CN1256094C - Deoxyadenosine in aplication of preparing bypolipidemic - Google Patents
Deoxyadenosine in aplication of preparing bypolipidemic Download PDFInfo
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Abstract
The present invention discloses the purpose of 3'-deoxyadenosine (disclosed in the general formula I) in reducing blood lipid, particularly the purpose of 3'-deoxyadenosine in reducing serum triglyceride.
Description
Technical field
The present invention relates to the application of 3 '-deoxyadenosine in the preparation blood lipid-lowering medicine, the particularly application of 3 '-deoxyadenosine in preparation reduction serum triglycerides medicine.
Background technology
Blood fat is the general name of contained lipid material in the blood.Lipid in the blood mainly comprises triglyceride, phospholipid, cholesterol and free fatty.Lipid content is compared with whole body lipid total amount and is only accounted for a littlely in the blood, but it transports between each tissue, often can reflect lipid metabolism situation in the body.Normal adult plasma lipid content is relatively stable, and certain fluctuation range is arranged.Blood lipid level also is subject to the influence of non-disease factor, comprises the influence that meals or short-term hunger are caused.But this influence is temporary transient, can return to normal condition.But, if, cause one or more lipids of blood plasma to continue to be higher than normal value because lipid metabolism or running take place unusually, then be called hyperlipemia (Hyperlipemia, HP).
Hyperlipemia can be divided into following three types according to the difference of the lipid composition that abnormal change takes place:
One, hypercholesterolemia: normal person's blood T-CHOL should be lower than 5.2 mMs/liter (mmol/L), as surpassing 5.7 mMs/liter diagnosable is hypercholesterolemia, the blood total cholesterol level is situated between, and the person is that marginality or criticality raise between the two, also belongs to abnormal conditions.
Two, hypertriglyceridemia: the ideal value of blood triglyceride should be lower than 1.70 mMs/liter; All blood triglycerides surpass this disease of 1.7 mMs/liter be.
Three, plyability hyperlipemia: in the blood T-CHOL and triglyceride simultaneously rising person can be diagnosed as primary disease.
A large amount of research datas show, hyperlipemia comprises that hypercholesterolemia (Hypercholesterolemia), hypertriglyceridemia (Hypertriglyceridemia) and plyability hyperlipemia are the important risk factor of apoplexy, coronary heart disease, myocardial infarction, cardiac sudden death.In addition, hyperlipemia also is an important risk factor that promotes hypertension, impaired glucose tolerance, diabetes.Hyperlipemia also can cause fatty liver, liver cirrhosis, cholelithiasis, pancreatitis, retinal hemorrhage, blind, peripheral vascular disease, limping, hyperuricemia.People know already and take in higher fatty acid and the hypercholesterolemia diet can bring out atherosclerosis, there is among the people of heritability lipid metabolism disorder performance apparent in view in a part, these people are owing to be difficult to remove neutral fat too much in the blood circulation and cholesterol, and cause that cholesterol and triglyceride concentration raise in the blood.
Hyperlipemia is a kind of commonly encountered diseases, particularly for the old people.Hyperlipemia is one of modern rich and honour ciril disease.In China, people with hyperlipidemia increases with expanding economy, and more and more rejuvenation and worrying.The medicine or the health food that search out effective blood fat reducing are significant, will bring very big social benefit and economic benefit.
At present, the hypolipidemic species is more, can be divided into regard to its main hypolipemic function falling T-CHOL (TC), mainly falling T-CHOL hold concurrently triglyceride reducing, triglyceride reducing (TG), the main double T-CHOL four big classes of falling of triglyceride reducing.
The cholic acid integrated agent as: resinae colestyramine (ChoIestyramine) (having another name called cholestyramine) and colestipol (CoIestipol) (having another name called cholestipol) etc. abroad clinical research and use morely, and the first line medicine of TC falls in Ceng Zuowei.But such medicine taste is poor, and easily causes constipation.
The HMG-CoA reductase inhibitor is the hypolipidemic of a class novelty, and it can suppress the biosynthesis of body inner cholesterol, and most of hypercholesterolemiapatients patients, the main ex vivo of TC is synthetic in the blood.The TC effect of falling of this class medicine is stronger and side effect is less than cholic acid integrated agent.Lovastatin (Lovastatin original name Mevinolin) (having another name called Lovastatin, Teroltrat) promptly belongs to this type of blood lipid-lowering medicine.Lovastatin class medicine can not only obviously reduce serum TC, LDL-C level, also can reduce the serum TG level moderately.But it also has a lot of toxic and side effects, for example: have approximately the patient of 2%-3% take medicine the back gastrointestinal dysfunction, feel sick, insomnia, muscle touch a tender spot and erythra.There is the visible liver of 2% usefulness lovastatin therapist source property transaminase to raise approximately, can gets back to normal after the drug withdrawal.Take visible cataract for a long time for every day Canis familiaris L. heavy dose (60-180mg/kg) lovastatin, technology personal care dosage lovastatin through 2～3 years detailed ophthalmologic examinationes, does not see that lenticular opacity takes place.Its toxic and side effects can be divided two classes in theory: a class is by due to the metabolite minimizing of mevalonic acid; Another kind of toxic action by itself is caused.
Nicotinic acid (Nicotinic Acid, having another name called Niacin) (genus vitamin B group) and derivant thereof such as acipimox (Acipimox) (having another name called olbetam (Olbetam)) all have anti-fat-splitting effect, wherein, the acting duration of acipimox is longer, usefulness is stronger.
Special class (Fibrates) medicine of shellfish such as chlorine Bei Te (Clofibrate), it mainly is by suppressing adenyl cyclase, make cAMP content minimizing in the adipose cell, suppressing the fatty tissue hydrolysis, make non-esterified fatty acid content minimizing in the blood, cause the synthetic and secretion minimizing of liver VLDL.It can make the increased activity of lipoprotein lipase simultaneously, quickens the catabolism of VLDL and TG.These make the content of VLDL in the blood, TG, LDL-C and TC reduce eventually.In addition, it also can pass through to suppress the synthetic drainage that reach increase cholesterol from intestinal of hepatocyte to cholesterol, makes TC content minimizing in the blood.
A new generation's hypolipidemic is as fenofibrate, olbetam, gemfibrozil etc.They all have stronger effect to cholesterol reducing and triglyceride, and toxic and side effects is less.But still have some contraindications to be noted.As anemia of pregnant woman and women breast-feeding their children's forbidding; Hepatitis active stage and renal function injury person forbidding; The patient that takes medicine for a long time must make regular check on liver, renal function and blood lipid level.Untoward reaction has symptoms such as stomach discomfort, loss of appetite, diarrhoea, headache, dizziness, paraesthesia, leukopenia, Glutamate pyruvate transaminase rises, erythra.
In sum, at present,, bringing into play important function aspect the treatment hyperlipemia though that existing many blood lipid-lowering medicines are applied to is clinical.But they more or less all have certain toxic and side effects, and blood lipid-lowering medicine also needs constantly to be optimized, and improve curative effect, reduce toxic and side effects.
3 '-deoxyadenosine (3-deoxyadenosine has another name called cordycepin: Cordycepin), and molecular formula C
10H
13N
5O
3, MW 251, are to separate to obtain nucleosides material from Cordyceps militaris (L.) Link. (Cordyceps militaris), and aspergillus nidulans (Aspergillus nidulans) also can produce this material.Its structural formula is as follows:
Do not see the report of the hypolipemic function of 3 '-deoxyadenosine in the prior art.Through the retrieval of patent retrieval referral centre of China national Department of Intellectual Property [entrusting numbering (G) 030358], do not see the report of the blood fat reducing of 3 '-deoxyadenosine yet.
Summary of the invention
In order to overcome the deficiency of lipidemia medicine in the prior art, the invention provides the application in the preparation blood lipid-lowering medicine of 3 '-deoxyadenosine shown in general formula (I).
Another object of the present invention is to 3 '-deoxyadenosine shown in the general formula (I) is provided is the pharmaceutical composition of active component.
Specifically, the effect for reducing blood fat of the 3 '-deoxyadenosine of the present invention serum triglycerides in the blood fat reducing preferably.
Hyperlipemia among the application comprises hypercholesterolemia (Hypercholesterolemia), hypertriglyceridemia (Hypertriglyceridemia) and plyability hyperlipemia.
Hyperlipemia can cause apoplexy, coronary heart disease, myocardial infarction, cardiac sudden death simultaneously; Also can promote hypertension, impaired glucose tolerance, diabetes.Hyperlipemia also can cause fatty liver, liver cirrhosis, cholelithiasis, pancreatitis, retinal hemorrhage, blind, peripheral vascular disease, limping, hyperuricemia.
In addition, take in higher fatty acid and hypercholesterolemia diet and can bring out atherosclerosis, have among the people of heritability lipid metabolism disorder performance apparent in view in a part.
Therefore, 3 '-deoxyadenosine of the present invention can prepare the medicine that prevents and/or treats the relevant cardiac and cerebral vascular diseases of hyperlipemia.Described cardiac and cerebral vascular diseases is apoplexy, coronary heart disease, myocardial infarction, cardiac sudden death, hypertension, atherosclerosis, peripheral vascular disease preferably.
3 '-deoxyadenosine of the present invention also can prepare the medicine that prevents and/or treats the relevant impaired glucose tolerance of hyperlipemia, diabetes, fatty liver, liver cirrhosis, cholelithiasis, pancreatitis, retinal hemorrhage, blind, limping, hyperuricemia.
3 '-deoxyadenosine of the present invention also can be treated the application in heritability lipid metabolism disorder patient's the medicine of hyperlipemia.
Pharmaceutical composition of the present invention contains the 3 '-deoxyadenosine shown in general formula (I) of effective dose, and acceptable carrier on the pharmacodynamics.
According to the present invention, described pharmaceutical composition can be tablet, capsule, pill, injection, slow releasing preparation, controlled release preparation and various particulate delivery system.
In safety experiment, 3 '-deoxyadenosine is with the administration of 5.0g/kg mouse stomach.Observed for two weeks continuously after the administration, record is tried situations such as mice behavior, activity, body weight, food ration, feces and death, puts to death after two weeks to perform an autopsy on sb.Smooth, behavioral activity, body weight gain of hair color after the mice administration, ingest, feces is normal, with solvent control group no significant difference relatively; And do not have dead in two weeks and other abnormal conditions generation.Perform an autopsy on sb after the execution, each main organs (heart, liver, spleen, lung, kidney) changes through the perusal no abnormality seen, compares no significant difference with the solvent control group.Illustrate that 3 '-deoxyadenosine does not have tangible toxic reaction, the mice maximum tolerated dose is 5.0g/kg, i.e. the peroral administration LD of 3 '-deoxyadenosine
50Greater than 5.0g/kg.
Take the TG level of the high blood lipid model mice of 3 '-deoxyadenosine and compare with model group, 3 '-deoxyadenosine 20mg/kg, 10mg/kg dosage group all can obviously reduce the serum TG level.Statistics shows that 3 '-deoxyadenosine 10mg/kg dosage group and high blood lipid model group have highly significant difference.3 '-deoxyadenosine 20mg/kg, 10mg/kg dosage group are compared there was no significant difference with fenofibrate group TG level, 3 '-deoxyadenosine is described at 10mg/kg, down to reduce the effect of serum triglycerides under 25mg/kg dosage suitable with fenofibrate for 20mg/kg dosage.
The CHO of hyperlipidemia model mice significantly increases.Each administration group is compared there was no significant difference with the CHO level of model group, shows that 3 '-deoxyadenosine does not have the effect of hypercholesterolemia reducing.3 '-deoxyadenosine mainly is to reduce serum triglycerides to the high blood lipid model mice, acts on stronger.
Compare with model group TG level, 3 '-deoxyadenosine 100mg/kg, 50mg/kg, 25mg/kg, three dosage groups all can obviously reduce the serum TG level, and statistics shows that highly significant difference is all arranged, show that 3 '-deoxyadenosine has the effect of triglyceride reducing preferably, but the action intensity there was no significant difference of three dosage groups of 3 '-deoxyadenosine triglyceride reducing.Illustrate that the administration of 3 '-deoxyadenosine has the effect that reduces serum triglycerides preferably to the high blood lipid model rat that feeds high lipid food formation.
Pharmaceutical composition of the present invention can prepare according to methods known in the art.When being used for this purpose, if desired, active component 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 uses.
Pharmaceutical composition of the present invention can the unit dosage form administration, and route of administration can be intestinal or non-intestinal, as oral, muscle, subcutaneous, nasal cavity, oral mucosa, skin, peritoneum or rectum etc.
The route of administration of pharmaceutical composition of the present invention can be drug administration by injection.Injection comprises intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection and acupoint injection therapy etc.
Form of administration can be liquid dosage form, solid dosage forms.As liquid dosage form can be true solution class, colloidal type, particulate formulations, emulsion dosage form, mixed suspension form.Other dosage forms are tablet, capsule, drop pill, aerosol, pill, powder, solution, suspensoid, Emulsion, granule, suppository, lyophilized injectable powder etc. for example.
Compositions of the present 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 is, for example diluent and absorbent are as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, carbamide, calcium carbonate, kaolin, microcrystalline Cellulose, aluminium silicate etc.; Wetting agent and binding agent are as 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.; Disintegrating agent, for example 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.; 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, 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.
For pill is made in the administration unit, can be extensive use of various carrier well known in the art.Example about carrier is, for example diluent and absorbent are as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, 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 suppository is made in the administration unit, can be extensive use of various carrier well known in the art.Example about carrier is, for example the ester of Polyethylene Glycol, lecithin, cocoa butter, higher alcohol, higher alcohol, gelatin, semi-synthetic glyceride etc.
For capsule is made in the administration unit, effective ingredient is mixed with above-mentioned various carriers, and the mixture that will obtain thus places hard gelatine capsule or soft capsule.Also effective ingredient 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, compositions of the present 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, Polyoxyethylene Sorbitol Fatty Acid Esters etc.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 coloring agent, antiseptic, spice, correctives, sweeting agent or other material.
The dosage of Pharmaceutical composition of the present invention depends on many factors, for example to prevent or treat the character and the order of severity of disease, the sex of patient or animal, age, body weight, personality and individual reaction, route of administration, administration number of times etc., therefore therapeutic dose of the present invention can have large-scale variation.In general, the using dosage of Chinese materia medica composition of the present invention is well known to a person skilled in the art.The actual active drug quantity that can be according to the present invention be contained in the last preparation in the Pharmaceutical composition, in addition suitable adjustment to reach the requirement of its treatment effective dose, is finished therapeutic purposes of the present invention.Usually to the about 75 kilograms of patients of body weight, the daily dose of the The compounds of this invention of giving is 0.5mg/kg body weight～20mg/kg body weight, preferred 4mg/kg body weight～16mg/kg body weight.Above-mentioned dosage can the single dose form or be divided into several, for example two, three or four dosage form administrations, this is subject to administration doctor's clinical experience and dosage regimen.
Term:
TG: triglyceride
CHO: T-CHOL
LDL-C: low density lipoprotein, LDL
HDL-C: high density lipoprotein
VLDL-C: very low density lipoprotein (VLDL)
The specific embodiment
The following examples are used for further specifying the present invention, but this and do not mean that the present invention is had any restriction.
One, the test of pesticide effectiveness
Embodiment 1:3 '-deoxyadenosine prevention administration is to the influence of high blood lipid model mice lipids contents
Materials and methods
[laboratory animal] Kunming mouse, male, body weight 18～20g, available from Test Animal Centre, Academy of Military Medical Sciences, P.L.A, credit number: SCXK (army) 2002-001.
[being subjected to test product] 3 '-deoxyadenosine (separate obtaining from Cordyceps militaris (L.) Link.sporophore, purity is more than 99.9% by analysis).
[feedstuff] normal feedstuff and high lipid food provide by Institute of Experimental Animals, Chinese Academy of Medical Sciences, credit number: the capital is moving is betrothed to 003, the quality certification number: 0015790.Normal feedstuff prescription: 20% flour, 10% rice flour, 20% corn, 20% Semen Glycines powder, 25% wheat bran, 2% bone meal, 2% fish flour.High lipid food prescription: 79% normal feedstuff, 10% Adeps Sus domestica, 10% yolk powder, 1% cholesterol.
[positive drug] fenofibrate (fenofibrate capsules), method national power Bo Funi drugmaker.Specification: the 100mg/ grain, lot number: 64801, the date of manufacture: 2000.11
[test kit] triglyceride (TG) test kit, T-CHOL (CHO) test kit, the safe clinical reagent company limited of Beijing northization, lot number: 030320.
[instrument] Seperate
TMMax 190 microplate reader, Molecular Devices CorporationSunnyvale, CA.
Method
[grouping and administration] mice is divided into six groups at random by body weight: dosage group (10mg/kg), 3 '-deoxyadenosine low dose group (5mg/kg), fenofibrate group (25mg/kg) in normal control group, hyperlipidemia model group, 3 '-deoxyadenosine high dose group (20mg/kg), the 3 '-deoxyadenosine, 10 every group.The normal control group gives normal diet, and other each groups are given high lipid food, continuous 14 days, all endless supply.Simultaneously, each administration group is irritated stomach once every day, and each is organized the administration volume and is 0.1ml/10g, successive administration 14 days.The hyperlipidemia model group gives the equal-volume normal saline every day.
After [evaluating drug effect] 14 days, mice is plucked eyeball and gets hematometry serum TG, CHO content, and assay method carries out according to TG, CHO test kit description, measures absorbance with microplate reader under the 500nm wavelength.Calculate content of triglyceride: TG (mg/dl)=mensuration pipe absorbance/standard pipe absorbance * 200 (mg/dl) by following formula; Calculate total cholesterol level: CHO (mg/dl)=mensuration pipe absorbance/standard pipe absorbance * 193 (mg/dl).
[data analysis] data represent that with mean+SD data analysis is taked the t check.
The result
1, (64.1 ± 8.1mg/dl) compare, and (134.20 ± 31.30mg/dl) have utmost point significant difference to model group TG level, show that this tests the modeling of high fat mouse model is successful with normal control group TG level.(seeing Table 1)
2, compare with model group TG level, 3 '-deoxyadenosine height, in two dosage groups all can obviously reduce the serum TG level, and statistics shows that the dosage group has highly significant difference in 3 '-deoxyadenosine; Compare with fenofibrate group TG level, the horizontal there was no significant difference of the middle and high dosage group of 3 '-deoxyadenosine TG, show 3 '-deoxyadenosine at 10mg/kg, 20mg/kg dosage reduces the effect suitable (seeing Table 1) of serum triglycerides down under 25mg/kg dosage with fenofibrate.
3, compare with normal group CHO level, model group CHO level has utmost point significant difference, shows that hyperlipidemia model mice CHO significantly increases.Each administration group is compared there was no significant difference with model group CHO level, shows that 3 '-deoxyadenosine does not have the effect of hypercholesterolemia reducing (seeing Table 2).
Conclusion
3 '-deoxyadenosine has the effect that reduces serum triglycerides preferably to the high blood lipid model mice that feeds high lipid food formation.
Table 1.3 '-deoxyadenosine is to the influence of high blood lipid model mice serum TG content (mean ± SD).
| Group | Dosage (mg/kg) | TG content (mg/dl) |
| Normal control group model group 3 '-deoxyadenosine fenofibrate group | -- -- 20 10 5 25 | 64.1±8.1 134.20±31.30 ## 101.7±14.64 * 93.73±17.19 ** 128.16±22.54 △△ 97.77±12.19 * |
##P＜0.01 is compared with the normal control group;
*P＜0.05,
*P＜0.01 is compared with model group;
△ △P＜0.01 is compared with the fenofibrate group.
Table 2.3 '-deoxyadenosine is to the influence of high blood lipid model mice serum CHO content (mean ± SD).
| Group | Dosage (mg/kg) | CHO content (mg/dl) |
| Normal control group model group 3 '-deoxyadenosine | -- -- 20 10 5 | 136.5±3.5 274.5±7.1 ** 279.9±7.2 264.3±6.8 289.5±7.5 |
*P＜0.01 is compared with the normal control group.
Embodiment 2:3 '-deoxyadenosine prevention administration is to the influence of content of triglyceride in the high blood lipid model rat serum
Material and method
[laboratory animal] Wistar rat, male, about body weight 220 ± 20g, available from Institute of Experimental Animals, Chinese Academy of Medical Sciences, credit number: SCXK-11-00-0006.
[being subjected to test product] 3 '-deoxyadenosine (separate obtaining from Cordyceps militaris (L.) Link.sporophore, purity is more than 99.9% by analysis).
[feedstuff] normal feedstuff and high lipid food provide by Institute of Experimental Animals, Chinese Academy of Medical Sciences, credit number: the capital is moving is betrothed to 003, the quality certification number: 0015790.Normal feedstuff prescription: 20% flour, 10% rice flour, 20% corn, 20% Semen Glycines powder, 25% wheat bran, 2% bone meal, 2% fish flour.High lipid food prescription: 79% normal feedstuff, 10% Adeps Sus domestica, 10% yolk powder, 1% cholesterol.
[positive drug] fenofibrate (fenofibrate capsules), method national power Bo Funi drugmaker.Specification: the 100mg/ grain, lot number: 64801, the date of manufacture: 2000.11
[test kit] triglyceride (TG) test kit, T-CHOL (CHO) test kit, LDL-C (LDL-C) test kit, highdensity lipoprotein-cholesterol (HDL-C) test kit, all available from Zhongsheng Beikong Biological Science ﹠ Technology Co., Ltd., lot number: 030313.
[instrument] Seperate
TMMax 190 microplate reader, Molecular Devices CorporationSunnyvale, CA.
[grouping and administration] rat is fed with normal diet and adapts to experimental situation 5 days, and capillary tube eyeground vein clump is got blood then, and centrifugal 300G got serum in 10 minutes, measures the preceding every blood lipids index value of modeling respectively.According to the TG level, carry out the stratified random grouping.Rat is divided into six groups: dosage group (50mg/kg), 3 '-deoxyadenosine low dose group (25mg/kg), fenofibrate group (36mg/kg) in normal control group, hyperlipidemia model group, 3 '-deoxyadenosine high dose group (100mg/kg), the 3 '-deoxyadenosine, 10 every group.The normal control group gives normal diet, and other each groups are given high lipid food, continuous 8 days, all endless supply.Simultaneously, each administration group is irritated stomach once every day, and each is organized the administration volume and is the 1.0ml/100g body weight, successive administration 8 days.The hyperlipidemia model group gives the equal-volume normal saline every day.
After [evaluating drug effect] 8 days, rat capillary tube eyeground vein clump is got hematometry serum total cholesterol (CHO), triglyceride (TG), low density lipoprotein, LDL (LDL-C) and high density lipoprotein (HDL-C) content.Assay method carries out according to the test kit description, measures absorbance with microplate reader (wavelength 500nm).Very low density lipoprotein (VLDL) (VLDL-C) is calculated by CHO-LDL-C.
[data analysis] data represent that with mean+SD data analysis is taked the t check.Blood lipid level adopts paired t-test before and after the administration.
The result
1, (125.5 ± 30.8mg/dl) compare, and (216.0 ± 83.2mg/dl) have utmost point significant difference to model group TG level, show that this tests the modeling of high fat rat model is successful with normal control group TG level.(seeing Table 3)
2, compare with model group TG level, high, medium and low three the dosage groups of 3 '-deoxyadenosine all can obviously reduce the serum TG level, and statistics shows, highly significant difference is all arranged, show that 3 '-deoxyadenosine has the effect of triglyceride reducing preferably, but the action intensity there was no significant difference of three dosage groups of 3 '-deoxyadenosine triglyceride reducing.(seeing Table 3)
Conclusion
3 '-deoxyadenosine prevention administration has the effect that reduces serum triglycerides preferably to the high blood lipid model rat that feeds high lipid food formation.
Table 33 '-deoxyadenosine prevention administration is to the influence of high blood lipid model rat blood serum content of triglyceride (mean ± sD)
| Group Normal group hyperlipidemia model group 3'-Deoxyadenosine high dose group fenofibrate group | Dosage (mg/kg) physiological saline physiological saline 100 50 25 36 | Blood fat (mg/dl) | |||||||||
| Before the administration | After the administration | ||||||||||
| Triglyceride (TG) | T-CHOL (CHO) | Very low density lipoprotein (VLDL) (VLDL-C) | Low density lipoprotein, LDL (LDL-C) | High density lipoprotein (HDL-C) | Triglyceride (TG) | T-CHOL (CHO) | Very low density lipoprotein (VLDL) (VLDL-C) | Low density lipoprotein, LDL (LDL-C) | High density lipoprotein (HDL-C) | ||
| 102.9±24.1 104.3±30.2 101.5±29.2 102.1±25.7 101.1±29.4 102.6±26.0 | 126.3±5.8 132.9±37.6 131.1±36.0 118.0±42.0 144.0±12.5 138.1±21.3 | 27.3±12.4 20.5±10.2 29.7±9.5 12.2±8.1 33.3±11.5 35.9±15.7 | 66.9±11.6 794±6.6 75.5±10.5 81.9±9.9 85.7±9.4 79.9±13.1 | 40.3±10.7 31.5±6.3 31.7±7.1 31.3±4.8 29.9±6.3 34.2±6.1 | 125.5±30. 8 216.0±83. 2 ##△△ 132.9±37. 6 **△△++ 121.1±36. 0 **++ 138.0±42. 0 **△++ 82.0±12.5 **△ | 125.6±7.0 135.5±35.3 135.1±24.4 99.5±27.8 * 112.5±11.8 102.9±14.7 * | 19.7±9.0 21.9±13.5 23.1±8.6 17.5±9.7 46.0±20.4 49.8±22.5 | 76.6±10.6 80.3±10.7 88.3±15.8 △++ 69.3±8.4 *△ △++ 68.7±7.6 *△ △++ 42.9±12.6 * *△△ | 35.1±21.3 21.3±13.6 △ 39.7±35.6 + 18.4±5.2 △△ 26.2±7.7 ++ 14.0±5.0 △△ | ||
*P＜0.01,
*P＜0.05 is compared with the hyperlipidemia model group;
##P＜0.01,
#P＜0.05 is compared with the normal control group;
++P＜0.01,
+P＜0.05 is compared with the fenofibrate group;
△ △P＜0.01,
△P＜0.05, paired t-test is compared with blood lipid level before the administration after the administration.
Two, safety experiment
Embodiment 33 '-the deoxyadenosine acute toxicity test
Material and method
[laboratory animal] Kunming mouse, body weight 18-22g, male and female half and half are provided quality certification 01-3049 by the department of the Chinese Academy of Sciences of Department Of Medicine, Peking University's experimental animal section
[being subjected to test product] 3 '-deoxyadenosine (obtain for this laboratory separates from Cordyceps militaris (L.) Link.sporophore, see embodiment 1).
[test method] gets 40 of Kunming mouses, body weight 18-22g, male and female half and half.Be divided into 2 groups at random, 20 every group, i.e. 3 '-deoxyadenosine group and solvent control group, fasting (can't help water) administration after 12 hours.3 '-deoxyadenosine group is once given mouse stomach administration 0.4ml/10g with 12.5% 3-deoxyadenosine, and then dosage is 5.0g/kg; The solvent control group is given the distilled water of equivalent.Observed for two weeks continuously after the administration, record is tried situations such as mice behavior, activity, body weight, food ration, feces and death, puts to death after two weeks to perform an autopsy on sb.
The result
Smooth, behavioral activity, body weight gain of hair color after the administration of 3 '-deoxyadenosine group mice, ingest, feces is normal, with solvent control group no significant difference relatively; And do not have dead in two weeks and other abnormal conditions generation.Two groups perform an autopsy on sb after putting to death simultaneously, and each main organs (heart, liver, spleen, lung, kidney) changes through the perusal no abnormality seen, with solvent control group no significant difference relatively.The results are shown in Table 4.
Conclusion
3 '-deoxyadenosine is once peroral administration mtd test result show: all do not have tangible toxic reaction after 20 mice administrations, also do not have dead in two weeks.Therefore, the once peroral administration mice maximum tolerated dose of 3 '-deoxyadenosine is 5.0g/kg, and promptly the peroral administration LD50 of 3 '-deoxyadenosine is greater than 5.0g/kg.
Table 43 '-deoxyadenosine oral administration mice mtd test result
| Group | Concentration (%) | Volume (ml/10g) | Dosage (g/kg) | Number of animals (only) | Dead animal number (only) | Maximum tolerated dose (g/kg) |
| 3 '-deoxyadenosine group | 12.5 | 0.4 | 5.0 | 20 | 0 | 5.0 |
| The solvent control group | - | 0.4 | - | 20 | 0 | - |
Claims (3)
1. 3 '-deoxyadenosine shown in general formula (I) falls application in the serum triglycerides medicine in preparation.
2. pharmaceutical composition is characterized in that: contain the 3 '-deoxyadenosine shown in general formula (I) of effective dose, and acceptable carrier on the pharmacodynamics.
3. according to the pharmaceutical composition of claim 2, it is characterized in that described pharmaceutical composition can be tablet, capsule, pill, injection, slow releasing preparation, controlled release preparation and various particulate delivery system.
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| CN101574144B (en) * | 2008-05-07 | 2016-01-20 | 中国医学科学院药物研究所 | 3'-Deoxyadenosine fat-reducing, insulin sensitivity enhancing and the lipometabolic purposes of improvement |
| CN103070878B (en) * | 2012-12-11 | 2014-10-22 | 上海浦东高星生物技术研究所 | Compound Caulis Sinomenii tablet |
| CN105085594A (en) * | 2014-05-23 | 2015-11-25 | 中国医学科学院药物研究所 | Preparation method and uses of N<6>-(1-(4-methoxyphenyl)ethyl)-adenosine |
| CN105193865A (en) * | 2015-09-15 | 2015-12-30 | 上海市农业科学院 | Preparation method of blood fat reduction cordyceps culture medium extractive |
| CN106565806A (en) * | 2016-10-20 | 2017-04-19 | 广东肇庆星湖生物科技股份有限公司 | Synthetic method for 3-deoxyadenosine and product thereof, and application of product |
| CN107737136A (en) * | 2017-08-23 | 2018-02-27 | 深圳清华大学研究院 | A kind of purposes of pharmaceutical composition in preventing and/or treating hyperlipidemia and be hypoglycemic |
| CN107898803A (en) * | 2017-11-23 | 2018-04-13 | 广东省微生物研究所 | Application of the cordycepin in anti-trioxypurine medicine is prepared |
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