CN100443083C - Use of aconine in medicine manufacture - Google Patents
Use of aconine in medicine manufacture Download PDFInfo
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- CN100443083C CN100443083C CNB2005100205799A CN200510020579A CN100443083C CN 100443083 C CN100443083 C CN 100443083C CN B2005100205799 A CNB2005100205799 A CN B2005100205799A CN 200510020579 A CN200510020579 A CN 200510020579A CN 100443083 C CN100443083 C CN 100443083C
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- aconine
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Abstract
The present invention discloses application of aconine in medicine preparation. Aconine has the obvious functions of relieving pain, raising blood pressure, strengthening the heart, increasing the cardiac contractility, resisting phlegmasia, enhancing the immunizing power, resisting local anesthesia, resisting coldness, etc. The aconine is used for preparing anodyne, narcotic, drug-breaking medicine and antifatigue. The aconine of the present invention completely reserves the original pharmacological activity of aconitine which is not hydrolyzed; compared with the toxicity of the aconitine, the toxicity is reduced by 2000 times; the aconine is safe and reliable in medicine preparation. Various preparations mainly prepared from the aconine are safe and nontoxic, and the function of medicine effect is strong, especially in analgesia. The preparation prepared from the aconine has the maximal characteristic of no dependency, and the medical prospect is wide.
Description
Technical field
The present invention relates to a kind of hydrolyzate aconine of aconitine, relate in particular to the purposes of aconine in pharmacy.
Background technology
The Aconitum carmichjaelii Debx. class is given birth in the product and is contained multiple di esters alkaloid, and as aconitine Aconitine, mesaconitine Mesaconitine, hypaconitine Hypaconitine etc., its active component is an aconine.Various pharmacological testings show: aconitine-type alkaloids in analgesia, cross the property blood pressure lowering, cross that property is boosted, all have obvious effect aspect decreased heart rate, heart tonifying, increase myocardial contraction, antiinflammatory, raising immunity, local anaesthesia and the cold resistance.Know again, isolated micro-effective ingredient higenamine dl-Demethylcoclaurine from Japanese Aconitum carmichjaelii Debx., Higenamine also has cardiotonic, and this alkali effect is strong, and it is diluted to 10
-9The time still manifest cardiac activity, the structural formula of this compound hydrochloride is as follows:
From Aconitum carmichjaelii Debx., isolated a kind of alkaloid coryneine Coryneine recently again
Its content in crude drug is about 0.1%, has and boosts and cardiotonic.But aconitine but has very strong toxicity, and people's lethal dose only is 3～4mg, therefore, because safety issue makes its application in pharmacy be subjected to very big restriction.
Summary of the invention
The present invention is intended to solve the aconitine strong toxicity, has the difficult problem of potential safety hazard in pharmacy, and a kind of hydrolyzate aconine and the purposes of aconine in pharmacy thereof of aconitine is provided.This hydrolyzate aconine has not only kept the original pharmacologically active of aconitine fully, and its toxicity reduces greatly than aconitine, thereby aconine is used in the pharmacy fool proof reliably, and its active function is fully played.
The present invention realizes the object of the invention by implementing following technical scheme:
The purposes of aconine in pharmacy comprises:
Aconine is used with single or compound preparation in the preparation analgesic.
Aconine is used with single or compound preparation in the preparation anesthetics.
Aconine is used with single or compound preparation in the preparation drug-breaking medicine.
Aconine is used with single or compound preparation in the preparation antifatigue.
Described single or compound preparation comprise cream, frost, liquid type externally applied liniment, spray and patch, oral capsule, tablet, granule and injection injection, lyophilized powder.
The preparation method of described aconine is as follows:
Aconitine at first becomes the less monoesters class alkali benzoyl aconine Benzoylaconine of toxicity through the secondary hydrolysis, changes the littler amine alcohols alkali aconine Aconine of toxicity into through further hydrolysis again.At this moment, the toxicity of benzoyl aconine has been reduced to 1/100～1/1000 of aconitine, and the toxicity of aconine is littler, only is about 1/2000 of aconitine.
Its hydrolytic process is as follows:
Pharmacological action of the present invention and clinical practice result are as follows:
1, to central nervous system's effect: adopt pressurization with aconine to the pressurization of mouse tail root after, can make its pain threshold improve 30～40%.Use the electricity irritation mouse tail, subcutaneous injection aconine 0.025mg/kg promptly has analgesic activity.Aconine 0.1mg/kg is also strong than the effect of morphine 6mg/kg; Hot plate method is measured, and hypo-aconine also has analgesia and sedation to mice.
2, analgesic activity: aconine has inhibitory action to experimental " arthritis ", and then more obvious when dosage is big, aconine has stronger analgesia, calmness and antiinflammatory action.Record the analgesia ED of aconine with hot plate method and writhing response method
50Dosage is respectively 0.2mg/kg, 10.13mg/kg (sc).Aconine has stronger surface anesthetic effect; Mice nerve trunk retardation is equivalent to 92 times of cocaines; The effect of Cavia porcellus intradermal injection infiltration anesthesia is equivalent to 53 times of cocaines.The analgesia of aconine and local anesthetic action are all strong than aconitine, and its acute toxicity is than aconitine low 1/2000.So its therapeutic index is bigger than aconitine, is 439.Someone thinks that mechanism such as temperature, pain are touched, pressure sensation disappearance may be that aconine directly or indirectly acts on unmyelinated and more very thin nerve fiber, thereby has stoped the generation and the conduction of impulsion.Reason may be aconine with calcium ion contention film on the combining of phospholipid, the sodium channel is changed, stoped the interior stream that produces the necessary sodium ion of action potential, thereby blocked the conduction of neural impulse, it is relevant with combining of receptor to influence materials such as the maincenter endogenous neurotransmitter 5-hydroxy tryptamine relevant with pain, catechol glue, acetylcholine, endorphins simultaneously.According to observations, aconine is done the time spent to a neural muscle specimen, and nerve and muscle action potential rise and all slow down mutually, show that organic passage activation process is unusual.
3, to cardiovascular influence: aconitine has tangible cardiotonic.Aconitine can increase heart contractility and the heart rate of animal.Aconitine can make stripped or of short duration heart tonifying appears in the frog heart on the throne, changes inhibition immediately over to, and heart contractility weakens, and cardiac arrhythmia occurs heart beating at last and stops to wait toxic action.The toxicity of aconitine hydrolyzate amine is 1/2000～1/4000 of protozoa alkali only, does not have tangible cardiotonic, but racemization demethyl coclaurine is a kind of weak beta-receptor analeptic, the also intensive cardiotonic of tool.Racemization demethyl coclaurine all has certain prevention and therapeutical effect to institute's proarrhythmia animal models such as verapamil and nicotine.Aconitine can make that the dirty frequency of guinea-pig heart is slack-off, heart contractility increases.Concentration is the aconine of 10～7g/ml, the mesaconitine of 3 * 10～8g/ml, and the excited earlier back of the guinea pig right atrium that exsomatizes is suppressed.Racemization demethyl coclaurine also has the effect that increases the ischemic myocardium blood perfusion.Because aconine can improve the Ischemic Heart work doing efficiency, can increase the oxygen supply function of ischemic myocardium again, thereby improve the demand balance of myocardium oxygen and reduced the ARR generation that causes because of anoxia.Aconitine 0.05mg/kg has the property a crossed hypotensive effect, and aconine then has the property a crossed boosting, and this effect can be suppressed more than 50% by hexamethonium, and can be suppressed fully by phentolamine, and its site of action may be the α receptor.
4, antiinflammatory action and to endocrine influence: oral or subcutaneous injection aconine can obviously suppress the ankle swelling that the mouse peritoneal vascular permeability increases and carrageenin causes that formaldehyde or Ovum Gallus domesticus album cause, its anti-inflammatory component is aconine, hypo-aconine, mesaconitine.Aconine can suppress the inductive arthritis of adjuvant, and the bone degeneration of the rats with arthritis that adjuvant is brought out is inhibited, and fibrinolytic function is descended inhibitory action (is index with the euglobulin lysis time) is also arranged.And aconine also has fibrinolytic to normal rat.Adopt the fibrin plate method, not seeing has this effect.Infer that aconine has the effect of histamine and analogued histamine.Though the dosage of aconitine is little of 10 μ g/kg, still can reduce ascorbic acid content in the rat adrenal gland, increase the drainage that rat urinates total 17-KS, reduce eosinophil leucocyte in the blood, therefore the effect of excited hypophysis-interrenal system is arranged.
5, to Immune Effects: aconine can improve immune function of mice and guinea pig serum complement content, but to the mould active obviously influence of not having of mice serum bacteriolyze; Aconine can make T cell and re rosette formation cell obviously rise, injection 4ml/ (kgd) totally 9 days, and subcutaneous injection can make lymhocyte transformation rate obviously rise.
6, cold resistance effect: aconine can postpone to be in chicken under the cold environment and the death time of rat, reduces the mortality rate in the same time, and the body temperature that delays chicken and rat descends.
The invention has the advantages that:
1, aconine has not only kept original pharmacologically active before the aconitine hydrolysis fully, and its toxicity is reduced to about 1/2000 greatly than aconitine, thereby aconine is used in the pharmacy fool proof reliably, and its active function is not fully exerted.
2, be that major ingredient is made various preparations with the aconine, safety non-toxic, drug action is strong, and especially at ease pain, its maximum characteristics are no dependences, have good prospect in medicine.
The specific embodiment
Toxicity test test before and after the embodiment 1 aconitine hydrolysis
| The processing situation | Total alkaloids (%) | Di esters alkali (%) | Monoesters class alkali (%) | LD 50Crude drug g/kg (mice) p.o. | LD 50Crude drug g/kg (mice) i.v. |
| Before the hydrolysis | 0.82～ 1.56 | 0.07～ 0.17 | 0.03～ 0.08 | 5.49 | 0.49 |
| After the hydrolysis | 0.12～ 0.29 | 0.02～ 0.04 | 0.02～ 0.05 | 161 | 2.8 |
As seen, the di esters alkaloid and the toxicity of aconitine its total alkaloids, severe toxicity after hydrolysis all reduce significantly.
Embodiment 2 acute toxicity test in mice
A, be subjected to the reagent thing
Aconine extract (1 gram is equivalent to 60 gram crude drug in whole) is mixed with 20mg/100ml with its concentration during human, 0.75ml/ time, 3～6 times/day, is calculated as 0.000015g/Kg day by people's kg body weight.The aconine extract Cmax of preparation is 0.3g/ml, uses for mouse stomach during experiment.
B, animal subject
Kunming mouse is provided by Sichuan Province's science institute Experimental Animal Center, and the dispensing full-valence pellet feed.Divide box to feed 5 in every box by sex after weighing.Laboratory temperature is controlled to be 18～22 ℃, and humidity is controlled at 50～60%.
C, test method
Administering mode adopts the gastrointestinal administration, carries out the prerun test before the formal experiment earlier, roughly measures the lethal dose scope that aconine causes mice 0%～100% mortality rate.In pilot study, mouse gavaging maximal dose aconine extract is not seen to cause death and the poisoning symptom generation, can't measure the lethal dose of 0%～100% mortality rate, so mtd test is adopted in formal test.
Get 20 of body weight 20 ± 2g mices, male and female half and half, water is can't help in fasting 12 hours, with above-mentioned maximal dose medicinal liquid, presses 0.4ml/10g body weight volume (metering is 12g/kg), in disposable filling stomach at 10 o'clock in the morning, observes continuously then 7 days.Observed after the administration 4 hours and whole test during the mice active situation, comprise ingest, drainage, behavior and have or not death etc.If there is dead mouse just immediately it to be dissected, the mice major organs that detects by an unaided eye with organize especially relevant immune organ and tissue with target organ.
D, result of the test
Mice shows as at once and is slow in action behind gastric infusion, but just recovers normal activity after a few hours.7 days duration of test, the mice daily routines are normal, and chroma of hair is normal, ingests and drains normally, dead mouse do not occur in 7 days.Test and cut open mice extremely, each major organs and tissues such as perusal mouse core, liver, lung, spleen, kidney, digestive tract, no abnormality seen phenomenon after finishing in 7th.
E, conclusion (of pressure testing)
Pressing the maximum administration capacity of maximum concentration 0.3g/ml and mice (0.4ml/10g) calculates, dosage is 12g/Kg, be 800000 times of human dosage 0.000015g/Kg, 20 test mices of 7 days duration of test do not have 1 death and toxic reaction take place, according to statistics Wright rule, existing assurance more than 99.99% proves the LD of mice oral administration
50Must show that the oral safety range of this medicine clinical dosage is bigger greater than 12g/Kg.
Embodiment 3 hot plate analgesic test
Choose 21 female white mice, be equally divided into 3 groups, 7 every group, on the sole of mice, smear different medicinal liquids respectively, test group is smeared aconine, and matched group is smeared morphine, and blank group is smeared normal saline.Three iron plates all are heated to 50 ℃, make three groups of mices movable on hot plate respectively, measure its pain threshold (promptly beginning to lick the time of extremity, twisting health) and mouse writhing number of times, the result is as follows:
Average pain threshold is turned round the body number of times
Test group 28 seconds 18 times
Matched group 23 seconds 26 times
Blank group 12 seconds 34 times
Can find out from above result: not only have fairly obvious significant difference P＜0.005 between test group and the blank group, and test group and matched group also have significant difference P＜0.05, show that aconine has significant analgesia role, and analgesic effect is better than morphine.
Embodiment 4 clinical experiments
Spray with the sore place of aconine analgesia spray 100 gout patients; With aconine analgesia ointment and/or frost 500 person-times of arthralgia and trigeminal neuralgia patient's sore place is massaged; With aconine analgesia spray or analgesia ointment (frost) 400 person-times of lumbago and skelalgia patients are carried out analgesia therapy.
The above-mentioned case of result is in medication 3 minutes, and pain is promptly slowed down or disappeared.
Claims (2)
1, aconine is used with single or compound preparation in the preparation analgesic.
2, application according to claim 1 is characterized in that: described single or compound preparation comprise cream, frost, liquid type externally applied liniment, spray or patch.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100205799A CN100443083C (en) | 2005-03-25 | 2005-03-25 | Use of aconine in medicine manufacture |
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| Application Number | Priority Date | Filing Date | Title |
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| CNB2005100205799A CN100443083C (en) | 2005-03-25 | 2005-03-25 | Use of aconine in medicine manufacture |
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| CN1836661A CN1836661A (en) | 2006-09-27 |
| CN100443083C true CN100443083C (en) | 2008-12-17 |
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| CNB2005100205799A Expired - Fee Related CN100443083C (en) | 2005-03-25 | 2005-03-25 | Use of aconine in medicine manufacture |
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Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110092806B (en) * | 2018-01-30 | 2022-05-17 | 中国医学科学院药物研究所 | Analgesic C of aconite19Diterpene alkaloid glucoside and application thereof |
| KR20200065740A (en) * | 2018-11-30 | 2020-06-09 | 한국기초과학지원연구원 | Compositions for preventing or treating pain comprising aconine as an active ingredient |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1087516A (en) * | 1992-09-23 | 1994-06-08 | 曲曰谦 | Pharmaceutical composition and be used for the treatment of the method for junkie withdrawal syndrome and withdrawal |
| CN1123027A (en) * | 1994-02-09 | 1996-05-22 | 三和生药株式会社 | Novel aconitine-like compound and antipyretic analgesic anti-inflammatory agent |
| CN1147766A (en) * | 1994-03-18 | 1997-04-16 | 株式会社津村 | Remedy for infectious diseases |
| CN1070852C (en) * | 1991-07-08 | 2001-09-12 | 三和生药株式会社 | Process for preparing 14-0-acylate of aconite alkaloid type compounds |
-
2005
- 2005-03-25 CN CNB2005100205799A patent/CN100443083C/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1070852C (en) * | 1991-07-08 | 2001-09-12 | 三和生药株式会社 | Process for preparing 14-0-acylate of aconite alkaloid type compounds |
| CN1087516A (en) * | 1992-09-23 | 1994-06-08 | 曲曰谦 | Pharmaceutical composition and be used for the treatment of the method for junkie withdrawal syndrome and withdrawal |
| CN1123027A (en) * | 1994-02-09 | 1996-05-22 | 三和生药株式会社 | Novel aconitine-like compound and antipyretic analgesic anti-inflammatory agent |
| CN1147766A (en) * | 1994-03-18 | 1997-04-16 | 株式会社津村 | Remedy for infectious diseases |
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Granted publication date: 20081217 Termination date: 20120325 |