CN102133215B - Application of butylphthalide in preparation of medicine for treating chronic alcoholism - Google Patents
Application of butylphthalide in preparation of medicine for treating chronic alcoholism Download PDFInfo
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- CN102133215B CN102133215B CN2011100667064A CN201110066706A CN102133215B CN 102133215 B CN102133215 B CN 102133215B CN 2011100667064 A CN2011100667064 A CN 2011100667064A CN 201110066706 A CN201110066706 A CN 201110066706A CN 102133215 B CN102133215 B CN 102133215B
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- butyphthalide
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- chronic alcoholism
- medicine
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Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to an application of butylphthalide or medicinal salts thereof or a medicinal composition containing any one of the butylphthalide and the medicinal salts thereof in preparing a medicament for preventing or treating chronic alcoholism. The medicine or the medicine composition has the characteristics of high efficiency, low toxicity and no addiction in the process of preventing or treating chronic alcoholism.
Description
Technical field
The present invention relates to butyphthalide or its pharmaceutical salts or contain the application of pharmaceutical composition any in them in prevention and treatment chronic alcoholism, belong to field of medicaments.
Background technology
Chronic alcoholism refers to because the central nervous system that long-term excessive consumption of alcohol causes seriously poisons.Ethanol is ethanol, chemical formula C
2H
5OH is close nerve.Get into the ethanol of human body owing to can not be digested and assimilated; Can destroy the neuron cell membrane along with blood gets into brain, weaken the central nervous system; And through activate inhibitory nerve former with suppress the activity neuron and cause cerebral activity slow, in case excessively just can cause a large amount of nerve cell deaths.Insobriety can cause alcoholic coma simultaneously.
Chronic alcoholism is also referred to as alcohol dependence or drinking habit; Be a kind of leave no choice but to drink can not force mental status; Can occur continuously or periodically, the mandatory experience of craving for He often need drinking that it can show as wine, the normal sense in the back that stops to drink is felt bad in the heart, is on tenterhooks; Or limb tremor occurs, feel sick, withdrawal symptoms such as vomiting, perspiration, this type symptom rapidly disappears to recover to drink then.Owing to drink for a long time, most bodies that merge damage, and serve as obvious with the heart, liver, nervous system; Modal is liver cirrhosis; Peripheral neuropathy and Epileptic fits, the then formation alcoholic-toxic mental disorder and the encephalopathia alcoholica that have, in recent years; The sufferer of chronic alcoholism has the trend that increases, and has caused the attention of medical circle and province of sociology.
The treatment chronic alcoholism is used one or more medicines possibly at present.The metabolic process of alleviating alcohol addiction sulfur (Disulfiram) interfere ethanol drinks that a small amount of wine will cause nausea, vomiting, confusion and dyspnea.Naltrexone (Naltrexone) can reduce the dependence to ethanol, but has big side effect, needs under physician guidance, to use.Benzodiazepine (Benzodiazepine) is an anxiolytic drugs, is usually used in treating alleviating alcohol addiction symptom such as anxiety and insomnia, also is used for preventing epilepsy and delirium, is careful when using them, because they also have addiction property.The tricyclic antidepressant thing can be used for controlling anxiety and the depression that any reason causes, but since these symptoms therefore along with alleviating alcohol addiction might disappear, after alleviating alcohol addiction as still exist these symptoms just to use this type of medicine.
Summary of the invention
Therefore, the objective of the invention is to seek a kind of high-efficiency low-toxicity that can effectively prevent or treat chronic alcoholism, do not have addicted medicine.
The chemical compound that the present invention relates to is butyphthalide (Butylphthalide is called for short NBP, can be levo form, d-isomer and raceme), and chemical formula is C
12H
14O
2, relative molecular weight is 190.24, chemical structural formula is following:
Butyphthalide can be protected mitochondrial function, improves the energy metabolism of brain, suppresses Ca
2+Interior stream is used for treating light, moderate acute ischemic cerebral apoplexy clinically.Pharmacology, toxicity and clinical test results according to butyphthalide treatment cerebral infarction can know that butyphthalide does not have addiction property.
Unexpectedly, the inventor finds after deliberation, the effect of chemical compound butyphthalide aspect prevention or treatment chronic alcoholism.In addition, after this chemical compound oral administration, therapeutic effect is good, no addiction property, thus overcome the defective of present treatment chronic alcoholism medicine.Therefore, the present invention relates to butyphthalide or its pharmaceutical salts or contain the application of pharmaceutical composition any in them in the medicine of preparation prevention or treatment chronic alcoholism.
Butyphthalide of the present invention can exist with the form of levo form and/or d-isomer or raceme when using.
Preferably, butyphthalide or its pharmaceutical salts or contain pharmaceutical composition any in them and can prepare the back with medicinal diluent or pharmaceutical carrier and use.
Preferably, can butyphthalide and for example oiliness carrier be mixed with soft capsule oral uses.In Chinese patent ZL 200310119336.1, narrated butyphthalide soft capsule and preparation method thereof.The butyphthalide soft capsule is become with the medicinal liquid line of oils by the capsule material, and its herb liquid oil is mainly formed by butyphthalide with as the vegetable oil of diluent, and the two weight ratio is 1: 1～10.The capsule material mainly is made up of sizing material, plasticizer, water, and three's part by weight is 1: 0.2～0.4: 0.8～1.3.
In Chinese patent ZL 200510136358.8, narrated butylphthalide dripping pill and preparation method thereof.Butylphthalide dripping pill is made up of active component butyphthalide, substrate, dispersant, coating material.Substrate is selected from Macrogol 4000, polyethylene glycol 6000, Macrogol 2000 0, poloxamer.Dispersant is selected from lightweight differential silica gel, polyvinylpolypyrrolidone.Coating material is selected from hypromellose, hydroxypropyl cellulose, ethyl cellulose, Eudragit E
30D.
In Chinese patent ZL 200410012533.8, narrated the method for preparing of butyphthalide lyophilized injectable powder.The lyophilized injectable powder of butyphthalide is mainly processed by butyphthalide, emulsifying agent and co-emulsifier, excipient and water for injection, and its raw material weight is than being butyphthalide 5～8: emulsifying agent 1～5: co-emulsifier 0～1: excipient 4～10: water for injection 5～11.Method for preparing is: by each component raw material of proportioning weighing, it is even earlier butyphthalide to be added part water for injection high-speed stirred with emulsifying agent and co-emulsifier; Other gets part water for injection excipient dissolving, adds the active carbon that accounts for gross weight 0.1%, and 100 ℃ of heating were taken off charcoal after 15 minutes; After again two kinds of solution being mixed; Add the active carbon of gross weight 0.01%, filter, take off charcoal, benefit adds to the full amount of water for injection; Survey pH value, content, behind the fine straining in the medicinal liquid sub-bottling lyophilizing promptly get lyophilized injection.
In Chinese patent ZL 200710062273.9, narrated butyphthalide tablet and preparation method thereof.The butyphthalide tablet mainly is made up of butyphthalide pressed powder and other pharmaceutic adjuvants, and wherein the butyphthalide pressed powder is made up of 9～30% butyphthalides, 0.01～1.2% emulsifying agent, 70～90% cyclodextrin or cyclodextrin derivative by weight percentage.
In addition, can also butylphthalide and acid reaction be generated ester, wherein acid can be pharmaceutically acceptable mineral acid or organic acid.In addition, the part ester can continue and acid or alkali reaction salify, can increase water solublity, strengthens drug effect, can be prepared into ejection preparation and use.
Under the prerequisite that guarantees drug effect; With the butyphthalide is principal agent, butyphthalide can also with the medicine or the nutritional labeling Combination application of same or similar function with treatment chronic alcoholism, bring into play their synergism; Strengthen drug effect; For example vitamin A, compound vitamin B, vitamin C, carnitine, magnesium, selenium, zinc, and necessary fatty acid and antioxidant, preferred nutritional labeling is thiamine (vitamin B1).
In an embodiment preferred of the present invention, studied NBP to alcohol dependence rat hippocampus hydrogen sulfide (H
2S) influence of content and N-methyl-D-aspartate (NMDA) receptor 2B subunit (NR2B) expression.84 SD male rats are divided into 6 groups at random; Except that normal group; Each group drink contains 6% (v/v) alcohol water blend 28d; Behind drink 6% (v/v) alcohol water blend 14d, NBP low (10mg/kg), in (20mg/kg), high (40mg/kg) dose groups rat oral gavage various dose NBP, detect the expression of withdrawal symptom scoring, hippocampal tissue H2S content, cystathionine beta-synthase (CBS) activity and NR2B.The result shows, the scoring of dose groups rat withdrawal symptom (12.27 ± 1.19), H among the NBP
2The expression (19.47 ± 0.86) of S content (30.25 ± 8.82), CBS active (72.44 ± 7.46) and NR2B mRNA is compared with the expression (29.13 ± 1.39) of the scoring of experiment contrast group rat withdrawal symptom (14.09 ± 2.21), H2S content (44.50 ± 6.65), CBS active (79.06 ± 4.57) and NR2B mRNA; All reduce, significant difference (P＜0.05) is arranged.The scoring of NBP high dose group rat withdrawal symptom (12.18 ± 1.08), H
2The expression (23.12 ± 1.86) of S content (33.00 ± 5.38), CBS active (67.81 ± 9.37) and NR2B mRNA is compared with experiment contrast group rat, all reduces, and significant difference (P＜0.05) is arranged.Therefore, the conclusion that can draw is the withdrawal symptom that NBP can alleviate the alcohol dependence rat, and this and NBP suppress H
2The S/CBS system is expressed and is suppressed NR2B mRNA and express relevant.
In zoopery, the effective dose of treatment chronic alcoholism is about the 20-40mg/kg body weight, and doubly measuring conversion by the conventional computational methods of this area with 5-10 serves as that in butyphthalide, its consumption is the 2-8mg/kg body weight when using human body; Preferably, its consumption is the 5-7mg/kg body weight; More preferably, its consumption is the 7mg/kg body weight.
The specific embodiment
Following examples are used to explain the present invention, but are not used for limiting scope of the present invention.Embodiment 1NBP is to alcohol dependence rat hippocampus H
2The influence that S content and NR2B express
Ca
2+Can make H
2The growing amount of S increases, calcium ion/calmodulin Mediated Signal Transduction approach especially, but quick adjustment H
2The growing amount of S.Expose the experiment surface with external long term alcohol in the body, the expression of NR2B subunit all raises, especially in cultured rat hippocampal and cortical neuron.After this experiment acts on the alcohol dependence rat through observation NBP, Hippocampus H
2S content, CBS activity, NR2B mRNA express and change and the withdrawal symptom scoring, and research NBP is to the influence of alcohol dependence rat.
One, material
1. key instrument and reagent
Bio-Tek ELx800 ELIASA is provided by U.S. Bio-Tek company, and the pcr amplification appearance is produced by U.S. MyCycler company.The L-cysteine is produced by U.S. Sigma company.Trizol reagent is produced by American I nvintrogen company.The butyphthalide preparation is produced by Enbipu Pharmacy Co., Ltd., Shiyao Group., and commodity are called En Bipu (following note is made NBP).
2. animal
Zhengzhou University's animal center provides cleaning level 84 of healthy Sprague-Dawley male rats (credit number: scxk (Henan) 2005-0001), body weight 120～160g.
Two, method
1. laboratory animal is divided into groups and is handled
84 rats are divided into A at random: normal group, B: alcohol dependence model group, C: experiment contrast group, D:NBP low dose group, dose groups among the E:NBP, F:NBP high dose group, 14 every group.Except that normal group, each group drink contains 6% (v/v) alcohol water blend 28d.Behind the 14d, NBP irritates stomach once with vegetable oil dilution back every day, and dosage is low dose group NBP 10mg/kg; Middle dose groups NBP 20mg/kg, high dose group NBP 40mg/kg, dosage vegetable oil such as experiment contrast group are irritated stomach 5ml/kg; The normal group normal diet waits water gaging to irritate stomach.
2. give up scoring
Each treated animal is pressed (Gray S such as Erden; Borgundvaag B; Sirvastava A; Et al.Feasibility and reliability of the SHOT:A short scale for measuring pretreatment severity of alcohol withdrawal in the emergency department.Acad Emerg Med; 2010,17:1048-1054.) give up grade form and observe withdrawal symptom (stereotyped behavior, excitation property, tail are tetanic, abnormal posture, audioepileptic seizure) 18min in the last back 6h that drinks.
3. H in the spectrophotography indirect determination hippocampal tissue
2The content of S
Measure absorbance at wavelength 670nm place with full-automatic ELIASA, according to H
2The S standard curve calculates the H in the solution
2S content, hydrogen sulfide content is with the amount of organizing hydrogen sulfide (nmol/g) expression (Ren Caili, the Li Dongliang of Unit Weight in the hippocampal tissue; Zhao Honggang; Deng. GBI-pour into the again dynamic change of rat cerebral tissue's endogenous hydrogen sulfide. Chinese cerebrovascular magazine, 2008,5:177-181).
4. the activity of CBS in the spectrophotography indirect determination hippocampal tissue
Measure absorbance with full-automatic ELIASA at wavelength 670nm; According to the content of CBS in the CBS standard curve calculating solution, the CBS activity generates hydrogen sulfide with being organized in of Unit Weight in the tissue in the unit interval amount (nmol/g tissue/h) expression (Ren Caili, Li Dongliang; Zhao Honggang; Deng. GBI-pour into the again dynamic change of rat cerebral tissue's endogenous hydrogen sulfide. Chinese cerebrovascular magazine, 2008,5:177-181).
5.RT-PCR detect the expression of NR2B mRNA
Operate the total mRNA of extraction hippocampal tissue according to Trizol (invitrogen) reagent description.Reverse transcription synthesizes cDNA article one chain.With cDNA is template, carries out the PCR reaction.The NR2B design of primers: the NR2B primer is through Primer 5.0 programmings; Primer sequence is: forward primer: 5 '-CTT ACT GAA GGC AAT CCT CG-3 '; Downstream primer: 5 '-TCCTCA GAA CAC CTT CGC TT-3 '; β-actin primer sequence is: forward primer: 5 '-ATGGAT GAC GAT ATC GCT GCG-3 ', downstream primer: 5 '-TCG TCC CAG TTGGTG ACA ATG-3 '.Giving birth to worker bio-engineering corporation by Shanghai synthesizes.Pcr amplification product carries out gray analysis with BandScan gel images process software behind 2.0% agarose gel electrophoresis, genes of interest mRNA water-glass is shown the ratio of the amplified production band gray value of genes of interest and β-actin.
6. statistical disposition
Data are represented with mean ± standard deviation
; Adopt " Chinese medicine encyclopedia medicostatistics " statistical package (PEMS 3.1) to carry out statistical analysis; Relatively adopt the t check between group; There is statistical significance P＜0.05, for difference has significance; P＜0.01 has utmost point significance for difference.
Three, result
1, the alcohol dependence rat is given up behavior sign and audioepileptic seizure scoring (seeing table 1)
Alcohol dependence model group, experiment contrast group rat sneeze occurs, very easily excitation, audioepileptic seizure number of times and intensity all increase after ethanol is removed 6h, comprehensive grading is obviously high than normal group, and significant difference is arranged.After giving the middle and high dosage intervention of NBP, comprehensive grading reduces, and has compared significant difference with the experiment contrast group; And after the low dosage NBP intervention, comprehensive grading does not have significant change, compares there was no significant difference with the experiment contrast group.
Table 1 alcohol dependence rat is given up behavior sign outbreak scoring
Annotate: * compares with the experiment contrast group, P＜0.05.# compares P＜0.01 with the experiment contrast group.
2, H in the hippocampal tissue
2S content and CBS activity change (seeing table 1)
The middle and high dose groups rat of NBP is compared H in the hippocampal tissue with experiment contrast group rat
2S content, CBS activity all reduce, and significant difference (P＜0.05) is arranged.
3, the expression of NR2B mRNA changes (seeing table 1) in the hippocampal tissue
The middle and high dose groups rat of NBP is compared with experiment contrast group rat, and the expression of NR2BmRNA reduces in the hippocampal tissue, and significant difference (P＜0.05) is arranged.
The method of freely drinking the aqueous solution 28d that contains 6% ethanol (v/v) for rat is adopted in this research, sets up the alcohol dependence rat model.Alcohol dependence is a kind of special mental state of drinking repeatedly and causing, be characterized in withdrawal symptom, recurrent and toleration, and withdrawal symptom is the heaviest after ethanol is removed 6h.This research alcohol dependence model group, experiment contrast group rat are after ethanol is removed 6h, and comprehensive grading is obviously high than normal group, and significant difference is arranged, and show that the alcohol dependence rat model makes successfully.After giving the middle and high dosage intervention of NBP, comprehensive grading reduces, and has compared significant difference with the experiment contrast group, shows that NBP can alleviate alcohol withdrawal symptom.
This result of study shows that NBP can reduce in the hippocampal tissue because the H that drinks and increase for a long time
2S content and CBS are active.After sulfur-containing amino acid (methionine) metabolism generates cysteine in the body, under CBS and CSE catalysis, generate H
2S, among the central nervous system, CBS mainly is distributed in positions such as Hippocampus, XIAONAO, cortex and brain stem, distributes higher with Hippocampus, XIAONAO and cortex.CBS produces H in the brain
2The main enzyme of S does not almost detect H in the mouse brain after cbs gene knocks out
2S, and can regulate H through the activity that changes CBS
2The generation of S is so this research has detected H
2The variation of S/CBS system.H
2S possibly influence nmda receptor (NMDAR) complex, and isolated experiment is found, is higher than the H of physiological concentration
2S can increase Ca in the neuronal cell
2+Concentration, and can reach degree of neurotoxicity, finally make the damage of cell generation irritability glutamate toxicity and death.Ca
2+Can make H
2The growing amount of S increases, calcium ion/calmodulin Mediated Signal Transduction approach especially, but quick adjustment H
2The growing amount of S.Drink for a long time and can make hippocampal cell Ca
2+Interior stream increases, and combines with one 19 amino acid fragment of CBS, and CBS is activated immediately, and activatory CBS can catalysis H
2The generation of S can be thought H in view of the above
2The generation of S is a kind of reaction that neuronal excitation has been done.Through further research confirmation of this experiment, the CBS activity increased H after rat was drunk for a long time
2The generation of S increases, and pair cell has toxic damages effect, H
2The concentration of S poisonous effect and its physiological concentration narrow range, toxic concentration is less than 2 times of its physiological concentration.And possibly bring into play its toxic damages effect thereby suppress Cellular respiration to neurocyte through suppressing cytochrome oxidase C.
Middle and high dosage NBP can make NR2B mRNA down-regulated expression.NBP can alleviate the intracellular calcium overload that glutamic acid causes, glutamic acid-neurotransmitter system is the site of the particular importance of alcohol function.Ethanol is strong effect and the selective depressant of NMDAR, can cause NMDAR compensatory " rise ", and the long term alcohol contact can cause the ultra excitatory state of NMDAR. this is a major reason of alcohol withdrawal symptom (especially epileptic outbreak).NMDAR is through regulating Ca
2+In stream and keep the neuron normal physiological function; The glutamic acid of NMDAR mediation can play a significant role in alcohol dependence forms by neurotransmission; The NMDAR subunit mainly is NR1, NR2A and NR2B; The NR2B subunit plays critical effect in the 26S Proteasome Structure and Function of NMDAR, through with cell in multiple protein have an effect, participated in directly alcohol dependence formation, develop and all pathophysiological processes such as keep.The NR2B up-regulated can cause excessive consumption of alcohol and recurrence, and NR2B can be used as a possible target of alcohol dependence pharmaceutical intervention.After NMDAR is activated, trigger Ca
2+In cationic, flow Ca
2+In central nervous system function, play an important role, participate in the transmission of nerve signal and the release of neurotransmitter as the second message,second messenger, the effect in drug dependence receives extensive concern.This experiments experiment matched group and normal group be NR2B mRNA up-regulated relatively, and difference has utmost point significance, and is consistent with similar experiment in the past; Middle and high dose groups of NBP and experiment contrast group compare, and hippocampal tissue NR2B mRNA expresses obviously and reduces, and difference has significance, and prompting NBP possibly make the minimizing of NMDAR quantity through making NR2B mRNA down-regulated expression, and then suppresses Ca
2+Interior stream alleviates Ca in the cell
2+Overload makes the activity downward modulation of CBS, H
2The growing amount of S reduces, and alleviates H
2The S poisonous effect and regulate and control NMDAR after pathway, the rat withdrawal symptom is alleviated.
The above is merely preferred embodiment of the present invention; Be not to limit practical range of the present invention with this; Those skilled in the art can be under spirit of the present invention and principle; Make different changes and modification, but these changes and modify should be covered by within the patent protection category that claims of the present invention define.
Claims (7)
1. butyphthalide or its pharmaceutical salts or contain the application of pharmaceutical composition any in them in the medicine of preparation prevention or treatment chronic alcoholism.
2. application according to claim 1 is characterized in that, said butyphthalide or its pharmaceutical salts or contain pharmaceutical composition any in them and prepare the back with medicinal diluent or pharmaceutical carrier and use.
3. application according to claim 1 is characterized in that, with butyphthalide or its pharmaceutical salts or contain pharmaceutical composition any in them and pharmaceutical carrier is processed soft capsule, tablet or injection.
4. application according to claim 3 is characterized in that, said injection is a lyophilized injectable powder.
5. according to each described application of claim 1-4, it is characterized in that during application, in butyphthalide, its consumption is the 2-8mg/kg body weight.
6. application according to claim 5 is characterized in that, during application, in butyphthalide, its consumption is the 5-7mg/kg body weight.
7. application according to claim 6 is characterized in that, during application, in butyphthalide, its consumption is the 7mg/kg body weight.
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