxification clinical trial
" anti-opiates withdrawal symptom clinical drug trial guideline " according to China former Ministry of Public Health bureau of drug policy ﹠ administration, selection meets test case 321 people of the standard of including in and exclusion standard, be divided into (early 3/time of medicine group 203 examples of the present invention at random, in 3/time, 4/time of evenings, 3 times on the one), clonidine hydrochloride (Changzhou pharmaceutical factory produce, lot number is 980605) control drug group 90 examples (3 times on the one, each 3), (prestige pharmaceutical factory, Lanzhou produces FUKANG PIAN, lot number 980116.) control drug group 28 examples (3 times on the one, each 3).Clinical indexes is withdrawal symptom rating scale, HAMA anxiety rating scale, the untoward reaction rating scale of this guideline regulation, and laboratory checking index is hematuria routine, hepatic and renal function, electrocardiogram, the qualitative determination of urine morphine.
The detoxification result of the test shows that each medicine group is all effective.The analysis of every withdrawal symptom is shown, with the clonidine matched group relatively, symptom score values obviously lower (P<0.05) such as the yawn of medicine group of the present invention, sleepy, shiver with cold, the posture of curling, weight average increases 0.44kg (P<0.05); The body weight of FUKANG PIAN and clonidine two matched groups is then distinguished decreased average 0.21kg and 0.32kg.The untoward reaction total points of medicine group of the present invention is low than the clonidine matched group obviously, and the difference of 1-8 day mostly is mild reaction according to significance (P<0.05), need not to handle to die away; The dizziness of clonidine matched group, instability of gait, whole body incidence rate unable, that have a headache, faint significantly higher (P<0.05); Delirium (with clonidine matched group P<0.05) has then appearred in the FUKANG PIAN matched group.Medicine group of the present invention also is starkly lower than the clonidine matched group to the influence of blood pressure, and there were significant differences for the two (P<0.05).Every result of the test is as shown in table 6.
The comparison of the withdrawal symptom of each medicine group of table 6 clinical trial treatment back
Withdrawal symptom Of the present invention group Clonidine group The FUKANG PIAN group The P value
Crave for 6.24±6.21 5.3 4.32±4.60 0.093
Anxiety 5.42±4.26 5.51±4.11 4.21±4.06 0.328
Yawn 10.75±7.20 13.58±9.42 10.79±7.15 0.017
Watery nasal discharge 9.45±7.42 8.96±6.680 5.79±5.79 0.040
Perspire 5.86±7.61 5.30±7.07 3.24±5.42 0.282
Sleepy 10.73±8.42 13.95±9.71 9.36±8.74 0.011
Shed tears 9.86±7.80 9.16±6.45 9.82±8.66 0.770
Tremble 7.68±11.03 8.13±12.06 8.86±10.66 0.875
Shiver with cold 7.68±13.02 25.01±12.35 25.96±18.76 0.007
The bone myalgia 20.10±15.39 22.83±15.86 12.68±12.69 0.022
Anorexia 13.92±14.70 12.60±13.69 13.64±1.29 0.776
Abdominal pain diarrhea 9.04±11.56 5.27±7.81 9.54±9.20 0.791
Withdrawal symptom Of the present invention group Clonidine group The FUKANG PIAN group The P value
Curling posture 8.97±12.98 14.03±14.70 11.46±11.02 0.011
Insomnia 47.7±30.56 51.42±26.44 33.68±25.83 0.020
Ferment 16.68±16.68 19.78±16.02 19.85±16.45 0.265
Nausea and vomiting 9.41±11.85 9.16±10.51 12.43±12.48 0.395
Annotate: the P value is of the present invention group of statistics comparative result with clonidine group
Above-mentioned every detoxification pharmacodynamics and clinical test results show that all pharmaceutical composition of the present invention has positive, sure curative effect aspect detoxification treatment.

Claims (10)

1. the pharmaceutical composition that has detoxication uses; it is characterized in that with natural drug raw material Radix Aconiti Lateralis Preparata, artificial Calculus Bovis, Flos Daturae, Ramulus Uncariae Cum Uncis, Margarita, Radix Ginseng, Radix Curcumae, Aloe and Radix Glycyrrhizae be the active drug composition; become oral type pharmaceutical preparation with acceptable auxiliary element mutual group in the pharmacy, consist of in the active drug composition of material medicine weight portion:
Radix Aconiti Lateralis Preparata 500-700, artificial Calculus Bovis 10-90, Flos Daturae 5-30, Ramulus Uncariae Cum Uncis 60-140,
Margarita 10-90, Radix Ginseng 20-100, Radix Curcumae 60-140, Aloe 60-140, Radix Glycyrrhizae 20-100.
2. the pharmaceutical composition with detoxication uses as claimed in claim 1; it is characterized in that each composition of Radix Ginseng, Margarita, artificial Calculus Bovis and Aloe in the said active drug composition directly is the powder of its crude drug, Radix Aconiti Lateralis Preparata, Flos Daturae, Ramulus Uncariae Cum Uncis, Radix Curcumae, each composition of Radix Glycyrrhizae are its ethanol extraction.
3. the pharmaceutical composition with detoxication uses as claimed in claim 1; it is characterized in that each composition of Radix Ginseng, Margarita, artificial Calculus Bovis and Aloe in the said active drug composition directly is the powder of its crude drug, Radix Aconiti Lateralis Preparata, Flos Daturae, Ramulus Uncariae Cum Uncis, Radix Curcumae, each composition of Radix Glycyrrhizae are its water extract.
4. as the described pharmaceutical composition of one of claim 1 to 3, it is characterized in that consisting of in the active drug composition of material medicine weight portion with detoxication uses:
Radix Aconiti Lateralis Preparata 600, the artificial Calculus Bovis 50, Flos Daturae 20, Ramulus Uncariae Cum Uncis 100, Margarita 50,
Radix Ginseng 60, Radix Curcumae 100, Aloe 100, Radix Glycyrrhizae 60.
5. as the described pharmaceutical composition of one of claim 1 to 3, it is characterized in that said medicine is a capsule preparations with detoxication uses.
6. as the described pharmaceutical composition of one of claim 1 to 3, it is characterized in that said medicine is a tablet with detoxication uses.
7. as the described pharmaceutical composition of one of claim 1 to 3, it is characterized in that said medicine is a granule with detoxication uses.
8. the pharmaceutical composition with detoxication uses as claimed in claim 4 is characterized in that said medicine is a capsule preparations.
9. the pharmaceutical composition with detoxication uses as claimed in claim 4 is characterized in that said medicine is a tablet.
10. the pharmaceutical composition with detoxication uses as claimed in claim 4 is characterized in that said medicine is a granule.
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