CN1113646C - Medicinal preparation containing shikimic acid and its derivatives, and its use in preparing anti-thrombosis and analgesic medicine - Google Patents

Abstract

The present invention relates to a medicinal preparation in which shikimic acid and derivates thereof are used as active ingredients. The present invention also relates to a new medicinal use of shikimic acid and derivates thereof, specifically to the application of shikimic acid triacetyl derivates (SA-2) in preparing medicines with the functions of antithrombosis and analgesia.

Description

Contain the pharmaceutical preparation and the application in formation of preparation antithrombotic and analgesic medicine thereof of shikimic acid and derivant thereof

The present invention relates to shikimic acid and derivant thereof is the pharmaceutical preparation of active component.The invention still further relates to the new medicine use of shikimic acid and derivant thereof, specifically be shikimic acid and shikimic acid triacetyl derivant (SA-2) preparation have that antithrombotic forms and analgesic medicine in application, belong to drug world.

Shikimic acid (Shikmic acid, SA-1), be the active ingredient that contains in the Chinese herbal medicine Magnoliaceae Illicium various plants fruit, its source is extracted through the methanol equal solvent by the fruit of many stamens of Winteraceae Radix Illicii Lanceolati Illicium henryivar.multistamineum and the mature fruit of other plant of Illicium, refining forming.Its molecular formula is C ₇H ₁₀O ₅, molecular weight is 174.15.In recent years, the exploitation of thrombosis Study on Mechanism and antithrombotic reagent is subjected to the concern of various countries the world of medicine deeply, and existing part active compound is in and the preclinical study stage clinical.Antithrombotic reagent is divided three classes according to its mechanism of action: anticoagulant, antiplatelet drug and thrombolytic drug.In the anticoagulant, except natural and recombinant human antithrombase-III, also have direct inhibitor hirudin, argatroban and Chinese medicine Pericarpium Zanthoxyli, the Radix Salviae Miltiorrhizae of thrombin, the crude extract of Radix Paeoniae Rubra; Antiplatelet drug is obtained many new progresses at present, the medicine Ramulus Uncariae cum Uncis alkali, ilexonin A, the Radix Paeoniae phenol that suppress arachidonic acid metabolic are arranged, the Tetrandrine that suppresses platelet activating factor, Semen Ginkgo lactone B and kadsurenone, find that also some Chinese medicine or composition by improving cAMP level in the platelet, reduce Ca in the platelet ²⁺Thereby concentration anticoagulant.Along with further illustrating of fibrinolytic mechanism in thrombotic disease pathomechanism and the body, the research of thromboembolism preventing and thrombolytic drug is more and more, and such medicine occupies an important position in the thromboembolism treatment of acute myocardial infarction.The aqueous solution of having found the Chinese medicine Pollen Typhae has the direct fibrinolysis activity that does not rely on fibrinolysin system.Bulbus Allii can obviously reduce plasma fibrinogen, and can directly activate fibrinolysin, and the segment of decomposing the fibrin generation is significantly increased, and Radix Paeoniae Rubra also all can produce thrombolytic effects in different links with the Lumbricus water extract.In a word, the research and development of antithrombotic reagent is very active, and the research of drug mechanism has been deep into molecule and acceptor levels.Although present work obtains many achievements, it is also more to have problems, and subject matter is that the research preparation purity of Chinese medicine is not enough, and impurity is many in the crude preparation by using, and drug effect, the mechanism of action and clinical administration approach are brought significant limitation.Therefore, pure monomer medicine is the main direction of developing from now on.The domestic and international at present research for shikimic acid only is confined to Pharmacological action study, the report of the relevant shikimic acid pharmaceutical preparation of Shang Weijian.Pharmacological research to shikimic acid and derivant thereof focuses mostly on aspect cell toxicant and the antibiosis, does not see relevant research to the blood system effect.In addition, do not see about shikimic acid yet and wait report aspect other pharmacological actions in analgesia.

The object of the invention provides one and has good antithrombotic formation and thrombolytic effect, and pharmaceutical preparation with analgesic activity, this medicine is an active component with shikimic acid (SA-1) and derivant SA-2 (SA-2) thereof, this active component is aboundresources, extract easily, simple in structure, the newtype drug monomer that is easy to synthetic, and untoward reaction is little.

Another object of the present invention provides shikimic acid (SA-1) and the application of derivant in formation of preparation antithrombotic and analgesic medicine thereof.

One of the active ingredient shikimic acid of medicine of the present invention and source of derivant thereof are to be extracted by following method:

Getting the mature peel of Illicium plant, pulverize, is solvent extraction with methanol, concentrates, place, and filtering-depositing, petroleum ether is handled, and the methanol repeated crystallization promptly gets shikimic acid.

Get shikimic acid, add acetic anhydride, drip concentrated sulphuric acid again, place, reactant is added to shake in the frozen water mixes, place, upper aqueous layer is with chloroform extraction, with this chloroform dissolution process lower floor reactant again, and the washing chloroform, the reclaim under reduced pressure chloroform promptly gets shikimic acid triacetyl thing.

Medicine of the present invention contains the shikimic acid and the derivant thereof of effective dose, the preferred SA-2 of said shikimic acid derivative.

Medicine of the present invention contains the shikimic acid and the derivant thereof of 1%-99% weight portion, the preferred SA-2 of said shikimic acid derivative.

Medicine of the present invention preferably contains the shikimic acid and the derivant thereof of 10%-80% weight portion, the preferred SA-2 of said shikimic acid derivative.

Medicine of the present invention more preferably contains the shikimic acid and the derivant thereof of 20%-60% weight portion, the preferred SA-2 of said shikimic acid derivative.

Medicine the best of the present invention contains the shikimic acid and the derivant thereof of 25% weight portion, the preferred SA-2 of said shikimic acid derivative.

Medicine of the present invention is except that shikimic acid that contains effective dose and derivant thereof, also contain in the pharmaceutics field drug excipient commonly used, for example, solvent, filler, flavoring agent, disintegrating agent, binding agent, lubricant, wetting agent, pigment, solubilizing agent, diluent, thickening agent etc.

According to the preparation technique of routine, medicine of the present invention can be prepared into any pharmaceutical preparation that is suitable for clinical use, for example, and pill, tablet, powder, injection, oral liquid, capsule, suspensoid, unguentum, granule, injectable powder, masticatory etc.

The preparation method of medicinal tablet of the present invention is as follows:

Component:

Shikimic acid 25 grams

Icing Sugar 22 grams

Starch 43 grams

10% starch slurry is an amount of

Magnesium stearate 0.5 gram

Make 1000

Method for making:

With shikimic acid, Icing Sugar pulverize separately, sieve, mix homogeneously, add starch slurry and stir evenly, the amount that adds starch slurry is advisable to reach the degree that is suitable for granulating, with the granulation of 16 order nylon mesh, 60 ℃ of dryings add the magnesium stearate mixing, tabletting, every contains 25 milligrams of shikimic acids.

The preparation method of drug injection of the present invention is as follows:

Component:

Shikimic acid 25 grams

Sodium chloride 9 grams

Water for injection adds to 1000 milliliters

Method for making:

Get 800 milliliters of waters for injection, add the sodium chloride stirring and dissolving, add shikimic acid again and make it dissolving, add water to capacity again, stirring, filtration, embedding, the sterilization in 30 minutes of 100 ℃ of flowing steams, promptly.

Medicine of the present invention and existing antithrombotic compare, have good antithrombotic and form and thrombolytic effect, and have effects such as analgesia, analgesic, antiinflammatory.And its active ingredient medicine monomer aboundresources, extract easily, simple in structure, be easy to synthetic.Shikimic acid (SA-1) and derivant SA-2 (SA-2) thereof have good anti-thrombosis function through the pharmacological evaluation proof, and its triacetyl derivant then can be strengthened its effect, also has thrombolytic effect again, be the newtype drug of the little treatment thrombotic disease of a kind of good effect and untoward reaction.Experimental example 1 shikimic acid anti-thrombosis function experimentation 1. shikimic acids influence experiment material (1) animal to rat artery and vein bypass thrombosis: Wistar kind male rat body weight 250g～350g Institute of Experimental Animals, Chinese Academy of Medical Sciences breeding field provides, and the quality certification is numbered (word is moved in the capital) 9201-R018 number.(2) be subjected to reagent: the pure product of shikimic acid are provided by professor Guo Yajian of medicine research department of this Beijing University of Chinese Medicine, preserve in the exsiccator.With the fresh preparation of normal saline, transfer pH=7 with 1N NaOH solution during use, injection for intravenous is used.(3) instrument: LIBROR AEG-220 type electronic balance, Japanese SHMADEE company product.Method and result get rat and are divided into 9 groups at random, and promptly matched group, shikimic acid 400mg/kg group, 100mg/kg group, 50mg/kg group, 25mg/kg organize, heparin 140 μ/only, ligustrazine 50mg/kg group, 25mg/kg group.Lumbar injection pentobarbital sodium 50mg/kg anesthesia is faced upward the position and is fixed, and operation on neck separates right common carotid artery and left external jugular vein.Get three sections polyethylene tubes (two sections long respectively 10cm, internal diameter 1mm, middle segment length 8cm, internal diameter 2mm), in the stage casing, put into number silk thread (weighing in advance) of a long 5cm, connect two sections tubules again.(50 μ/ml), be full of tube chamber, an end of pipe inserts left external jugular vein, other end insertion right common carotid artery to inject heparin-saline solution from an end.The operation finish after immediately by vena femoralis injection medicine (administration group) and normal saline (matched group), open blood flow, Herba Clinopodii in after 15 minutes, taking out silk thread rapidly weighs, gross weight deducts the line line and heavily is thrombus weight, baking was weighed after 1 hour in 60 ℃ of baking boxs, deducted silk thread and heavily was the thrombosis dry weight.Calculate suppression ratio by following formula.

Table 1 shikimic acid influences group dosage number of animals wet weight of thrombus suppression ratio thrombosis dry weight suppression ratio to rat arteriovenous shut thrombosis

(mg/kg) (n) (mg) (mg) (mg) (%) matched group-11 25.9 ± 12.2 6.7 ± 3.7-shikimic acids 400 10 9.1 ± 4.9 ^*65 2.8 ± 1.5 58.2 shikimic acids 200 10 5.9 ± 2.7 ^{* *}77 1.6 ± 1.2 76.1 shikimic acids 100 10 0.2 ± 3.8 ^{* *}76 1.8 ± 1.2 73.1 shikimic acids 50 10 12.5 ± 8.1 ^*52 2.4 ± 1.8 64.2 shikimic acids 25 10 8.6 ± 3.3 ^*67 1.8 ± 1.3 73.1 ligustrazine 50 11 10.9 ± 4.9 ^{* *}58 2.4 ± 1.8 64.2 ligustrazine 25 12 8.6 ± 2.3 ^{* *}67 1.8 ± 1.1 73.1 liver ropes, 140 μ/only 10 2.2 ± 1.0 ^{* *}92 0.3 ± 0.3 95.5 ^*With ^{* *}: with relatively P＜0.01 and P＜0.001 table 1 result demonstration of matched group, intravenous injection shikimic acid 400mg/kg～25mg/kg has the effect of antagonism artery-vein loop thrombosis, and action intensity and ligustrazine are similar.But do not see obvious and the dose-effect relationship of rule.2. shikimic acid is to the thrombotic experiment material that influences of rat carotid artery: (1) animal: Wistar kind male rat body weight 250g～350g, provided by laboratory animal experiment institute of Chinese medicine institute breeding field, the quality certification is numbered (word is moved in the capital) 9209-R018 number.(2) be subjected to reagent: the pure product of shikimic acid are provided by this school medicine professor Guo Yajian of teaching and research room, and exsiccator is preserved.The fresh preparation of normal saline service time is transferred pH=7 with 1N NaOH solution, for quiet notes.(3) instrument: the experimental thrombus in vivo of BT87-3 type forms analyzer, the development of packet header medical college.Method and result: rat is divided into 5 groups at random, lumbar injection barbital sodium 50mg/kg anesthesia.Face upward the position and be fixed on the operating-table, cut skin of neck, the stimulating electrode that separate right carotid 3cm, BT877-3 type experimental thrombosis is formed analyzer is placed in the tremulous pulse proximal part, and the temperature sensing electrode is placed in distal end, two electrode spacing 2.5cm.With electrode be fixed on the operation stand, operation finishes back administration group respectively at vena femoralis injection shikimic acid solution 400mg/kg, 200mg/kg, 100mg/kg, heparin group gives 1% heparin solution 0.1ml/ only, the capacity normal saline such as to give according to group.Start thrombosis instrument switch after the administration, give 1.5m ν galvanic stimulation 7 minutes, with endothelial cell injury, temperature pointer zeroing after 10 minutes, formation along with the intracavity thrombosis, tremulous pulse distal end temperature bust, instrument is reported to the police, and shows obstruction of artery time OT (occlusion time), the results are shown in Table 2.

Table 2 shikimic acid intravenously administrable is to the thrombotic group dosage number of animals thrombus formation time that influences of rat carotid artery

(mg/kg) (only) OT (capacity 10 966.1 ± 125.9 shikimic acid groups 400 10 1432.2 ± 147.2 such as matched group of X ± SD) ^{* *}Shikimic acid group 200 10 1460.6 ± 190.3 ^{* *}Shikimic acid group 100 10 1362.8 ± 127.9 ^{* *}Heparin group 140U/ only 10 1598.8 ± 271.2 ^{* *}Annotate: ^{* *}Compare P＜0.001 with matched group

The result shows: compare with matched group, shikimic acid 400mg/kg group, 200mg/kg group, 100mg/kg have organized significant prolongation thrombus formation time (P＜0.001, P＜0.001, P＜0.001), act on similar person with heparin group, the two is compared does not have significant difference between group.3. shikimic acid is to influence (1) animal of rat postcava thrombosis: Wistar kind male rat, and body weight 300～350g is provided by Institute of Experimental Animals, Chinese Academy of Medical Sciences's breeding field, and the quality certification is numbered (word is moved in the capital) 9209-R018 number.(2) be subjected to reagent and other medicines: the pure product of shikimic acid are provided by this school medicine professor Guo Yajian of research department, with the fresh preparation of normal saline, transfer pH=7 with 1N NaOH solution during use, for quiet notes usefulness, with using for irritating stomach behind 1%CMC (sodium carboxymethyl cellulose) suspendible; The every mg of heparin tires and is 140U, lot number 930412, China Drug Co.'s Beijing purchasing and supply station product.(3) instrument: DF206 electric drying oven with forced convection, Beijing Jing Tong instrument plant product.Method and result: 1. intravenous administration acts on rat ligation postcava thrombosis [1].

Get rat and be divided into 5 groups at random, lumbar injection pentobarbital sodium solution 50mg/kg anesthesia.It is fixing to face upward the position, opens abdomen and separates postcava.By the vena femoralis injection administration, the shikimic acid group is given shikimic acid solution 400mg/kg, 200mg/kg, 100mg/kg respectively, and heparin group gives 0.1% heparin 0.1ml/ only, and matched group is given and waited the capacity normal saline.After the administration below postcava vena renalis dextra bifurcation the ligation postcava, with No. 5 silk threads caval vein is tightened.Sew up stomach wall, open abdomen after 6 hours again, 2cm place folder closes blood vessel below binding place, cuts tube chamber open, and removal of thromboses claims weight in wet base, bakes then to claim dry weight after 1 hour in 60 ℃ of baking boxs, the results are shown in Table 3.

The quiet notes of table 3 shikimic acid to rat ligation postcava thrombotic influence organize other dosage number of animals wet weight of thrombus (the thrombosis dry weight of X ± SD) (X ± SD)

(mg/kg) (only) (mg) capacity 8 30.2 ± 8.0 10.0 ± 3.9 shikimic acid groups 400 8 33.9 ± 22.0 11.1 ± 7.0 shikimic acid groups 200 8 10.6 ± 6.6 such as (mg) matched group ^{* *}2.6 ± 1.7 ^{* *}Shikimic acid group 100 8 19.4 ± 9.7 ^*5.6 ± 2.8 ^*Heparin group 140U/ only 8 1.8 ± 1.2 ^*0. ± 0.5 ^*Annotate: ^{* *}P＜0.001 ^*P＜0.05

The result shows: compare with matched group, shikimic acid 200mg/kg group has reduced thrombosis significantly and has done weight in wet base (P＜0.001), and the effect of shikimic acid 100mg/kg group is (P＜0.05) obviously.The effect of shikimic acid 400mg/kg group is not obvious.2. oral successive administration to rat ligation postcava thrombotic influence get rat and be divided into 4 groups at random, the shikimic acid group is irritated a shikimic acid 1%CMC of stomach solution 400mg/kg, 200mg/kg every day; The aspirin group is irritated stomach aspirin 1%cmc solution 30mg/kg.Matched group is given and is waited capacity 1%CMC.Successive administration 3 days, last administration operation in 60 minutes.Observe the thrombotic influence of ligation postcava, method is seen this model intravenously administrable part, the results are shown in Table 4.

The oral shikimic acid of table 4 is to the thrombotic influence of rat ligation postcava (successive administration) group dosage number of animals wet weight of thrombus thrombosis dry weight

(mg/kg) (only) (mg) (mg) matched group 100 5 20.4 ± 20.5 7.4 ± 7.8 aspirin groups 30 6 45.7 ± 40.0 15.1 ± 12.7 shikimic acid groups 400 4 9.5 ± 6.2 ^*2.8 ± 1.7 ^*Annotate shikimic acid group 200 5 32.0 ± 22.8 18.0 ± 19.8: ^*P＜0.05

The result shows: shikimic acid continuous oral 400mg/kg group has the ligation postcava thrombosis effect (P＜0.05) of inhibition, and oral 200mg/kg group of shikimic acid and the effect of aspirin group are not obvious.4. shikimic acid influences experiment material (1) animal to mouse lung thromboembolism model: Male Kunming strain mice body weight 25～30g is provided quality certification numbering (word is moved in the capital) 8806M038 by laboratory animal supply department of Beijing Medical University.(2) medicine: provided by this school medicine professor Guo Yajian of research department by the pure product of reagent shikimic acid, with the fresh preparation of normal saline,, penetrate usefulness during use for quiet master forever with 1N NaOH pH value of solution=7.The ADP thrombin is a Sigma company product; Adrenalin hydrochloride is commercially available.Method and result

Get 50 of male mices, body weight 25～30g is divided into 5 groups at random.The fresh blood coagulation mixed liquor of joining, pour point depression hemase 5mg dissolves in the 5ml normal saline; ADP1.74mg is dissolved in the 2.5ml normal saline; Get 0.1% epinephrine 0.125ml again.Three kinds of solution are mixed.Get mice respectively at the tail vein injection administration, the shikimic acid group is given shikimic acid solution 200mg/kg, 100mg/kg, 50mg/kg.Matched group is given and is waited the capacity normal saline.Inject thrombin mixed liquor 0.1ml/10g again at every mouse tail vein after 1 minute for said medicine.The record mouse diing time, death toll is calculated mortality rate, the results are shown in Table 5.

Table 5 shikimic acid intravenously administrable influences group dosage number of animals death toll mortality rate death time (X ± SD) to what thrombin brought out the chmice acute pulmonary infarction

(mg/kg) (only) (only) (%) capacity 10 10 100 299.8 ± 116.42 shikimic acid groups 10 10 9 90 313.0 ± 238.08 shikimic acid groups 50 10 5 50 623.1 ± 361.93 Δ shikimic acid groups 100 10 8 80 377.1 ± 319.31 shikimic acid groups 200 10 4 40 663.9 ± 313.32 Δ Δs such as (S) control group annotate: through the meaningful Δ of Chi-square Test, the Δ Δ is compared P＜0.01 with control group

The result shows: control group mice causes pulmonary infarction, and mortality rate is 100%, and quiet notes shikimic acid 200mg/kg group and 50mg/kg group have significantly reduced mortality rate.The two mortality rate is respectively 40%, 50% and significantly prolong the death time (P＜0.01, P＜0.05).Shikimic acid 100mg/lg, the effect of 10mg/kg group is not obvious.5. shikimic acid influences experiment material (1) animal to clotting time: Male Kunming strain mice, body weight 25～30g is provided by laboratory animal supply department of Beijing Medical University, quality certification numbering (word is moved in the capital) 8806M038.(2) medicine: be subjected to reagent: the pure product of shikimic acid are provided by this school medicine professor Guo Yajian of research department, add the fresh preparation of an amount of normal saline after transferring pH with 0.2N NaOH during use.Method and result's 1. shikimic acid intramuscular injection are to the influence (slide method) of clotting time of mice

Get 48 of male mices, be divided into 4 groups at random, administration group injection muscles injection shikimic acid solution 200mg/kg, 100mg/kg, 50mg/kg, matched group respectively such as gives at the capacity normal saline.After 30 minutes, cut off rapidly at distance mouse tail point 1cm place with operation, crowded one bleeds is on the clean microscope slide, the about 5mm of drop of blood diameter, and use manual time-keeping immediately.Stirred gently once inwards from the drop of blood edge with the cleaning pin every 30 seconds after 2 minutes, observation has or not the blood streak to generate, and is clotting time when having the blood streak to provoke.The results are shown in Table 6.

The intramuscular injection of table 6 shikimic acid is to influence (slide method) the group dosage number of animals clotting time of clotting time of mice

(mg/kg) (only) (capacity 12 255 ± 60.7 shikimic acid groups 200 12 257 ± 71.0 shikimic acid groups 100 12 385 ± 62.4 such as matched group of X ± SD) ^{* *}Shikimic acid group 50 12 360 ± 15.3 ^{* *}Annotate: ^{* *}P＜0.001

The result shows: compare with matched group, shikimic acid intramuscular injection 100mg/kg group, 50mg/kg organize significant prolongation clotting time (P＜0.001, P＜0.001).The effect of 200mg/kg group is not obvious.2. the shikimic acid intramuscular injection is to the influence (capillary tube method) of clotting time of mice

Get 80 of male mices, body weight 25～30g is divided into 4 groups at random, and the administration group is intramuscular injection shikimic acid solution 100mg/kg, 50mg/kg respectively, ligustrazine group intramuscular injection Rhizoma Chuanxiong solution 100mg/kg, and matched group is given the equivalent normal saline.Get a capillary glass-tube (long 10cm after 30 minutes, internal diameter 1mm), insert mice endocanthion ball rear vein beard, pick up counting after dark 4～5mm autoblood is filled with tube chamber, take out the hair and blood glass-tube, horizontal positioned, capillary tube two ends 0.5cm fractureed every 30 seconds after 2 minutes, and slowly draw back, whether have clotting strands occur, be clotting time when having clotting strands to occur if observing.The results are shown in Table 7.

The intramuscular injection of table 7 shikimic acid is to influence (capillary glass-tube method) the group dosage number of animals clotting time of clotting time of mice

(mg/kg) (only) (capacity 20 199.5 ± 38.04 shikimic acid groups 100 20 244.5 ± 46.98 such as matched group of X ± SD) ^*Shikimic acid group 50 20 240.0 ± 38.93 ^*Ligustrazine group 100 20 247.5 ± 51.39 ^*Annotate: ^*P＜0.01

The result shows: compare with matched group, shikimic acid 100mg/kg group prolongs clotting time effect significantly (P＜0.01, P＜0.001), act on similarly with ligustrazine, the two is compared does not have significant difference between group.3. shikimic acid is observed the dose-effect relationship that influences of clotting time: experiment material (1) animal: Kunming mouse, body weight 18～22g is provided by laboratory animal supply department of Beijing Medical University, quality certification numbering (word is moved in the capital) 8806M038.(2) be subjected to reagent: the pure product of shikimic acid are provided by this school medicine professor Guo Yajian of teaching and research room, and now with the current before injection every day, solution is transferred pH to 6.5～7.0 with 0.5N NaOH.Method and 80 of mices as a result, be divided into 4 groups at random by body weight: shikimic acid 8mg/kg, 40mg/kg, 200mg/kg (the dosage ratio is 1: 5: 25) and normal control group, administration group intraperitoneal injection every day once, matched group waits the normal saline of capacity, continuous 18 days, during respectively at administration the 4th day, the 8th day, the 11st day, the 15th day and the 18th day, get blood with capillary tube from the eyeball of mouse venous plexus, fractureed capillary tube once every 15 seconds, inspection has or not blood coagulation to occur, and record is got blood and added up to clotting time and between organizing.The results are shown in Table 8.

Table 8 shikimic acid is observed group dosage clotting time (S, X ± SD) to the clotting time of mice dose-effect relationship

(mg/kg) 4 days 8 days 11 days 15 days 18 days control group-98.8 ± 15.1 101.2 ± 40.5 92.6 ± 37.4 103.1 ± 85 103.1 ± 19.9 shikimic acids 8 113.5 ± 26.4 90.2 ± 31.4 75.1 ± 27.4 79.2 ± 25.5 80.0 ± 27.0 shikimic acids 40 158.3 ± 19.3 121.5 ± 34.1 144.9 ± 46.2 161.6 ± 21.1 279.5 ± 84.0 shikimic acid 200 177.0 ± 76.1 126.8 ± 32.8 104.9 ± 27.2 139.4 ± 33.4 216.3 ± 42.0 of administration

Table 8 is the result show, shikimic acid 8mg/kg does not have obvious influence to clotting time.40mg/kg was from administration 4 days to the 18th day, clotting time of mice is prolonged, act on relatively stable, do not find to act on enhanced visible trend with the increase of medication natural law, the effect of 200mg/kg dosage group is not better than 40mg/kg, thereby do not see that obvious dose-effect relationship, this result remain further to be repeated demonstration.The brief summary shikimic acid has anti-thrombosis function, dosage range angular vein injection at dosage 25mg/kg～400mg/kg, the weight in wet base, dry weight, suppression ratio that can alleviate rat artery and vein loop thrombosis are between 52%～77%, also suppress venous thrombosis, alleviate the dry weight and the weight in wet base of the formed thrombosis of ligation postcava.The quiet notes of shikimic acid 50mg/kg～200mg/kg can be to the acute mouse lung thromboembolism due to antithrombase, ADP and the epinephrine mixed liquor, reduce mortality rate, prolong the death time.Shikimic acid 50mg/kg, 100mg/kg and 200mg/kg intramuscular injection can make clotting time of mice prolong, but do not see obvious dose-effect relationship.Experimental example 2 shikimic acid analgesic activity experimentatioies 1. shikimic acid analgesic activities are observed (1) mice hot plate method: experiment material I. animal: the female body weight 18～22g of Kunming mouse, the quality certification number (word is moved in the capital) M139290 number is provided by Institute of Experimental Animals, Chinese Academy of Medical Sciences's breeding field.II. be subjected to reagent: shikimic acid is provided by this school medicine professor Guo Yajian of teaching and research room, uses with the normal saline preparation, and transfers pH to 7.0 with 0.5N NaOH, uses for intramuscular injection; The tetrahydropalmatine injection, drink state, Guangxi area pharmaceutical factory produces lot number 9401001.III. instrument: hot plate method is surveyed threshold of pain device, and (small-sized three use water tank, Xicheng District, Beijing medical apparatus and instruments factory; Plumbous box, stopwatch, thermometer).Method and as a result A. mice is placed on 55 ° of 10.5 ° of water bath with thermostatic control hot plates, be the threshold of pain response time incubation period that record adds metapedes, greater than 30 " discard need not; get 60 of the qualified mices in the threshold of pain; be divided into 5 groups after weighing at random; the normal saline matched group; shikimic acid 50mg/kg; 100mg/kg, the 200mg/kg group, positive control drug tetrahydropalmatine 15mg/kg group, route of administration adopts intramuscular injection, capacity is 0.1ml/20g, and before administration, after the administration 60 ', 120 ', 180 ', 240 ', 360 ' threshold of pain time, and matched group is organized a t check, with not significant difference is relatively arranged before the administration, the results are shown in Table 9.

Table 9 shikimic acid causes the group dosage number of animals administration preceding threshold of pain time that the influences (X ± SD) of pain to the mice hot plate method

(mg/kg), 60 ' 120 ' 180 ' 240 ' 360 ' normal saline 200 12 16.60 after (only) administration ± 2.12 15.79 ± 4.78 20.10 ± 6.00 21.61 ± 8.22 20.27 ± 5.57 20.25 ± 5.47 shikimic acid 200 12 17.27 ± 5.14 33.98 ± 18.26 ^*39.47 ± 20.04 ^*31.72 ± 13.98 ^*43.8 ± 32.52 ^*29.82 ± 12.70 ^*Shikimic acid 100 12 20.18 ± 4.39 21.65 ± 8.34 ^*35.33 ± 23.29 ^*20.12 ± 5.05 40.96 ± 28.68 ^*26.80 ± 11.09 shikimic acids 50 12 16.25 ± 3.85 23.25 ± 5.64 ^*27.32 ± 9.11 Δ Δ Δs 28.50 ± 16.54 Δs 24.73 ± 6.13 Δ Δ Δs 21.02 ± 10.12 tetrahydropalmatine 15 12 18.46 ± 3.88 31.38 ± 11.30 ^{* *}36.97 ± 14.13 34.48 ± 21.15 34.10 ± 19.14 30.12 ± 16.12 ^{* *}, ^*With ^*: compare P＜0.001 with matched group, P＜0.01 and P＜0.05 Δ Δ Δ, Δ Δ and Δ: with comparison P＜0.001 before the administration, P＜0.01 and P＜0.05B. get 60 of the qualified mices of Fructus Vitis viniferae threshold, grouping and the same A of medication, 15 ', 30 ', 60 ', 120 ' and 180 ' surveys the mice threshold of pain time after administration, between statistics administration group and the matched group, after the administration with before the administration not significant difference is arranged.The results are shown in Table 10.

Table 10 shikimic acid causes the group dosage number of animals administration preceding threshold of pain time that the influences (X ± SD) of pain to the mice hot plate method

(mg/kg), 15 ' 30 ' 60 ' 120 ' 180 ' physiological saline 200 12 16.58 after (only) administration ± 4.27 13.70 ± 3.63 15.56 ± 5.49 15.66 ± 5.92 17.00 ± 7.18 16.88 ± 7.37 shikimic acids 200 11 14.47 ± 2.83 17.07 ± 6.33 13.87 ± 3.53 20.13 ± 7.40 Δs, 19.82 ± 4.21 Δ Δ Δs^*29.73 ± 17.61 ^*Shikimic acid 100 12 16.577 ± 3.99 17.31 ± 7.52 17.25 ± 5.90 21.81 ± 5.20 Δs ^*26.27 ± 10.52 19.37 ± 5.84 shikimic acid 50 12 15.40 ± 2.83 18.89 ± 7.13 ^*18.10 ± 6.25 25.68 ± 9.17 Δ Δs ^*29.51 ± 14.52 Δ Δs ^*29.68 ± 12.64 Δ Δ Δs ^*Tetrahydropalmatine 60 12 19.14 ± 3.80 40.55 ± 16.56 ^{* *}43.82 ± 15.88 ^{* *}46.83 ± 16.99 ^{* *}34.81 ± 19.51 ^*32.70 ± 18.74 ^*Remarks: ^{* *}, ^*With ^*: with normal saline comparison P＜0.001, P＜0.01 and P＜0.05 Δ Δ Δ, Δ Δ and Δ: with comparison P＜0.001 before the administration, P＜0.01 and P＜0.05

Hot plate method experiment showed, that shikimic acid 50mg/kg, 100mg/kg, 200mg/kg all have analgesic activity, and acting on the obvious time is 1h, sustainable 4～6h.Effect is slower than tetrahydropalmatine onset time, but the persistent period obviously is longer than tetrahydropalmatine.C. the oral administration shikimic acid is got 70 of mices to the effect of mice hot plate method, is divided into 7 groups (seeing Table 11) at random and irritates when stomach gives 1h, 2h after the Folium illicii Lanceolati acid aspirin administration of various dose, 3h, 4h and survey the threshold of pain, the results are shown in Table 11.

Table 11 shikimic acid to the impact of hot plate method in mice induced pain (before the medicine animals administer of X ± SD) after the mouse administration different time mouse pain (S) and dosage count the threshold of pain (S) 1h 2h 3h 4h control group 10 12.3 ± 2.1 13.9 ± 7.6 14.8 ± 7.3 20.5 ± 7.9 15.5 ± 9.5 shikimic acid 0.6g/kg and organize 10 15.0 ± 2.8 41.4 ± 17.1 Δ Δs^*23.9 ± 7.7 Δ Δs ^*20.6 ± 9.1 Δ Δs 17.1 ± 5.0 shikimic acid 0.4g/kg organize 10 14.6 ± 3.3 19.4 ± 7.3 18.7 ± 7.4 31.6 ± 9.5 ^*22.3 ± 9.5 Δ shikimic acid 0.2g/kg organize 10 12.6 ± 3.9 15.2 ± 4.2 20.2 ± 8.4 Δ Δs, 24.7 ± 11.9 Δ Δs, 27.8 ± 9.3 Δ Δ shikimic acid 0.1g/kg and organize 10 16.1 ± 2.9 16.3 ± 4.4 14.7 ± 4.1 18.6 ± 5.2 21.8 ± 8.3 aspirin 0.4g/kg and organize 10 11.0 ± 2.8 14.0 ± 4.4 20.1 ± 10.9 Δs 14.5 ± 5.2 20.0 ± 10.1 Δ aspirin 0.2g/kg and organize 10 16.1 ± 3.7 20.5 ± 4.8 Δs^*18.9 ± 3.0 ^*26.0 ± 11.1 28.7+7.7 Δ Δs ^*Annotate: compare with matched group: ^*P＜0.05, ^*P＜0.01

With compare before the administration: Δ P＜0.05 Δ Δ P＜0.01

The result shows: the oral 0.6g/kg of shikimic acid, 0.4g/kg, 0.2g/kg have certain analgesic activity, regard as with required dosage bigger than intramuscular injection from dosage.(2) mice acetic acid twisting method experiment material 1. animals: Kunming mouse male and female half and half, body weight 18～22g is provided by Institute of Experimental Animals, Chinese Academy of Medical Sciences's breeding field, the quality certification number (word is moved in the capital) N139290 number.II. medicine: the pure product of shikimic acid are provided by this school medicine professor Guo Yajian of teaching and research room, and matching while using is dissolved in the normal saline, transfer pH=7 with 0.5N NaOH, use as intramuscular injection; Glacial acetic acid is an analytical pure, Beijing Chemical Plant's product; The tetrahydropalmatine injection, Liuzhou Pharmaceutical Factory, Guangxi Autonomous Region produces, lot number 9401001.Experimental result a. gets 100 of mices, male and female half and half, be divided into 5 groups at random after weighing; Normal saline group, shikimic acid 200g/kg, 100g/kg, 80g/kg group, the plain 15mg/kg of Rhizoma Corydalis second.Each organizes intramuscular administration according to dosage, and the 1h pneumoretroperitoneum is injected 0.6% acetum 0.1mg/10g, mouse writhing number of times in 0 '～10 ', 10 '～20 ' time of record, and organize a significance relatively, the results are shown in Table 12.

Table 12 is the result show, intramuscular injection shikimic acid 200mg/kg, 100mg/kg, 50mg/kg all can reduce the mouse writhing number of times, wherein 200mg/kg and 50mg/kg dosage effect highly significant, and tetrahydropalmatine 15mg/kg also has similar effect.B. get 86 of mices, male and female half and half are pressed table 12 grouping, and gastric infusion, and all the other methods the results are shown in Table 13 with experiment a.

Table 13 is the result show, mice orally give shikimic acid 0.6mg/kg, 0.4mg/kg, 0.2mg/kg and 0.1mg/kg Dichlorodiphenyl Acetate induced mice writhing response have obvious antagonism, illustrate that analgesic activity is stronger, with aspirin 0.2mg/kg, the effect of Chlorzoxazone 0.2g/kg is similar.

Table 12 shikimic acid is turned round body number of times (X ± SD) to the group dosage number of animals that influences that mice acetic acid causes pain

Mg/kg (only) 0 '～10 ' 10 '～20 ' normal saline 200 19 28.57 ± 13.86 32.78 ± 10.80 shikimic acids 200 20 16.10 ± 8.75 ^*21.25 ± 10.72 ^*Shikimic acid 100 21 24.00 ± 11.90 27.19 ± 12.37 shikimic acids 50 19 18.52 ± 7.13 ^*21.94 ± 10.54 ^*Tetrahydropalmatine 15 19 15.21 ± 12.00 15.21 ± 11.67 ^{* *}Remarks: and with normal saline P＜0.001 relatively, P＜0.01 and P＜0.605

Table 13 shikimic acid Dichlorodiphenyl Acetate causes the influence of mouse writhing, and (the medicine animal writhing response of X ± SD) is counted incubation period 0～10min, 10～20min matched group, 18 298.3 ± 143.7 19.9 ± 13.5 28.7 ± 9.6 shikimic acid 0.6g/kg for behind the acetic acid different time mouse writhing number of times and dosage and is organized 10 586.0 ± 310.2 ^{* *}7.2 ± 8.1 ^*9.0 ± 7.1 ^*Shikimic acid 0.4g/kg organizes 10 394.3 ± 92.8 ^*5.9 ± 3.6 ^*9.7 ± 3.9 ^*Shikimic acid 0.2g/kg organizes 10 584.9 ± 385.9 ^*6.9 ± 9.0 ^*9.0 ± 9.1 ^*Shikimic acid 0.1g/kg organizes 10 671.2 ± 391.4 ^*3.9 ± 8.7 ^*7.5 ± 7.4 ^*Aspirin tablet 0.1g/kg organizes 10 338.6 ± 98.1 5.6 ± 2.8 ^*10.3 ± 3 ^*Chlorzoxazone 0.2g/kg organizes 18 369.7 ± 172.9 7.4 ± 6.0 ^*12.1 ± 2.3 ^*Annotate: compare with matched group: ^*P＜0.05, ^*P＜hot tail-flick method the experiment material of 0.01 (3) rat light radiation I. animal: the Wistar kind, male, body weight 150～220g is provided by Institute of Experimental Animals, Chinese Academy of Medical Sciences's breeding field, and the quality certification is numbered (word is moved in the capital) 9209-R018 number.II. be subjected to reagent: shikimic acid is provided by this school medicine professor Guo Yajian of teaching and research room, and with the normal saline preparation, and with 0.5N NaOH accent PH to 7.0, for intramuscular injection, tetrahydropalmatine injection, drink state, Guangxi area pharmaceutical factory produces lot number 9401001.III. instrument: heat radiation is measured threshold of pain device, and by the self-control of apparatus guarantee chamber, this school, this teaching and research room supervises.Experimental technique a. gets 50 of male rats, be divided into 5 groups at random, every rat 1/3 place outside its afterbody removes the peel fat with 75% wipes of alcohol earlier, spread charcoal rope ink, be radiated at rat tails blacking place with the halogen lamp under the 18V electric current of voltage regulation after focusing on, the record TFL is less than 30, and " be qualified; after surveying its basic threshold value, each organizes mice intramuscular injection normal saline, shikimic acid 200mg/kg, 100mg/kg, 50mg/kg tetrahydropalmatine 15mg/kg respectively.Respectively at 30 ', 60 ', 120 ' and 180 ' mensuration rat TFL after the administration, and compare between organizing.The results are shown in Table 14.B. get 60 of male rats, be divided into outside 6 groups of each dosage of (seeing Table 15) oral administration at random, measure threshold of pain reaction after the administration when 1h, 2h, 3h, 5h, method the results are shown in Table 15 with experiment a.

Table 14 shikimic acid causes the group dosage number of animals administration preceding threshold of pain time that the influences (X ± SD) of pain to the rat light radiation

(mg/kg) 30 ' 60 ' 120 ' 180 ' normal saline 200 10 6.81 after (only) administration ± 2.44 3.40 ± 0.98 3.88 ± 1.5 23.63 ± 1.97 2.57 ± 0.58 shikimic acid 200 10 7.49 ± 3.08 8.99 ± 5.02 ^*10.49 ± 4.2 39.26 ± 6.44 ^*8.28 ± 4.70 ^*Shikimic acid 100 10 6.82 ± 1.89 4.89 ± 2.03 7.9 ± 4.10 ^*6.27 ± 4.00 4.50 ± 1 .62 ^*Shikimic acid 50 10 6.69 ± 2.19 8.11 ± 3.00 ^{* *}7.28 ± 3.09 ^*8.69 ± 4.89 ^*5.92 ± 4.32 ^*Rhizoma Corydalis second rope 15 10 6.67 ± 3.21 6.69 ± 8.60 ^{* *}15.29 ± 6.20 ^{* *}5.51 ± 2.25 3.70 ± 2.65 remarks: ^{* *}, ^*With ^*: compare P＜0.001, P＜0.01 and P＜0.05 with normal saline

Table 14 is the result show: the normal saline control rats repeatedly radiation cause the pain after, responsive to the pain reaction, the whipping time is between 2.57 seconds-3.88 seconds, intramuscular injection shikimic acid 200mg/kg, 100mg/kg, 50mg/kg all have analgesic activity. with significant difference (P＜0.05, P＜0.01 and P＜0.001) is relatively arranged with time normal saline group.Action intensity is weaker than tetrahydropalmatine, but longer duration.

Table 15 shikimic acid is to the influence of rat radiostimulation whipping reaction, (different time mice pain after the mice administration before the medicine animals administer of X ± SD), (S) and dosage count the threshold of pain, (S.) 1h 2h 3h 4h matched group 10 7.6 ± 2.4 6.2 ± 3.7 5.6 ± 2.6 7.8 ± 4.4 9.1 ± 6.8 shikimic acid 0.4g/kg organize 10 8.5 ± 3.0 15.4 ± 5.0 Δ Δs ^*15.6 ± 5.1 Δ Δs ^*10.0 ± 4.6 7.7 ± 5.1 shikimic acid 0.2g/kg organize 10 7.5 ± 2.9 13.5 ± 5.0 Δ Δs ^*8.2 ± 5.8 10.7 ± 6.2 8.8 ± 6.8 shikimic acid 0.1g/kg organize 10 7.2 ± 3.6 8.5 ± 4.1 7.7 ± 4.6 8.7 ± 4.6 5.9 ± 4.9 aspirin 0.4g/kg and organize 10 7.5 ± 2.8 12.6 ± 5.6 Δ Δs ^*13.4 ± 5.2 Δ Δs ^*12.9 ± 5.3 Δs 5.5 ± 2.1 aspirin 0.2g/kg organize 18 6.4 ± 3.4 19.0 ± 3.3 Δs ^*15.3 ± 5.1 Δ Δs ^*12.3 ± 6.3 Δs ^*8.3 ± 6.6 annotate: compare with matched group: ^*P＜0.05, ^*P＜0.01

With compare before the administration: Δ P＜0.05 Δ Δ P＜0.01 table 15 result proves that shikimic acid oral administration 0.4mg/kg, 0.2mg/kg, 0.1mg/kg all can make the threshold of pain response time prolong, wherein 0.4mg/kg and 0.2mg/kg dosage group and matched group relatively have significant difference.Effect and aspirin, Chlorzoxazone is similar, there was no significant difference between group.Brief summary mice hot plate method, mice acetic acid twisting method, rat radiation thermic pain method prove, shikimic acid 50mg/kg, 100mg/kg, 200mg/kg intramuscular injection and oral administration have obvious analgesic activity, can keep action time more than 6 hours, action intensity and aspirin, Chlorzoxazone are similar, the drug administration by injection effect is weaker than Rhizoma Corydalis second element, but is longer than tetrahydropalmatine action time.2. shikimic acid analgesia characteristics research experiment material I. animal: Wistar kind male rat, body weight 180～220g is provided by Institute of Experimental Animals, Chinese Academy of Medical Sciences's breeding field, and the quality certification is numbered (word is moved in the capital) 9209-R018 number; Male Kunming strain mice, body weight 18～22g is provided by Chinese Academy of Medical Sciences's institute breeding field, the quality certification number (word is moved in the capital) M139290 number.II. medicine: be subjected to reagent: shikimic acid is provided by this school medicine professor Guo Yajian of teaching and research room, and with the normal saline preparation, 0.5N NaOH transfers pH to 7.0 to use for intramuscular injection; Pentobarbital sodium, the import packing of purchasing station, China Drug Co. Beijing; Prednisone acetate tablets: Tianjin Lik-Sang pharmaceutical factory product, lot number 940806; Beer yeast: BJ Beer Factory produces: antondin: Datong District's curry favour reaches pharmaceutical factory's product, lot number 921229.III. instrument: MK-ANIMEX mice autonomic activities instrument, Japan produce.The Synergism Testing of method and result (1) shikimic acid and pentobarbital sodium: get 40 of male mices, be divided into 4 groups (seeing Table 16) at random, each organizes intramuscular injection according to dosage, 5 ' pneumoretroperitoneum injection pentobarbital sodium 30mg/kg, with righting reflex loss and the time between reappearing be the length of one's sleep, not diversity is arranged between observation group.See Table 16.

Table 16 shikimic acid influences group dosage number of animals righting reflex loss to the pentobarbital sodium hypnotic and counts the length of one's sleep (X+S)

Mg/kg, (only), (only), (branch) normal saline+penta 200 10 7 33.43 ± 18.04 shikimic acid+penta 200 10 8 41.75 ± 28.27 shikimic acid+penta 100 10 8 26.63 ± 11.07 shikimic acid+penta 50 10 7 45.43 ± 3.68

The above results shows that shikimic acid acts on no obvious synergistic or antagonism to the eye of urging of pentobarbital sodium.(2) shikimic acid is got 110 of mices to the influence of mice autonomic activities, male and female half and half, be divided into 5 groups at random, difference intramuscular injection normal saline, shikimic acid 200mg/kg, 100mg/kg, 50mg/kg tetrahydropalmatine 15mg/kg, after administration, observe mice autonomic activities situation in 6 ' in 60 ', 180 ', 360 ' the mice autonomic activities instrument, the results are shown in Table 17

Table 17 shikimic acid influences group dosage number of animals autonomic activities number of times (6 ') (X+S) to the mice autonomic activities

(mg/kg) (only) 1h 3h 6h physiological saline 200 22 741.50 ± 144.60 559.36 ± 167.09 592.00 ± 119.07 shikimic acid 200 22 743.36 ± 126.89 551.00 ± 173.47 529.32 ± 160.87 shikimic acids 100 22 786.41 ± 58.75 594.23 ± 130.47 586.91 ± 78.40 shikimic acid 50 22 733.73 ± 54.66 581.86 ± 145.26 524.95 ± 169.85 tetrahydropalmatines 15 22 618.00 ± 151.52^*528.23 ± 117.83 586.91 ± 103.84

The above results shows, intramuscular injection shikimic acid 200mg/kg, 100mg/kg, 50mg/kg and normal saline group are relatively, mice autonomic activities number of times no significant difference, and can reduce the mice activity significantly 60 ' time to the tetrahydropalmatine group, and relatively there are significant difference in numerical value and normal saline group, recover normal in the time of 180 ', illustrate that the intramuscular injection shikimic acid is to maincenter unrestraint or excitation.(3) observation of shikimic acid refrigeration function is got male big or small 50 to the influence that beer yeast method causes the heating rat, by body weight, divide 5 groups at random, surveyed the normal saline suspension of normal thermometric back part subcutaneous injection 10% beer yeast, survey the anus temperature behind the 5h, raise about 1 ℃, the intramuscular injection normal saline, shikimic acid 200mg/kg, 100mg/kg, 50mg/kg and lumbar injection positive control drug antondin 0.15mg/100g, 1h, 2h, 3h, 5h survey the anus temperature after administration, significant difference between the statistics group the results are shown in Table 18.

Table 18 shikimic acid influences body temperature (X+S) after the basis administration of group dosage number of animals to what beer yeast caused that rat temperature raises

(mg/kg) 1h 2h 3h 5h normal saline 200 10 37.10 ± 0.61 38.32 ± 0.61 39.28 ± 0.24 38.31 ± 0.52 38.07 ± 0.48 37.34 ± 0.62 shikimic acid 200 10 37.23 ± 0.59 38.40 ± 0.67 38.26 ± 1.02 before the administration of (only) body temperature ^*37.56 ± 0.67 ^*37.47 ± 0.41 ^*37.1 ± 0.71 shikimic acid 100 10 37.02 ± 0.63 38.44 ± 0.52 37.22 ± 1.01 ^{* *}37.83 ± 0.62 37.40 ± 0.43 ^*36.88 ± 0.69 shikimic acid 50 10 37.16 ± 0.73 38.17 ± 0.63 37.95 ± 0.96 ^{* *}37.58 ± 0.78 ^*37.92 ± 0.54 37.16 ± 0.59 antondin 105 10 37.10 ± 0.61 38.72 ± 0.63 36.45 ± 0.85 ^{* *}36.71 ± 0.83 ^{* *}37.02 ± 0.61 ^{* *}37.10 ± 0.69 remarks: ^{* *}, ^*With ^*: compare P＜0.001, P＜0.001 and P＜0.05 with the normal saline group

The above results shows, three dosage groups of intramuscular injection shikimic acid raise at the rat temperature that 1h, 2h, 3h all can reduce due to the beer yeast significantly, wherein the stable administration 1h effect of positive control is obvious, body temperature continues to go up when 2h, 3h, the body temperature of administration group then continues to descend, and illustrates that the intramuscular injection shikimic acid has refrigeration function to the rat fever due to the beer yeast.(4) the shikimic acid antiinflammatory action is observed---and on Carrageenan causes the influence of rat paw edema and gets 50 of male rats, body weight 180～200g, be divided into 5 groups at random, the intramuscular injection normal saline, shikimic acid 200mg/kg, 100mg/kg, 50mg/kg, the oral CMC-Na suspension 40mg/kg that gives the positive control drug prednisone, left back foot subcutaneous injection 1% carrageenin 0.01mg/kg behind the 1h, measure to 60 ', 180 ', 300 ', 360 ' the rat toes portion girth behind the carrageenin, calculate swelling degree, statistical result table 19

Table 19 shikimic acid diagonal angle dish glue rat paw edema influence group dosed administration number of animals paw swelling (X ± S)

Mg/kg mode (only) 1h 3h 5h 6h normal saline 200 intramuscular injection 10 0.355 ± 0.146 0.671 ± 0.160 0.945 ± 0.239 0.855 ± 0.202 shikimic acid, 200 intramuscular injection 10 0.180 ± 0.063 ^*0.565 ± 0.118 0.770 ± 0.23 0.855 ± 0.176 shikimic acid 100 intramuscular injection 10 0.280 ± 0.149 0.6778 ± 0.239 0.785 ± 0.207 0.85 ± 0.211 shikimic acid, 50 intramuscular injection 10 0.165 ± 0.136 ^*0.505 ± 0.164 ^*0.705 ± 0.248 ^*0.85 ± 0.169 prednisone 40 oral 10 0.165 ± 0.120 ^*0.300 ± 0.150 ^{* *}0.595 ± 0.286 ^*0.575 ± 0.278 ^*Remarks: ^{* *}, ^*With ^*: compare P＜0.001 with the normal saline group, P＜0.01, P＜0.05 table 18 result shows, the foot swelling of rat acute inflammatory has certain anti-effect due to intramuscular injection shikimic acid 200mg/kg, 100mg/kg, the 50mg/kg on Carrageenan, and 200mg/kg, 50mg/kg effect are more remarkable when administration 1h.The explanation of brief summary shikimic acid analgesic activity characteristics result of study, in the dosage range of analgesic, no central inhibitory action has certain refrigeration function and antiinflammatory action.

Embodiment 1

Shikimic acid 25 grams

Icing Sugar 22 grams

Starch 43 grams

10% starch slurry is an amount of

Magnesium stearate 0.5 gram

Make 1000

With shikimic acid, Icing Sugar pulverize separately, sieve, mix homogeneously, add starch slurry and stir evenly, the amount that adds starch slurry is advisable to reach the degree that is suitable for granulating, with the granulation of 16 order nylon mesh, 60 ℃ of dryings add the magnesium stearate mixing, tabletting, every contains 25 milligrams of shikimic acids.

Embodiment 2

Shikimic acid 25 grams

Sodium chloride 9 grams

Water for injection adds to 1000 milliliters

Get 800 milliliters of waters for injection, add the sodium chloride stirring and dissolving, add shikimic acid again and make it dissolving, add water to capacity, stirring, filtration again, embedding, the sterilization in 30 minutes of 100 ℃ of flowing steams, promptly.

Claims (4)

1, shikimic acid has application in the medicine of anti-thrombosis function in preparation.

2, shikimic acid has application in the medicine of analgesic activity in preparation.

3, SA-2 has application in the medicine of booster action at preparation antagonism thrombosis and analgesic activity.

4, SA-2 has application in the medicine of thrombus effect in preparation.