CN100364526C - Application of bicychol in preparation of medicine for preventing and/or treating acute alcoholism and acute/chronic alcoholic liver injury - Google Patents
Application of bicychol in preparation of medicine for preventing and/or treating acute alcoholism and acute/chronic alcoholic liver injury Download PDFInfo
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- CN100364526C CN100364526C CNB2004100583092A CN200410058309A CN100364526C CN 100364526 C CN100364526 C CN 100364526C CN B2004100583092 A CNB2004100583092 A CN B2004100583092A CN 200410058309 A CN200410058309 A CN 200410058309A CN 100364526 C CN100364526 C CN 100364526C
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/32—Alcohol-abuse
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/36—Opioid-abuse
Abstract
The present invention discloses an application of dicyclic alcohol disclosed in a general formula (I) in preparing medicine for preventing or treating acute alcoholic intoxication, acute alcoholic liver damage and chronic alcoholic liver damage.
Description
Technical field
The present invention relates to the application of bicyclol in the medicine of preparation prevention or treatment acute alcoholism and acute and chronic alcoholic liver injury.
Background technology
Alcoholic liver disease can be divided into alcoholic fatty liver by its pathological change, alcoholic hepatitis, the concurrent hepatocarcinoma of alcoholic cirrhosis and alcoholic cirrhosis.In recent years, along with the raising of living standards of the people and the consumption figure of drinking increase, alcoholic liver disease has in China increases trend gradually, is the second largest hepatopathy that is only second to viral hepatitis at present.
The definite mechanism of at present relevant alcoholic liver disease is unclear fully as yet.It is generally acknowledged that a series of physiology in the toxicity of the generation development of alcoholic liver disease and ethanol and metabolite acetaldehyde thereof and the body that thereupon causes, biochemical reaction disorder are closely related.
The clinical major measure that is used for the treatment of alcoholic liver disease is alleviating alcohol addiction at present, and the kind of Drug therapy is very limited.Though as the colchicine long-term prescription certain curative effect is arranged, also has certain toxicity.Therefore, seek the medicine of effective, safe resisting alcoholic hepatopathy still for studying focus.
Bicyclol, chemical name: 4,4 '-dimethoxy-2,3,2 ', 3 ' ,-two (methylene-dioxy)-6-methylols-6 '-methoxycarbonyl group biphenyl, structural formula is
Be the anti-hepatitis new drug of China's one class that I developed.Its liver protection and antioxidation all are confirmed on number of chemical, medicine, the experimental liver damage animal model of immunity.Bicyclol has remarkable hepatoprotective effect and has certain hepatitis virus resisting effect, the serum transaminase effects that 4 kinds of animal models such as chmice acute hepatic injury that carbon tetrachloride, D-galactosamine, acetaminophen are caused and mouse immune hepatitis all have significant reduction to raise alleviate the infringement of liver organization pathomorphology.In addition, to rat chronic carbon tetrachloride hepatic injury model, bicyclol reduces the serum transaminase effect that raises except that having, and has the effect of improving serum albumin/globulin ratio and liver proline content concurrently, and the effect that alleviates hepatic fibrosis is promptly arranged.Bicyclol has inhibition hepatitis B virus core antigen (HBeAg), hepatitis B virus ribonucleic acid (HBV-DNA) and the excretory effect of hepatitis B virus surface antigen (HbsAg) and find no toxicity in long-term chronic toxicity test, does not also have teratogenesis and mutagenic toxicity.
Clinical research is the result show: bicyclol all has the good clinical symptoms and glutamate pyruvate transaminase lowering (ALT) and glutamic oxaloacetic transaminase, GOT (AST) improved to act on to chronic type B viral hepatitis and hepatitis C patients, and can make part patient's cloudy commentaries on classics of HBeAg, HBV-DNA.Evident in efficacy and non-evident effect, safety and better tolerance.Bicyclol obtains the New Drug Certificate that National Drug Administration issues in calendar year 2001, and formally puts on market October calendar year 2001 with " hundred match promise " trade name.
But there be not the record of bicyclol in the prior art to alcoholism and alcoholic liver injury protective effect.
Summary of the invention
In order to overcome the deficiencies in the prior art, the object of the present invention is to provide the chemical compound of a kind of prevention or treatment acute alcoholism and acute and chronic alcoholic liver injury,
Bicyclol shown in general formula (I) particularly is provided
As the application that prevents or treat the medicine of acute alcoholism and acute and chronic alcoholic liver injury.
The present invention is by setting up acute alcoholism and acute and chronic alcoholic liver injury model, observes bicyclol to the protective effect of alcoholism and alcoholic liver injury and inquire into its mechanism of action.Result of study shows that bicyclol has good protective action to experimental acute alcoholism and acute and chronic liver injury.
The present invention is by making mice oral ingestion dosage ethanol (50%, 12-24ml/kg) or after the oral 5%Liber-Decarli feedstuff complete nutrition wine seminal fluid body diet, the record mice righting reflex loss time, mortality rate, measure serum glutamic pyruvic transminase (ALT), triglyceride (TG), cholesterol (CHOL), high density lipoprotein (HDL) and low density lipoprotein, LDL LDL level, the generation of liver lipid peroxidation product malonaldehyde (MDA) and polyphenoils glutathion (GSH) content, liver mitochondrion membrane fluidity and swelling degree, liver glutathion-sulfydryl transferring enzyme (GST) activity, serum ethanol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH) and concentration of ethanol in serum, the active and pathomorphism change of liver NDMA-demethylase.
Experimental result shows that bicyclol (150-300mg/kg) can obviously reduce the Serum ALT that ethanol causes, the rising of liver MDA and TG, CHOL, LDL, alleviate the decline of liver GSH and GST, suppress decline of liver mitochondrion membrane fluidity and the rising of mitochondrial swelling degree that ethanol causes, significantly induce HDL, ADH and ALDH, the NDMA-demethylase activity that suppresses rising reduces concentration of alcohol in the blood.In addition, bicyclol can shorten the righting reflex loss time that ethylism causes, reduces mortality rate.
The present invention can draw to draw a conclusion: the bicyclol oral administration can obviously reduce dead mouse and the hepatic injury that ethylism causes; improve the liver fat change; polyphenoils GST and GSH in its protective effect and the inductor; improve the hepatocyte oxidation resistance; protection mitochondrial injury and function; regulation and control participate in the drug metabolism enzyme of alcohol metabolism, and it is closely related to reduce the blood determining alcohol.
Specifically, the present invention finds the protective effect of bicyclol to the acute alcoholism mice.The influence that bicyclol prolongs the acute alcoholism mouse sleep time has been investigated in invention.Experimental animal is observed mice righting reflex loss and recovery time after irritating stomach 50% ethanol 16ml/kg, will be decided to be the length of one's sleep blanking time.The result shows that behind the oral ethanol, reach 3.6 hours the length of one's sleep of mice, and bicyclol all can obviously shorten the length of one's sleep that ethanol causes, and shows good dose-effect relationship, and wherein only be 10% of model group the average length of one's sleep of heavy dose of group.
Bicyclol can reduce the influence that ethylism causes dead mouse.Experimental animal is irritated stomach 50% ethanol 24ml/kg, and record is to the death toll of 8,12,24 hours animals behind the ethanol.The result indicates that 8,12,24 hours mortality of mice are respectively 60%, 80%, 100% behind the oral ethanol.Oral bicyclol can obviously reduce the ethylism mortality of mice.
Bicyclol has protective effect to the chmice acute hepatic injury that ethanol causes.After experimental animal irritates behind the stomach 50% ethanol 12ml/kg 6, Serum ALT obviously raise (1.8 times), liver TG increases to 1.3 times of normal control, and the MDA of reflection lipid peroxidation injury degree generates and increases, and liver polyphenoils GSH and GST reduce to normal 87% and 77% respectively simultaneously.Bicyclol can obviously suppress the rising of the ALT that ethanol causes and the decline of liver GSH, also can reduce the liver TG and the MDA of rising, makes it restore to normal level.In addition, heavy dose of bicyclol can be induced liver GST, improves the oxidation resistance of body.
Pathological change has protective effect to bicyclol to the chmice acute alcoholic liver injury.Irritate stomach
Behind the Chinese liquor 10 days, animal liver cell mainly is that 1-2 layer hepatocyte swelling occurs, become circle around the central vein, and the hepatocyte endochylema is loose, produce cavity in the part liver endochylema, but liver cell nuclear is not seen obvious change.The visible special mess hepatocyte of nearly half model group animal (3-5 hepatocyte) necrosis, the special mess inflammatory cell infiltration does not see that hepatic cell fattydegeneration and hyaline bodies form.And the bicyclol animal does not see obvious hepatocyte injury, with the normal control group than no significant difference.
Behind the oral ethanol of laboratory animal, ethanol raises rapidly in the blood, is 35 times of normal control.Bicyclol can make the blood determining alcohol of rising descend 31%.For the alcohol metabolism enzyme, bicyclol can significantly be induced liver ADH and ALDH activity, is respectively 215% and 122% of normal control group, can suppress NDMA-demethylase activity simultaneously, and suppression ratio is 21%.
Because but the free radical lesion wire plastochondria membrane lipid that produces in the alcohol metabolism process causes the mobile decline of mitochondrial membrane.Bicyclol can obviously improve the mitochondrial membrane degree of polarization that ethanol causes and the rising of microviscosity.Liver mitochondrion swelling degree under the high calcium condition obviously increases, and bicyclol can make the mitochondrial swelling degree obviously reduce, and maintains normal level substantially, thereby guarantees mitochondrial normal function.
Bicyclol is to the protective effect of the chronic alcoholic liver injury of mice.Mice is after 5% alcohol liquid diet fed for 4 weeks, and Serum ALT levels obviously rises.After the bicyclol administration, no matter be treatment group or prevention group, the ALT level all returns to normal level, and the prompting bicyclol has tangible resisting alcoholic hepatic injury effect.
Mice liver TG content not only occurs and significantly rises after the alcoholic liquid diet fed for 4 weeks, and as seen change of serum C HOL, LDL, HDL slightly raise.Compare with model group, administration group liver TG, change of serum C HOL, LDL level significantly descend, and the serum hdl level significantly raises, and the prompting bicyclol can effectively prevent the athero that ethanol causes, quickens fat transfer.
After mice gave the spirituosity diet for a long time, not only GSH content descended in the liver, and GST and the also obviously reduction of glutathion reductase (GR) activity.Behind the oral bicyclol, GSH level, GST activation recovering are to normal level in the Mouse Liver, and while GR activity rises to 1.2 times of matched group.The above results prompting, bicyclol have the GSH of promotion regeneration, strengthen the effect of liver radical scavenging activity.
Laboratory animal is raised for a long time with behind the ethanol, induces P450 2E1 to express and strengthens, and can further cause lipid peroxidation, increases the weight of hepatic injury.This experiment is by measuring NDMA-DH indirect reaction P450 2E1 activity.Discover that the activity that bicyclol can significantly suppress to take in for a long time the P450 2E1 that ethanol causes increases, and makes this enzyme maintain normal level.The result is similar to the acute alcohol liver damage, and bicyclol can significantly be induced the ALDH activity, to endochylema ALDH activity inducement particularly evident (be model group 2.9 times), quicken the removing of acetaldehyde, thereby alleviates the hepatic injury that is caused by acetaldehyde.In addition, bicyclol does not have influence to ADH.
Bicyclol has protective effect to chronic alcoholic liver injury pathological change.Mice 5% alcohol liquid feedstuff, 4 Zhou Houke that take food cause hepatic cell fattydegeneration, become the most serious with lobule central vein hepatocyte fat.Though steatosis does not take place the hepatocyte around some lobule central vein, swelling of liver cell is obvious, and endochylema is loose.In addition, also observe phenomenons such as liver venule congestion, but do not see obvious inflammatory cell infiltration and hepatic necrosis.After the bicyclol administration, hepatic cell fattydegeneration obviously alleviates, and swelling of liver cell do not occur.
Contain as the bicyclol of active ingredient and the pharmaceutical composition of conventional medicine excipient or adjuvant according to the invention still further relates to.Usually pharmaceutical composition of the present invention contains the bicyclol of 0.1-95 weight %.
The pharmaceutical composition that contains The compounds of this invention can be according to method preparation well known in the art.When being used for this purpose, if desired, The compounds of this invention and one or more solids or liquid medicine excipient and/or adjuvant can be combined, make and can be used as suitable administration form or the dosage form that people's medicine or veterinary drug use.
The compounds of this invention or contain its pharmaceutical composition can the unit dosage form administration, route of administration can be intestinal or non-intestinal, as in oral, muscle, nasal cavity, oral mucosa, skin, transdermal, subcutaneous, Intradermal, peritoneum, rectum, intravenous, intramuscular, the sheath, epidural, ophthalmic, intracranial, vagina administration etc.
The compounds of this invention or the route of administration of closing its pharmaceutical composition can be drug administration by injection.Injection comprises intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, acupoint injection therapy, intrathecal injection and peritoneal injection etc.
Form of administration can be liquid dosage form, solid dosage forms.SOLUTION PROPERTIES as liquid dosage form can be true solution class, colloidal type, particulate formulations, emulsion dosage form, mixed suspension form.The liquid dosage form form can be syrup, elixir, injection solution, non-aqueous solution, suspension or emulsion; But solid dosage forms is tablet, lozenge, capsule, drop pill, pill, granule, powder, cream, solution, suppository dispersion powder such as lyophilized injectable powder, aerosol etc. for example.
The compounds of this invention can be made ordinary preparation, also can be slow releasing preparation, controlled release preparation, targeting preparation and various particulate delivery system.
For the unit form of administration is made tablet, can be extensive use of various carrier well known in the art.Example about carrier comprises that excipient is calcium carbonate, lactose, calcium phosphate, sodium phosphate for example; Diluent and absorbent be starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, carbamide, calcium carbonate, kaolin, microcrystalline Cellulose, aluminium silicate, glucosan, colloidal silica, arabic gum, gelatin, magnesium trisilicate, keratin etc. for example; Wetting agent and binding agent be water, glycerol, Polyethylene Glycol, ethanol, propanol, starch slurry, dextrin, syrup, Mel, glucose solution, mucialga of arabic gummy, gelatine size, sodium carboxymethyl cellulose, lac, methylcellulose, potassium phosphate, polyvinylpyrrolidone etc. for example; Disintegrating agent is dry starch, alginate, agar powder, laminaran, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol fatty acid ester, dodecyl sodium sulfate, methylcellulose, ethyl cellulose etc. for example; Disintegrate inhibitor, for example sucrose, glyceryl tristearate, cocoa butter, hydrogenation wet goods; Absorption enhancer, for example quaternary ammonium salt, sodium lauryl sulphate etc.; Lubricant, for example Pulvis Talci, triethylamine magnesium stearate, triethylamine stearic acid, silicon dioxide, corn starch, stearate, boric acid, liquid paraffin, Polyethylene Glycol etc.Tablet further can also be made coated tablet, for example sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablet and multilayer tablet postponing its disintegrate and absorption in gastrointestinal tract, and provide continuous action in a long time thus.
For example, can be extensive use of various carrier well known in the art for pill is made in the administration unit.Example about carrier is, for example diluent and absorbent are as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, Kaolin, Pulvis Talci etc.; Binding agent is as arabic gum, Tragacanth, gelatin, ethanol, Mel, liquid sugar, rice paste or batter etc.; Disintegrating agent is as agar powder, dry starch, alginate, dodecyl sodium sulfate, methylcellulose, ethyl cellulose etc.
For example for capsule is made in the administration unit, the effective ingredient The compounds of this invention is mixed with above-mentioned various carriers, and the mixture that will obtain thus places hard gelatine capsule or soft capsule.Also the effective ingredient The compounds of this invention can be made microcapsule, be suspended in and form suspensoid in the aqueous medium, in the hard capsule of also can packing into or make injection and use.
For example, comprise emulsion, solution, suspension, syrup etc. for oral liquid is made in the administration unit.Suitable carriers comprises solution, suspension, syrup etc., and optional additive for example wetting agent, emulsifying agent and suspending agent, sweeting agent, correctives and the spice etc. of containing.
For example, The compounds of this invention is made injection preparation, as solution, suspensoid solution, Emulsion, lyophilized injectable powder, this preparation can be moisture or non-water, can contain acceptable carrier, diluent, binding agent, lubricant, antiseptic, surfactant or dispersant on a kind of and/or multiple pharmacodynamics.Can be selected from water, ethanol, Polyethylene Glycol, 1 as diluent, the isooctadecanol of ammediol, ethoxylation, the isooctadecanol of polyoxyization, vegetable oil be for example ethyl oleate, polyoxyethylene sorbitol, fatty acid ester etc. of olive oil and Semen Maydis oil, gelatin and injectable organic ester for example.Such dosage form can also contain adjuvant for example antiseptic, wetting agent, emulsifying agent and dispersant.In addition, ooze injection, can in injection preparation, add proper amount of sodium chloride, glucose or glycerol, in addition, can also add conventional cosolvent, buffer agent, pH regulator agent etc. in order to prepare etc.These adjuvants are that this area is commonly used.
In addition, as needs, also can in pharmaceutical preparation, add for example for example sucrose, lactose, glucide etc. or other material of Herba Menthae, Ilicis Purpureae wet goods, sweeting agent of coloring agent, antiseptic, spice, correctives.
The used sterile media of the present invention can make by the well-known standard technique of those skilled in the art.They can be sterilized, for example by filter via biofilter, by in compositions, add biocide, by with the compositions radiation treatment or by compositions being heated Song's sterilization.Can also they be made sterile injectable medium facing with preceding.
For reaching the medication purpose, strengthen therapeutic effect, medicine of the present invention or pharmaceutical composition can be with any known medication administrations.Certainly the route of administration that is used to implement chemical compound of the present invention depends on the position that disease and needs are treated.Because the pharmacokinetics of The compounds of this invention and pharmacodynamic profile have to a certain degree different, the most preferred method that therefore obtains treatment concentration in tissue is to increase dosage gradually and monitor clinical effectiveness.For such therapeutic dose of increase gradually, predose will depend on route of administration.
For any particular patient, the concrete treatment effective dose level of The compounds of this invention pharmaceutical composition depends on many factors, for example to prevent or treat the character of disease, disease severity, route of administration, administration number of times, therapeutic purposes, the removing speed of this chemical compound, the treatment persistent period, this particular compound associating or the concrete medicine that uses simultaneously, the sex of patient or animal, age, body weight, personality, diet, the well-known factors in medical science field such as individual reaction and general health situation, therefore therapeutic dose of the present invention can have large-scale variation.According to treatment patient's disease, may must make some change, and under any circumstance, all determine the suitable dose of individual patient by the doctor to dosage.
Dosage is meant and does not comprise the weight of vehicle weight at the chemical compound of interior (when using carrier).In general, the using dosage of Chinese materia medica composition of the present invention is well known to a person skilled in the art.Can be according to the actual drug quantity that is contained in the preparation last in the The compounds of this invention compositions, in addition suitable adjustment to reach the requirement of its treatment effective dose, is finished prevention of the present invention or therapeutic purposes.Can be the single dose form administration or be divided into several, for example two, three or four dosage form administrations; This is subject to administration doctor's clinical experience and comprises the dosage regimen of using other treatment means.Chemical compound of the present invention or compositions can be taken separately, or merge use and adjust dosage with other treatment medicine or symptomatic drugs.
Term
Liber-Decarli complete nutrition wine seminal fluid body feedstuff;
ALDH: aldehyde dehydrogenase;
ALT: glutamate pyruvate transaminase;
TG: triglyceride;
CHOL: cholesterol;
HDL: high density lipoprotein;
DL: low density lipoprotein, LDL;
MDA: malonaldehyde;
GSH: glutathion;
GST: glutathion-sulfydryl transferring enzyme;
ADH: ethanol dehydrogenase;
The ALDH aldehyde dehydrogenase;
NDMA-DH: N-nitrosodimethylamine-demethylase;
GR: glutathion reductase
Description of drawings
Fig. 1 bicyclol causes the influence that mouse sleep time prolongs to ethanol
Fig. 2 bicyclol is to the influence of concentration of alcohol in the ethylism mice blood
Fig. 3 bicyclol causes the influence that mice mitochondrial membrane swelling degree changes to ethanol.The result represents with mean ± SD.
The influence that Fig. 4 bicyclol raises to chronic alcoholic liver injury mice serum ALT.The result represents with mean value SD.M: ethanol group T2/3: bicyclol (200/300mg/kg) treatment group, Y2/3:Bicyclol (200/300mg/kg) prevention group.##P＜0.01 is compared with matched group
*P＜0.01 is compared with model group.
The influence that Fig. 5 bicyclol raises to the chronic alcoholic liver injury liver of mice TG.The result is with mean value SD.M: bicyclol treatment ethanol T2/3:(200/300mg/kg), Y2/3: bicyclol (200/300 mg/kg) prevention.##P＜0.01 is compared with matched group,
*P＜0.05,
*P＜0.01 is compared with model group.
The influence that Fig. 6 bicyclol descends to the chronic alcoholic liver injury liver of mice GSH.The result is with mean value SD.M: bicyclol treatment ethanol T2/3:(200/300mg/kg), Y2/3: bicyclol (200/300mg/kg) prevention, ##P＜0.01 is compared with matched group,
*P＜0.05,
*P＜0.01 is compared with model group.
The influence that Fig. 7 bicyclol descends to the chronic alcoholic liver injury liver of mice GST.
The influence that Fig. 8 bicyclol descends to the chronic alcoholic liver injury liver of mice GR.The result is with mean value SD.M: bicyclol treatment ethanol T2/3:(200/300mg/kg), Y2/3: bicyclol (200/300mg/kg) prevention, ##P＜0.01 is compared with matched group,
*P＜0.05,
*P＜0.01 is compared with model group.
Fig. 9 bicyclol is to the active influence of the chronic alcoholic liver injury liver of mice endochylema NDMA-DH.The result is with mean value SD.M: bicyclol treatment ethanol T2/3:(200/300mg/kg), Y2/3: bicyclol (200/300mg/kg) prevention.##P＜0.01 is compared with matched group,
*P＜0.05,
*P＜0.01 is compared with model group.
The specific embodiment
The following examples can help those skilled in the art more fully to understand the present invention, but do not limit the present invention in any way.
One. bicyclol is to the protective effect of acute alcoholism mice
The influence that embodiment 1. bicyclols prolong the acute alcoholism mouse sleep time
Male mice in kunming, body weight 22-24 gram is divided into 4 groups at random, 10 every group, wherein 3 groups respectively at the experiment afternoon first day and morning and afternoon next day oral bicyclol 75,150,300mg/kg.Matched group is given with the volume excipient.Behind each treated animal overnight fasting, irritate stomach 50% ethanol 16ml/kg.Observe mice righting reflex loss and recovery time behind the oral ethanol, close in the time of will being decided to be sleep blanking time.
The result shows that behind the oral ethanol, reach 3.6 hours the length of one's sleep of mice, bicyclol 150,300mg/kg all can obviously shorten the length of one's sleep that ethanol causes, and shows good dose-effect relationship, and wherein only be 10% of model group the average length of one's sleep of heavy dose of group.The results are shown in Figure 1.
Male mice in kunming, body weight 22-24 gram is divided into 4 groups at random, 10 every group, wherein 3 groups respectively at the experiment afternoon first day and morning and afternoon next day oral bicyclol 100,200,300mg/kg, matched group is given with the volume excipient.Behind each treated animal overnight fasting, irritate stomach 50% ethanol 24ml/kg, record is to the death toll of 8,12,24 hours animals behind the ethanol.The result is as shown in table 1, and 8,12,24 hours mortality of mice are respectively 60%, 80%, 100% behind the oral ethanol.Oral bicyclol (200,300mg/kg) can obviously reduce the ethylism mortality of mice.
Table 1 bicyclol causes the influence of dead mouse to ethanol
| | Ethanol | 50%24mlkg -1 | Bicyclol 100mgkg -1 | Bicyclol 200mgkg -1 | Bicyclol 300mgkg -1 |
| Time after the administration | 8h 60％ 12 80％ 24 100％ | 50％ 60％ 70％ | 30％ 30％ a 40％ b | 0％ b 0％ c 10％ c |
Two. bicyclol causes the protective effect of chmice acute hepatic injury to ethanol
Male mice in kunming, body weight 22-24 gram is divided into 5 groups at random, 10 every group, wherein 3 groups respectively at the experiment afternoon first day and morning and afternoon next day oral bicyclol 75,150,300mg/kg, matched group is given with the volume excipient.Behind each treated animal overnight fasting, except that the normal control group, all the other each treated animals are irritated stomach 50% ethanol 12ml/kg, and matched group is given 20% Glucose Liquid with homenergic.Give behind the ethanol 6 hours with sacrifice of animal, get determination of serum ALT, get liver and measure TG, MDA and GSH and GST content.As shown in table 2, behind the oral ethanol of mice, liver TG increases to 1.3 times of normal control, and Serum ALT is obviously rising (1.8 times) also, the MDA of reflection lipid peroxidation injury degree generates and increases, and liver polyphenoils GSH and GST reduce to normal 87% and 77% respectively simultaneously.Bicyclol (75,150,300mg/kg) can obviously suppress the rising of the sALT that ethanol causes and the decline of liver GSH.Meanwhile, and bicyclol (150,300mg/kg) also can reduce the liver TG and the MDA of rising, make it restore to normal level.In addition, heavy dose of bicyclol can be induced liver GST, improves the oxidation resistance of body.
Table 2 bicyclol causes hepatic injury mouse liver TG, GSH to ethanol; GST, the influence of MDA and Serum ALT levels
| Group | Liver TG/ mgdL -1 | ALT/U·dL -1 | MDA/ nmol·g -1 | GSH/ nmol·g -1liver | GST/ nmol·min -1·mg -1prot |
| Normal control | 290.8±62.3 a | 31.10±7.58 c | 45.50±6.77 a | 5.17±0.41 a | 85.57±6.74 a |
| |
377.0±30.0 | 55.42±8.37 | 57.24±6.12 | 4.51±0.48 | 65.48±19.46 |
| Bicyclol 75 mgkg -1 | 368.8±42.4 | 31.10±5.58 c | 53.90±2.56 | 5.90±0.63 c | |
| |
226.6±53.3 c | 30.70±7.58 c | 41.30±7.62 b | 6.41±0.84 c | |
| |
225±22.7 c | 28.71±5.18 c | 37.31±4.41 c | 7.61±0.71 c | 114.58±11.14 c |
A.P＜0.05, bP＜0.01, cP＜0.001 is compared with model group.
Irritate stomach 56g Chinese liquor after 10 days, animal liver cell mainly is that 1-2 layer hepatocyte swelling occurs, become circle around the central vein, and the hepatocyte endochylema is loose, produce cavity in the part liver endochylema, but liver cell nuclear is not seen obvious change.The visible special mess hepatocyte of nearly half model group animal (3-5 hepatocyte) necrosis, the special mess inflammatory cell infiltration does not see that hepatic cell fattydegeneration and hyaline bodies form.Bicyclol (300mg/kg) treated animal is not seen obvious hepatocyte injury, with the normal control group than no significant difference.
(1) bicyclol is to the influence of mice serum concentration of alcohol
Male mice in kunming, body weight 22-24 gram is divided into 3 groups, 7 every group at random.The administration group is in the oral bicyclol 300mg/kg experiment afternoon first day and morning and afternoon next day, and matched group is given with the volume excipient.Each treated animal overnight fasting after the last administration.Morning next day except that the normal control group, the oral 50% ethanol 16ml/kg of all the other animals.Give behind the ethanol 1 hour with sacrifice of animal, get the hematometry ethanol content.The result shows that behind the oral ethanol, ethanol raises rapidly in the blood, is 35 times of normal control.Bicyclol can make the blood determining alcohol of rising descend 31%.
(2) bicyclol is to mouse liver ADH, ALDH and the active influence of NDMA-demethylase
Male mice in kunming, body weight 22-24 gram is divided into 2 groups, 10 every group at random.The administration group is respectively at the oral bicyclol 300mg/kg experiment afternoon first day and morning and afternoon next day, and matched group is given with the volume excipient.Each treated animal overnight fasting after the last administration.Get the animal sacrificed by decapitation liver and measure ADH, ALDH and NDMA demethylase activity morning next day.The result shows that bicyclol can significantly be induced liver ADH and ALDH activity, is respectively 215% and 122% of normal control group, can suppress NDMA-demethylase activity simultaneously, and suppression ratio is 21%.Table 3 bicyclol is to mouse liver ADH, the active influence of ALDH and NDMA-demethylase
| Group | ADH/nmol·min -1·g -1liver | NDMA demethylase /nmol·min -1·mg -1pro tein | ALDH /μg·min -1·mg -1protein |
| Contrast bicyclol 300mgkg -1 | 6.16±1.72 13.25±0.56 c | 2.03±0.06 1.61±0.13 c | 3.27±0.11 4.02±0.52 b |
(1) influence that descends of bicyclol hepatic mitochondria membrane fluidity that the chmice acute alcoholic liver injury is caused
Male mice in kunming, body weight 22-24 gram is divided into three groups, 10 every group at random.Behind 56 ° of Chinese liquor 10ml/kg of mouse stomach, but because the free radical lesion wire plastochondria membrane lipid that produces in the alcohol metabolism process causes the mobile decline of mitochondrial membrane.Bicyclol (200,300mg/kg) can obviously improve the mitochondrial membrane degree of polarization that ethanol causes and the rising of microviscosity.
Table 4 bicyclol causes the mobile influence that changes of mice mitochondrial membrane to ethanol
| Group | P | η |
| Normal control ethanol ethanol+bicyclol (200mg/kg) ethanol+bicyclol (300mg/kg) | 0.164±0.02 0.183±0.006 # 0.170±0.01 * 0.173±0.007 ** | 1.12±0.23 1.33±0.07 # 1.17±0.15 * 1.21±0.08 ** |
The result represents with mean ± SD
#P＜0.05 is compared with matched group
*P＜0.05,
*P＜0.01 is compared with model group
(2) bicyclol is to the influence of Mouse Liver mitochondrial swelling degree
Male mice in kunming, body weight 22-24 gram is divided into four groups, 10 every group at random.56 ° of Chinese liquor 10ml/kg of mouse stomach are after 10 days, liver mitochondrion swelling degree under the high calcium condition obviously increases, and bicyclol (200,300mg/kg) the mitochondrial swelling degree is obviously reduced, substantially maintain normal level, thereby guarantee mitochondrial normal function.The results are shown in Figure 3
Three. bicyclol is to the protective effect of the chronic alcoholic liver injury of mice
The influence that embodiment 7 bicyclols raise to the chronic alcoholic liver injury Serum ALT of mice
Male mice in kunming, body weight 22-24 gram is divided into six groups, 10 every group at random.Mice is after 5% alcohol liquid diet fed for 4 weeks, and Serum ALT levels obviously rises.After the bicyclol administration, no matter be treatment group (200mg and 300mg/kg) or prevention group (200mg and 300mg/kg), the ALT level all returns to normal level, and the prompting bicyclol has tangible resisting alcoholic hepatic injury effect.The results are shown in Figure 4
Mice liver TG content not only occurs and significantly rises after the alcoholic liquid diet fed for 4 weeks, and as seen change of serum C HOL, LDL, HDL slightly raise.Compare with model group, administration group liver TG, change of serum C HOL, LDL level significantly descend, and the serum hdl level significantly raises, and the prompting bicyclol can effectively prevent the athero that ethanol causes, quickens fat transfer.The results are shown in Figure 5
Table 5 bicyclol is to the chronic alcoholic liver injury serum hdl of mice, the influence of LDL and CHOL level
| Group | HDL (mmol/L) | LDL (mmol/L) | CHOL (mmol/L) |
| Normal control ethanol ethanol+bicyclol (200mg/kg, treatment) ethanol+bicyclol (300mg/kg, treatment) ethanol+bicyclol (200mg/kg, prevention) ethanol+bicyclol (300mg/kg, prevention) | 5.26±1.22 5.60±1.33 9.56±1.48 ** 9.03±1.38 ** 8.97±1.23 ** 10.54±1.27 ** | 0.92±0.18 1.16±0.36 0.84±0.21 * 0.83±0.30 * 0.68±0.26 ** 0.76±0.19 ** | 2.61±0.34 2.98±0.52 2.22±0.64 ** 2.43±0.39 * 2.15±0.43 ** 2.38±0.39 ** |
The result is with mean value SD M: ethanol T2/3: bicyclol (200/300mg/kg) treatment
Y2/3: bicyclol (200/300mg/kg) prevention
*P＜0.05,
*P＜0.01 is compared with model group.
Embodiment 9 bicyclols are to the influence of mouse liver antioxidation
After mice gave the spirituosity diet for a long time, not only GSH content descended in the liver, and GST and the also obviously reduction of glutathion reductase (GR) activity.Behind the oral bicyclol, GSH level, GST activation recovering are to normal level in the Mouse Liver, and while GR activity rises to 1.2 times of matched group.The above results prompting, bicyclol have the GSH of promotion regeneration, strengthen the effect of liver radical scavenging activity.The results are shown in Figure 6,7,8
Ethanol accounts for about 10% of total ethanol intake through the amount of MEOS (MEOS) oxidative metabolism.The superoxide anion that this metabolic process produces can generate hydroxyl under magnesium ion catalysis.Now confirm MEOS metabolism ethanol process dependent cells cytochrome p 450 2E1.And laboratory animal is raised for a long time with behind the ethanol, induces P450 2E1 to express and strengthens, and can further cause lipid peroxidation, increases the weight of hepatic injury.
This experiment is by measuring NDMA-DH indirect reaction P450 2E1 activity.Discover that the activity that bicyclol can significantly suppress to take in for a long time the P450 2E1 that ethanol causes increases, and makes this enzyme maintain normal level.
The result is similar to the acute alcohol liver damage, and bicyclol can significantly be induced the ALDH activity, to endochylema ALDH activity inducement particularly evident (be model group 2.9 times), quicken the removing of acetaldehyde, thereby alleviates the hepatic injury that is caused by acetaldehyde.In addition, bicyclol does not have influence to ADH.
Table 6 bicyclol is to the chronic alcoholic liver injury serum of mice ADH, the influence of ALDH level
| Group | ADH (U/mg albumen) | ALDH (U/mg albumen) | |
| Liver homogenate | Normal control ethanol ethanol+bicyclol (300mg/kg, prevention) | 7.42±1.73 6.17±1.04 6.95±1.32 | 8.79±0.88 9.02±0.96 10.73±1.65 ** |
| Endochylema | Normal control ethanol ethanol+bicyclol (300mg/kg, prevention) | 2.60±0.26 2.62±0.43 2.85±0.39 | 3.89±0.81 2.71±0.91# 8.09±1.33 ** |
The result is with mean value SD
M: bicyclol treatment ethanol T2/3:(200/300mg/kg), Y2/3: bicyclol (200/300mg/kg) prevention, ##P＜0.01 is compared with matched group,
*P＜0.05,
*P＜0.01 is compared with model group.
Embodiment 11 bicyclols are to the protective effect of chronic alcoholic liver injury pathological change
The influence that table 7 bicyclol changes the chronic alcoholic liver injury pathology of mice index
| Group | The pathology index |
| Normal control ethanol ethanol+bicyclol (300mg/kg, prevention) ethanol+bicyclol (300mg/kg) | 0.2±0.27 2.50±0.53## 1.35±1.25 * 0.65±0.53 ** |
The result is with mean value SD
##P＜0.01 is compared with matched group,
*P＜0.05,
*P＜0.01 is compared with model group.
Claims (3)
1. the application of bicyclol in the medicine of preparation prevention or treatment acute alcoholism shown in general formula (I)
Shown in general formula (I) bicyclol in preparation prevention or treat application in the medicine of acute and chronic alcoholic liver injury
3. according to the purposes of claim 1 or 2, wherein said medicine is tablet, capsule, pill, injection, slow releasing preparation, controlled release preparation and various particulate delivery system.
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| PCT/CN2005/001236 WO2006015546A1 (en) | 2004-08-11 | 2005-08-11 | Use of bicyclol for manufacturing a medicament for preventing and/or treating acute alcoholism and acute or chronic alcoholic liver injury |
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| CN103923077B (en) * | 2013-07-05 | 2016-03-02 | 高尔医药科技(上海)有限公司 | Two kinds of acetaldehyde dehydrogenase agonists, Preparation Method And The Uses |
| CN109106711A (en) * | 2017-06-23 | 2019-01-01 | 北京协和药厂 | Bicyclic alcohols and its pharmaceutical usable derivatives are used to prevent or the purposes of medicine physical property hepatic injury |
| CN112755192A (en) * | 2019-10-21 | 2021-05-07 | 北京协和药厂 | Application of bicyclol compounds in preparation of medicines for preventing or treating atherosclerotic diseases and pharmaceutical composition |
| CN114869901B (en) * | 2022-05-06 | 2023-10-27 | 安徽医科大学 | Application of verbena glycoside in medicine for treating alcoholic liver injury |
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