CN101721400A - Action of ferulic acid on enhancing drug effect of some medicaments and purpose thereof - Google Patents
Action of ferulic acid on enhancing drug effect of some medicaments and purpose thereof Download PDFInfo
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Abstract
The invention relates to an action of ferulic acid on enhancing the drug effect of some medicaments and a purpose thereof, wherein the medicaments mainly comprise alkaloid medicaments including matrine, kushenin, sophocarpine, hyoscyamine, narceine, hanfangchin A, jamaicin, morphine, codeine, evodiamine, strychnine, catharanthine, vincristine, taxol, verticine, peimine, peiminine, ephedrine, pseudoephedrine, wilfordine, triptolide, tripdiolide and the like, and flavonoid medicaments including puerarin, ginsenoside, ginsengenin, mangiferin, scutelloside, alkannin, meletin, rutin, hesperidin, daidzin, soybean isoflavone, daidzein, carthamin, catechin and the like. The ferulic acid and the medicaments can form a compound or a medicament compound, or the ferulic acid and the medicaments can generate a chemical reaction (including salification, esterification, amidation, ketonization, etherification and the like), and/or the ferulic acid and the medicaments can generate a synergistic effect and an additive effect.
Description
Technical field: the present invention relates to ferulic acid in drug action that increases some drugs and uses thereof.
Background technology
Ferulic acid (ferulic acid), chemistry 4-hydroxy 3-methoxybenzene acrylic acid by name is a kind of phenolic acid that comes from various plants, becomes the skeleton of cell wall in cell wall with polysaccharide and protein bound.Studies show that ferulic acid is one of effective ingredient of plurality of Chinese such as Resina Ferulae, Rhizoma Chuanxiong, Radix Angelicae Sinensis, Rhizoma Cimicifugae, Herba Equiseti Hiemalis.
Ferulic acid is a cinnamic acid, molecular formula C
10H
10O
4, molecular weight 194.18, structural formula is as follows, and cis and trans two kinds of products are arranged, and cis is a yellow oil, and trans is oblique policy crystallization (water), and strong anti-oxidation and reproducibility are arranged.
Because the alkane in the ferulic acid molecule is shorter, and contain two keys, hydrophilic is stronger, active group in the molecule has phenolic hydroxyl group, carboxyl, ethylene linkage and aromatic ring, salify can take place, become ester, generate ester, amide, anhydride and electrophilic addition reaction generation alkane, halogenide, alcohol etc. take place with condensations such as alcohol, amine, carboxylic acids.
We studies show that, can obviously increase the curative effect of some medicines after ferulic acid and some medicines formation compositions.Its mechanism may with the water solublity that has increased medicine and/or fat-soluble, having increased medicine, to pass biomembranous ability relevant.The compositions that its ferulic acid and medicine form comprises and some medicines form double salt, amide etc., makes medicine be easy molten attitude in solution, ferulic acid kurarinone amide for example, ferulic acid berberine salt etc.Ferulic acid can ester in addition, the form and the medicine of ketone or ether be combined into complex, has increased medicine and has passed biomembranous ability.Formation water-soluble attitude, liposoluble attitude and the bound state passable with medicine.
Ferulic acid itself has antiplatelet aggregation in addition, antithrombotic; Remove nitrite, oxygen-derived free radicals, peroxidating nitroso-group; Anti-inflammation; Antitumor; Mutation; Defying age; Increase immunologic function; Strengthen human body motility of sperm and mobility's drug action, thereby these drug actions can form the curative effect that cooperative effect or additive effect have increased medicine with the drug action of some medicines.
Because the complex that ferulic acid and some medicines form has changed some physicochemical properties of these medicines, make the water solublity and/or the fat-soluble increase of some medicines, thereby increased the manufacturability of medicine on pharmaceutics, can be made into paclitaxel injection after for example having increased the dissolubility of paclitaxel, thereby changed a large amount of ethanol, propylene glycol, soil temperature, Semen Ricini wet goods problems of adding in injection, reduced the toxic and side effects of medicine.We discover ferulic acid can and some alkaloids medicament and flavonoid medicine etc. form complex, associated complex or double salt etc. between shla molecules, reduce its surperficial freedom, thereby make medicine and water or lipid well fused together, increased the water solublity of alkaloids medicament and flavonoid medicine etc. and/or fat-soluble.Can obviously increase medicine and pass biomembranous characteristic, increase bioavailability of medicament, the preparation stabilization phase is long, keeps the pharmacological action of original medicine, and/or increases its drug effect.Being beneficial to medicine makes oral and preparation such as injection grade.Do not appear in the newspapers in this new discovery home and abroad.
Summary of the invention
The present invention relates to ferulic acid in drug action that increases some drugs and uses thereof.
The ferulic acid that the present invention relates to comprises positive ferulic acid and Hesperetic acid and their isomers.Chemical name is a 4-hydroxy 3-methoxybenzene acrylic acid, molecular weight 194.18, and the architectural feature of cis and trans-ferulaic acid is seen relevant document [Zhang Juan, Jin Qingzhe, Wang Xingguo.Synthetic and the pharmacological research progress of ferulic acid and derivant thereof, grain and oils and fats, 2007 the 1st phases, 43-45].
Some drugs involved in the present invention comprises alkaloids medicament and the salt of forming with inorganic salt thereof: as matrine, kurarinone, sophocarpine, hyoscyamine, papaverine, tetrandrine, berberine, morphine, morphine, codeine, rutaecarpin, strychnine, vinblastine, vincristine, paclitaxel, peimine, ephedrine, pseudoephedrine, wilfordine, etc.
Some drugs involved in the present invention comprises flavonoid (glycosides and aglycon) medicine, for example puerarin, ginsenoside, ginsengenin, chimonin, baicalin, shikonin, Quercetin, rutin, Hesperidin, daiazi, soybean isoflavone, big legumin, saffloside, catechin, etc.
The drug action of ferulic acid increase medicine involved in the present invention can realize by the physical property that changes medicine, for example increase the water solublity, fat-soluble of medicine, reduce the pH of medicine, improve bioavailability of medicament, increase the characteristic (comprise skin, intravital tract membrane structure, cell membrane, tunica vasculose, blood brain barrier etc.) of medicine by the biomembrane ability.The pharmacokinetics of change medicine and tissue distribution and drainage properties etc. are realized.
Ferulic acid involved in the present invention increase medicine drug action can by with the medication medication compound recipe, form pharmaceutical composition, comprise forming complex, associated complex, the double salt between shla molecule with medicine or becoming realization such as amidic-salt.
Ferulic acid involved in the present invention increases the drug action of medicine can be by producing realizations such as complex that chemical reaction (becomes the ester effect, become ketolysis, become ether effect etc.) forms with medicine.
Thereby the curative effect that the antiplatelet aggregation that the curative effect that the present invention relates to ferulic acid and increase some medicines can be a ferulic acid itself to be had, antithrombotic, antioxidation, free radical resisting, anti-inflammation, antitumor, mutation, defying age, antilipemic, arteriosclerosis, increase immunologic function, the drug action formation cooperative effect or the additive effect of drug action and some medicines that strengthens human body motility of sperm and mobility have increased medicine.Its curative effect effect that increases medicine relates to antiplatelet aggregation, antithrombotic, antioxidation, free radical resisting, anti-inflammation, antitumor, mutation, defying age, antilipemic, arteriosclerosis, increase immunologic function, enhancing human body motility of sperm and the mobility's of medicine and ferulic acid itself drug action.
The compositions that ferulic acid involved in the present invention and these medicines are formed, comprise compound preparation, salt, ketone, esters, ethers, amide-type etc., its ferulic acid can be made compound preparation and/or salt, ketone, esters, ethers, amide-type preparation etc. with a kind of medicine, also can make compound preparation and/or organic salt, ketone, esters, ethers, amide-type preparation etc. with medicine more than 2 kinds and 2 kinds.The molecule mol ratio of its ferulic acid and medicine is 0.01-10: 1.
The pharmaceutical composition of these types comprises compound preparation, salt, ketone, esters, ethers, amide-type etc., can adopt pharmaceutically acceptable mode to make pharmaceutical dosage form, comprises injection, oral formulations, mucocutaneous absorbable preparation etc.Be used for the treatment of flu, heating, osteoarthrosis and muscle swelling, senile dementia, pain, senile dementia, rheumatism, cardiovascular disease, arteriosclerotic disease, tumor, anaphylactic disease, mosquito bite and insect bite etc.
Specific embodiment:
Embodiment one, ferulic acid increase the water miscible observation of alkaloids medicament
Get ferulic acid and alkaloids medicament, respectively with 1: 1; 1: 2; 1: 3; 1: 4; 1: 5; After 1: 6 mixed in molar ratio, place in the ball mill and grind.After 15 minutes, take out medicine, observe water miscible change.
The results are shown in Table 1.
Table 1. ferulic acid is to the observation (mg/mL) of alkaloids medicament dissolubility in aqueous solution
Embodiment two, ferulic acid increase flavonoid medicine water solublity and fat-soluble observation
Get ferulic acid and flavone bases medicine, respectively with 1: 1; 1: 2; 1: 3; 1: 4; 1: 5; 1: 6 mol ratio is according to the method for chemosynthesis, and synthetic salt, ketone, esters, ethers, amide-type medicine after the separation and purification, are observed water solublity and fat-soluble change.
The results are shown in Table 2,3.
Table 2. ferulic acid is to the observation (mg/mL) of flavone bases medicine dissolubility in aqueous solution
Table 3. ferulic acid is to the observation (mg/mL) of flavone bases medicine dissolubility in fat
The dissolubility of embodiment three, ferulic acid Ramulus et folium taxi cuspidatae alcohol ketone and the observation of anti-tumor activity
Paclitaxel has good anti-cancer activity, becomes third generation antitumor drug.Paclitaxel treatment ovarian cancer, breast carcinoma have good effect, and treatment carcinoma of prostate, last intestines and stomach cancer, cellule type and lung cancer in non-cellule type are had good prospects.Because paclitaxel is water-soluble hardly, need to add cosolvent in the use.Yet its cosolvent can cause serious patient irritated even indivedual dead, thereby has restricted its application.Adopt ferulic acid to become ester to react the ester type compound that is generated with paclitaxel, can increase the water solublity of paclitaxel greatly, and its anti-tumor activity is had the obvious synergistic effect.
Materials and methods:
Gastric cancer BGC2823 cell is available from Shanghai cell biological institute of the Chinese Academy of Sciences, and paclitaxel is available from Ramulus et folium taxi cuspidatae Technew SA of Shanghai Fudan University.
The preparation of medicine and configuration: 2: 1 mixed in molar ratio of paclitaxel and ferulic acid, after sulfuric acid catalysis became ester, its water solublity can be increased to 200mg/L for 0.25 milligram from every premium on currency dissolving.Ferulic acid Ramulus et folium taxi cuspidatae alcohol ester is configured to 0,0.05 μ mol/L with normal saline, 0.1 μ mol/L, 0.5 μ mol/L, 1 μ mol/L, the solution of 2 μ mol/L.
External intervention experiment to stomach cancer cell:
Cell culture: with the RPMI1640 culture medium that contains 10% calf serum at 37 ℃, cultivate in the incubator of 5%CO2, cell culture changed liquid in 2～3 days or goes down to posterity according to cell growth state in the culture bottle of 100mL, the cell of trophophase of taking the logarithm is tested, be divided into be 4 greatly the group, be respectively the blank group, the paclitaxel injection matched group, ferulic acid medicine matched group, paclitaxel ferulic acid medicine group, every group of 6 drug level, pharmaceutical intervention concentration is seen the configuration of going up medicine.
Seed cells in 96 orifice plates, every hole 100 μ L remove culture fluid behind 8～12h, and every hole adds the culture fluid totally 100 μ L that contain relative medicine, and each drug level is all established 3 multiple holes, 37 ℃, 5%CO
2, cultivate 24h under the saturated humidity condition after, the trichloroacetic acid (TCA) that adds 50 μ L 50% in every hole, culture fluid surface is fixing, behind the placement 5min, culture fluid is moved to 4 ℃ placed 1 hour under the room temperature, outwell fixative, every hole is washed 5 times with deionized water, dries air drying, every hole adds 100 μ LSRB, room temperature is placed 10min, and reuse 1% acetic acid is washed 5 times, air drying.Bonded SRB measures absorbance (OD) value with 150 μ L 10mmol/L non-buffering Tris alkali liquor (pH10.5) vibration dissolving with microplate reader at wavelength 570nm place.The increment quantity of representing cell with the size of OD.
The result: the ferulic acid paclitaxel can obviously suppress the growth of gastric cancer BGC2823 cell, and it acts on than the obvious enhancing of paclitaxel injection (seeing Table 4)
Table 4. ferulic acid paclitaxel is to gastric cancer BGC2823 cell inhibiting effect (OD value;
)
| Concentration (μ mol/L) | Paclitaxel injection | The ferulic acid paclitaxel |
| ??0 | ??2.36±0.25 | ??2.46±0.15 |
| ??0.05 | ??2.23±0.11 | ??2.47±0.17 |
| ??0.1 | ??2.01±0.17* | ??1.53±0.28** |
| ??0.5 | ??1.34±0.12** | ??1.49±0.13** |
| ??1 | ??1.23±0.27** | ??1.52±0.39** |
| ??2 | ??1.32±0.21** | ??1.57±0.48** |
Compare with matched group,
*P＜0.05
*P＜0.01
Embodiment four, ferulic acid strengthen the observation of curative effect of kind berberine antibacterial action
Berberine is a kind of important alkaloid, is that China uses Chinese medicine for a long time.Can from plants such as Rhizoma Coptidis, Cortex Phellodendri, Radix Berberidis, extract.It has significant bacteriostasis.Berberine hydrochloride commonly used is berberine hydrochloride again, and berberine all has inhibitory action to dysentery bacterium, staphylococcus and streptococcus etc.Clinical being mainly used in treated bacillary dysentery and gastroenteritis, its no Drug resistance and side effect.This test employing ferulic acid and berberine share and are used for the treatment of recurrent oral ulceration, its determined curative effect, and mouthfeel is good, and patient is easy to accept.
After 1: 1 grade of ferulic acid and berberine hydrochloride (berberine hydrochloride) mole mixes.Method according to conventional dose is made buccal tablet.Every 50mg.30 couples of recurrent oral ulceration patients are divided into test of cure group and matched group.Every group 30 example, test group adopts the method for buccal, and every day 4-6 time, be 5 days the course of treatment.Matched group adopts containing of berberine hydrochloride tablet, and every day 4-6 time, be 5 days the course of treatment.
Observation of curative effect: ulcer surface disappears substantially, is produce effects; Ulcer surface dwindles, for effectively; Ulcer surface changes little, for invalid.
Patient compliance is observed: it is that compliance is good that patient can finish the intact 1 tablet of medicine of containing.Can not the intact 1 tablet of medicine of containing be poor compliance.
The result: test group produce effects 12 examples, effective 16 examples, total effective rate is that 93%, 100% patient can finish containing.Matched group produce effects 9 examples, effective 11 examples, total effective rate is 67%.11 people can finish containing, and account for whole experiment patients 37%, and most patients can not be finished containing.Many patients are mandatory finishing.
The observation of embodiment five, ferulic acid kurarinone amide analgesic activity
The preparation of ferulic acid kurarinone amide: take by weighing the ferulic acid and the kurarinone of 1: 2 mol ratio, behind the employing salify technology salify, post separates, and gets the ferulic acid kurarinone amide of purity＞98%.
Choosing healthy mice, be divided into 6 groups at random, is respectively kurarinone 50mg/kg, kurarinone 10mg/kg, ferulic acid kurarinone amide 50mg/kg, ferulic acid kurarinone amide 25mg/kg, ferulic acid kurarinone amide 12.5mg/kg and blank group.Every group 10.Each group is gastric infusion respectively, for three days on end, behind the last administration 30min, lumbar injection 0.6% acetic acid 10ml/kg, the writhing response number of times appears in mice in the record 15min.Calculate medicine analgesia percentage rate.
Medicine analgesia percentage rate (%)=(matched group is turned round body number of times treatment group and turned round the body number of times)/matched group is turned round body number of times * 100%
The result: kurarinone 10mg/kg does not see significant analgesia role, and kurarinone 50mg/kg has certain analgesic activity, and ferulic acid kurarinone amide 12.5,25,50mg/kg all have significant analgesia role (table 5).
Table 5. ferulic acid is to the influence of kurarinone analgesic activity
| Group | ??n | Turn round body and suppress percentage rate (%) |
| The blank group | ??10 | |
| Kurarinone 50mg/kg | ??10 | ??29.98 |
| Kurarinone 10mg/kg | ??10 | ??2.56 |
| Kurarinone 10mg/kg+ ferulic acid 2.5mg/kg | ??10 | ??48.30 |
| Kurarinone 10mg/kg+ ferulic acid 5mg/kg | ??10 | ??52.86 |
| Kurarinone 10mg/kg+ ferulic acid 10mg/kg | ??10 | ??43.29 |
The observation of the antiinflammatory action of embodiment six, ferulic acid ephedrine salt.
The preparation of ferulic acid ephedrine salt: a certain proportion of ferulic acid and ephedrine are mixed into reactant salt.
Choose mice, be divided into 5 groups at random, be respectively ephedrine 5mg/kg, ephedrine 20mg/kg, ephedrine 5mg/kg+ ferulic acid 10mg/kg, ephedrine 5mg/kg+ ferulic acid 5mg/kg, ephedrine 5mg/kg+ ferulic acid 2.5mg/kg, 10 every group.Weigh behind the labelling, the auris dextra of mice is contacted 5 minutes with the dimethylbenzene cotton balls, left side ear in contrast, after causing scorching 10min, causing on the scorching auricular concha respectively, applying and giving drug level is 1% to be subjected to the reagent thing, the blank group is given normal saline, behind the 30min mice dislocation is put to death, with diameter 6mm card punch get a homalographic left side (own control) in the same area of ear, auris dextra (dimethylbenzene processing) is weighed, calculating ear swelling rate.
Ear swelling rate (%)=(auris dextra weight-left ear weight)/left ear weight * 100%.
Ferulic acid can obviously increase the ear swelling effect (seeing Table 6) due to the anti-dimethylbenzene of ephedrine as a result.
Table 6. ferulic acid is to the influence of the antiinflammatory action of ephedrine
| Group | ??n | Swelling rate (%) |
| The blank group | ??10 | ??165.34 |
| Ephedrine 10mg/kg | ??10 | ??92.98 |
| Ephedrine 5mg/kg | ??10 | ??142.56 |
| Ephedrine 5mg/kg+ ferulic acid 2.5mg/kg | ??10 | ??78.30 |
| Ephedrine 5mg/kg+ ferulic acid 5mg/kg | ??10 | ??82.38 |
| Ephedrine 5mg/kg+ ferulic acid 10mg/kg | ??10 | ??63.29 |
Embodiment seven ferulic acids are to the observation of vincristine intestinal absorption effect.
The preparation of ferulic acid vincristine salt: with ferulic acid and 1: 1 mole of proportioning salify of vincristine, after post separates promptly.
Experimental technique: get 100 of rats, body weight 200-250g, male and female half and half.1 gastric infusion 2mg/kg, respectively after administration 10,30,60,120 and 180min eye socket venous plexus get blood, measure blood plasma vincristine blood drug level [Wang Xiaochen, Wang Xiangwei, Qin Yan according to literature method, Xu Zhiru, Wang Guangfeng celebrates duty, Yang Zhengmao, Liu Quanhai, the pharmacokinetics of liposomal vincristine body and antitumor action thereof.Laboratory animal and comparative medicine, 2007; 27 (1): the 15-19 page or leaf], the result shows that Chang Chunxin alkali oral absorption is relatively poor, and ferulic acid vincristine salt can obviously increase the absorption of vincristine.Its AUC
0-∞(area under the drug-time curve) is 5 times (seeing Table 5) of vincristine approximately.
Table 5. ferulic acid is to the influence of vincristine pharmacokinetics
| Chemical compound | Unit | Vincristine | Ferulic acid+vincristine |
| ??A | ??1.59. | ??9.75 | |
| ??α | ??30.24 | ??15.33 | |
| ??B | ??5.48 | ??2.37 | |
| ??β | ??1.03 | ??0.06 | |
| ??Vd | ??L/Kg | ??0.12 | ??0.08 |
| ??VL | ??L/Kg | ??0.07 | ??0.08 |
| ??T 1/2α | ??Min | ??36 | ??28 |
| ??T 1/2β | ??Min | ??15 | ??16 |
| Chemical compound | Unit | Vincristine | Ferulic acid+vincristine |
| ??AUC 0-∞ | ??Mg/L·hr | ??0.69 | ??3.67 |
Embodiment eight, ferulic acid are to the influence of Bulbus Fritillariae Uninbracteatae total alkaloids relieving cough and resolving phlegm effect
Antitussive action: get 40 of the qualified mices of 22 ± 3g, the male and female dual-purpose, be divided into 4 groups by cough number of times and sex stratified random, irritating stomach respectively gives and NS, 25mg/kg Bulbus Fritillariae Uninbracteatae total alkaloids, ferulic acid 25mg/kg, 50mg/kg Bulbus Fritillariae Uninbracteatae total alkaloids, 25mg/kg Bulbus Fritillariae Uninbracteatae total alkaloids+ferulic acid 25mg/kg, behind the 20min, draw according to literature method ammonia and to cough, [Xu Shuyun, Bian Rulian, old repairing. pharmacological experimental methodology [M] the 3rd edition. Beijing: People's Health Publisher, 2002,1359], cough number of times in the record 3min.The result shows that 25mg/kg Bulbus Fritillariae Uninbracteatae total alkaloids and ferulic acid 25mg/kg do not have antitussive effect, and 50mg/kg Bulbus Fritillariae Uninbracteatae total alkaloids, 25mg/kg Bulbus Fritillariae Uninbracteatae total alkaloids+ferulic acid 25mg/kg antitussive action are obvious, and Bulbus Fritillariae Uninbracteatae total alkaloids and the effect of ferulic acid drug combination are best.
Phlegm-dispelling functions: adopt the phenol red excretion method of mice [the same antitussive action of list of references], dosage and the same antitussive action of grouping.30 minutes lumbar injections 0.25% phenol red (0.2ml/10g) immediately after administration respectively are with spectrophotometric instrumentation 558nm place trap.The result shows that 5mg/kg Bulbus Fritillariae Uninbracteatae total alkaloids and ferulic acid 25mg/kg do not have phlegm-dispelling functions, and 50mg/kg Bulbus Fritillariae Uninbracteatae total alkaloids, 25mg/kg Bulbus Fritillariae Uninbracteatae total alkaloids+ferulic acid 25mg/kg phlegm-dispelling functions are obvious, and Bulbus Fritillariae Uninbracteatae total alkaloids and the effect of ferulic acid drug combination are best.
Embodiment nine ferulic acids are to the observation of the oral blood drug level of berberine
Instrument: 1100 high performance liquid chromatography (HPLC) instrument comprises G1315A ultraviolet-visible light diode array detector (hewlette-packard).
Test method: get 12 of beasle dogs, be divided into 2 groups at random, fasting is 14 hours before the test, weigh, the 1st group of berberine 200mg/kg that swallows, the 2nd group give with berberine 200mg/kg+ ferulic acid 100mg/kg respectively after administration 0,0.5,1,2,3,4,6h keeps somewhere in femoral vein and is detained needle tubing, regularly get blood 2ml, place the centrifuge tube that adds the heparin sodium anticoagulant, the centrifugal 20min of 2000r/min, get the content of supernatant according to literature method mensuration serum berberine, the result shows that ferulic acid can obviously increase the blood drug level (table 6) of berberine.
Table 6. ferulic acid is to the influence of berberine concentration
The observation of embodiment ten, ferulic acid kurarinone arteriosclerosis
There is report to show that ferulic acid has blood fat reducing, improves the effect of hemorheology and arteriosclerosis, but kurarinone is not seen the report of the effect of blood fat reducing and arteriosclerosis, its antiinflammatory and anti-fibrosis effect can with the effect generation synergism of ferulic acid, thereby its arteriosclerosis effect is stronger than using the effect of ferulic acid separately.This experimental observation can obviously improve the arteriosclerosis level of high blood lipid model animal to the ferulic acid kurarinone.
Test method:
Medication preparation: with after 1: 2 molecule mixed in molar ratio, place the ball mill mixing to get final product the ferulic acid kurarinone.
Carry out [Liu Zhantao, Liu Sai, Wang Shoulan, Zhang Jian, Zhong Weizhen according to literature method.The comprehensive extract of seashells is to the therapeutical effect of experimental atherosclerosis.2005 the 13rd the 3rd phases of volume of China's arteriosclerosis magazine; 305-308].
Get 140 of male Carnis Coturnicis japonicaes, be divided into 7 groups at random, normal control group, model group, positive controls (sieve cut down its fourth 10mg/kg), the high, medium and low dosage group of oral matched group of ferulic acid (40mg/kg) and medicine (administration 10,20 respectively, 40mg/kg).Except that the normal control group is fed normal feedstuff, set up high fat bait arteriosclerosis model according to literature method for all the other 5 groups.
Each medication group gastric infusion, once a day, 4 weeks of continuous use.Respectively at the 4th weekend after the medication, get 10 its serum lipids of zoometry for every group.Carnis Coturnicis japonicae to survival when experiment finishes carries out the pathology detection.
The serum lipids assay: each organizes the 2nd, 4 weekend after medication, and fasting 12h is after jugular vein is got blood 2mL, and separation of serum adopts enzymatic assays serum cholesterol (TC), triglyceride (TG) level.
The result: the ferulic acid kurarinone can obviously reduce arteriosclerosis model Carnis Coturnicis japonicae serum TC, TG level, and it acts on than the obvious enhancing of ferulic acid (table 7).The most aortas of model group have tangible pathological changes, and most As pathological changes are more than 2 grades, and ferulic acid kurarinone group atherosclerosis of aorta lesion degree is lighter, how below 1～2 grade (table 8).Visible most arteries inner membrance is complete under the mirror, and part has slight lipid to soak into, and includes and is dispersed in foam cell.
Table 7. ferulic acid kurarinone is to the influence of high blood lipid model Carnis Coturnicis japonicae blood fat
| Grouping | ??TC(mmol/L) | ??TG(mmol/L) |
| The normal control group | ??4.96±0.88 | ??0.87±0.21 |
| Model group | ??25.23±5.32 | ??5.66±1.21 |
| Sieve cuts down its fourth matched group | ??10.19±2.07 | ??1.68±0.36 |
| The ferulic acid matched group | ??16.88±6.31 | ??3.52±0.73 |
| The test high dose group | ??11.43±4.38 | ??1.75±0.54 |
| Dosage group in the test | ??14.67±5.95 | ??2.87±0.45 |
| The test low dose group | ??15.86±6.67 | ??2.99±0.38 |
Table 8. ferulic acid kurarinone is to the influence of high blood lipid model Carnis Coturnicis japonicae aorta artery sclerosis pathological changes
Claims (10)
1. the present invention relates to ferulic acid in drug action that increases some drugs and uses thereof.
2. according to claim 1, the ferulic acid that the present invention relates to comprises positive ferulic acid and Hesperetic acid and their isomers.Chemical name is 4 hydroxyls, 3 methoxybenzene acrylic acid, molecular weight 194.18, and the architectural feature of cis and trans-ferulaic acid is seen relevant document [Zhang Juan, Jin Qingzhe, the synthetic and pharmacological research progress of Wang Xingguo ferulic acid and derivant thereof, grain and oils and fats, 2007 the 1st phases, 43-45].
3. according to claim 1, some drugs involved in the present invention comprises alkaloids medicament and the salt of forming with inorganic salt thereof: as matrine, kurarinone, sophocarpine, hyoscyamine, papaverine, tetrandrine, berberine, morphine, morphine, codeine, rutaecarpin, strychnine, vinblastine, vincristine, paclitaxel, peimine, ephedrine, pseudoephedrine, wilfordine, etc.
4. according to claim 1, some drugs involved in the present invention comprises flavonoid (glycosides and aglycon) medicine, for example puerarin, ginsenoside, ginsengenin, chimonin, baicalin, shikonin, Quercetin, rutin, Hesperidin, daiazi, soybean isoflavone, big legumin, saffloside, catechin, etc.
5. according to claim 1-4, the passable physicochemical property of passing through the change medicine of drug action of ferulic acid increase medicine involved in the present invention realizes, for example increase the water solublity, fat-soluble of medicine, reduce the pH of medicine, improve bioavailability of medicament, increase the characteristic (comprise skin, intravital tract membrane structure, cell membrane, tunica vasculose, blood brain barrier etc.) of medicine by the biomembrane ability.The pharmacokinetics of change medicine and tissue distribution and drainage properties etc. are realized.
6. according to claim 1-4, ferulic acid involved in the present invention increase medicine drug action can by with the medication medication compound recipe, form pharmaceutical composition, comprise forming complex, associated complex, the double salt between shla molecule with medicine or becoming realization such as amidic-salt.
7. according to claim 1-4, ferulic acid involved in the present invention increases the drug action ferulic acid of medicine can be by producing realizations such as behaviors such as complex that chemical reaction (becomes the ester effect, become ketolysis, become ether effect etc.) forms with medicine.
8. according to claim 1-4, thus the curative effect that it can be the antiplatelet aggregation, antithrombotic, antioxidation, free radical resisting, anti-inflammation, antitumor, mutation, defying age, antilipemic, arteriosclerosis, the increase immunologic function that have of ferulic acid itself that the ferulic acid that the present invention relates to increases the curative effect of some medicines, the drug action formation cooperative effect or the additive effect of the drug action that strengthens human body motility of sperm and mobility and some medicines have increased medicine.Its curative effect scope effect that increases medicine relates to antiplatelet aggregation, antithrombotic, antioxidation, free radical resisting, anti-inflammation, antitumor, mutation, defying age, antilipemic, arteriosclerosis, increase immunologic function, enhancing human body motility of sperm and the mobility's of the effect of medicine itself and ferulic acid itself drug action.
9. according to claim 1-8, the compositions that ferulic acid involved in the present invention and these medicines are formed, comprise compound preparation, salt, ketone, esters, ethers, amide-type etc., its ferulic acid can be made compound preparation and/or salt, ketone, esters, ethers, amide-type preparation etc. with a kind of medicine, also can make compound preparation and/or organic salt, ketone, esters, ethers, amide-type preparation etc. with medicine more than 2 kinds and 2 kinds.The molecule mol ratio of its ferulic acid and medicine is 0.01-10: 1.
10. according to claim 1-9, the pharmaceutical composition of these types, comprise compound preparation, salt, ketone, esters, ethers, amide-type etc., can adopt pharmaceutically acceptable mode to make pharmaceutical dosage form, comprise injection, oral formulations, mucocutaneous absorbable preparation etc.Be used for the treatment of flu, heating, osteoarthrosis and muscle swelling, senile dementia, pain, senile dementia, rheumatism, cardiovascular disease, arteriosclerotic disease, tumor, anaphylactic disease, mosquito bite and insect bite etc.
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