CN103877208A - Pharmaceutical composition for treating functional dyspepsia - Google Patents

Abstract

The invention provides a pharmaceutical composition for treating functional dyspepsia. The pharmaceutical composition is a preparation prepared by following bulk drugs in parts by weight: 300-500 parts of mangnolia officinalis, 288-360 parts of immature bitter orange, and 150-300 parts of rheum officinale. The invention also provides a preparation method and application of the pharmaceutical composition. The pharmaceutical composition comprising mangnolia officinalis, rheum officinale and immature bitter orange has a reasonable formula, precise compatibility of medicines, significant effect and no toxic or side effects, is small in usage amount and clear and definite in main syndrome to be treated, has functions of promoting circulation of qi and relieving dyspepsia, is applicable to interior excess and stagnation of qi, helps to empty gastrointestinal tract, inhibit gastric juice and protease of the stomach from discharging and improve muscular tension of intestinal canal, and is used for treating functional dyspepsia.

Description

A kind of pharmaceutical composition for the treatment of functional dyspepsia

Technical field

The present invention relates to a kind of pharmaceutical composition for the treatment of functional dyspepsia.

Background technology

Functional dyspepsia (Functional dyspepsia, FD) be above abdominal pain, discomfort, glutted, belch, inappetence and to feel sick etc. be cardinal symptom, get rid of on inspection one group of clinical syndrome of the organic disease that causes these symptoms.In recent years, prevalence is high, and American-European countries's statistics reaches 19%-41%, average 32%; Domestic is 18%-45%, accounts for the 20%-40% of Patients With Digestive Tract Diseases.

The pathogenesis of FD is still not clear, may be extremely in close relations with gastrointestinal movement dysfunction and sensory function, psychology and neural factors and environment, diet, gut hormone, gastric acid and HP infect and participate in falling ill, and strong tea, ethanol, high lipid food, coffee can increase the weight of by induced symptom.(1) gastrointestinal motility dysfunction gastrointestinal motility dysfunction is the main pathogenesis of FD.Mainly comprise slowly (patient FD of 30-80% has this symptom), interdigestive phase and period of digestion power abnormality, gastric food abnormal distribution, duodenogastric reflux, stomach electrical anomaly of gastric emptying.Except stomach and parenteral, also there is biliary motility dysfunction in patient's FD power abnormality.There is gastric emptying, gall bladder emptying simultaneously and fill and delay again in FD patient.Between three, the disorder of mutual relation may be dyspeptic major reason.(2) tetchiness of the abnormal visceral nerve of stomach sensory function may make FD patient increase the reactivity of multiple stimulating factor.When normal person takes food there is receptive relaxation in stomach, and the compliance of stomach increases makes intragastric pressure or coat of the stomach tension force without obvious rising, and stomach tension adjustment makes stomach have different sensitivity to expansion.The mechanism of visceral sense Increased sensitivity may have many.As change, the conduction abnormalities of sensory information or the change of maincenter threshold value of coat of the stomach machinery receptor threshold value.(3) the affecting motilin, Gastrin etc. and can cause that the stomach electricity rhythm and pace of moving things accelerates of gut hormone, NO and gonadal hormone, brings out the generation of spike potential, promotes the emptying of stomach.Somatostatin, glicentin, Gastric inhibitory polypeptide, gastrin etc. have inhibitory action to gastrointestinal motility.Discharge with the NO of the vagus nerve mediation of exciting nerve relevant the power that participates in regulating stomach.FD disease is more common in women, and progesterone, estradiol and lactotropin affect the contraction of smooth muscle and make gastrointestinal tract pass through time lengthening.(4) Nervous and Mental Factors such as psychological Nervous and Mental Factors anxiety or depression and stress state play a role in the morbidity of FD.(5) to infect the effect of HP in FD morbidity be one of current the most controversial problem to HP, the patient 50%FD HP positive.HP infects the effect existence dispute after elimination, FD patient symptom being improved, and not yet determines that at present HP infection and gastrointestinal motility function and sensory function change have irrelevant.(6) other gastric acid; Autonomic nervous dysfunction; Stomach duodenum chronic inflammatory disease etc.

Because the FD cause of disease and pathogenesis are still not clear, doctor trained in Western medicine there is no any special measures aspect treatment, does not have unified standard to follow at present, and not every patient all needs Drug therapy, and placebo may be effectively, and small number of patients can spontaneous remission.Generally, according to different clinical manifestations and possible mechanism of causing a disease, follow principle of individuation, select and formulate corresponding treatment measure and medicine.The traditional Chinese medical science mainly contains differentiation of symptoms and signs for classification of syndrome treatment, the treatment of square foundation plus-minus and special side or Chinese patent drugs for treatment to the Therapeutic Method of FD, is main mainly with differentiation of symptoms and signs for classification of syndrome treatment.Conventional single Chinese medicine and compound has: Fructus Aurantii Immaturus, Fructus Aurantii, Pericarpium Citri Reticulatae Viride, Pericarpium Citri Reticulatae, decoction of four noble drugs, SHENLING BAISHU SAN etc.

Summary of the invention

The object of the present invention is to provide a kind of pharmaceutical composition that can effectively treat functional dyspepsia.The present invention also provides preparation method and the purposes of this pharmaceutical composition.

The invention provides a kind of pharmaceutical composition for the treatment of functional dyspepsia, it is the preparation being prepared from by the crude drug of following weight proportion:

Cortex Magnoliae Officinalis 300-500 part, Fructus Aurantii Immaturus 288-360 part, Radix Et Rhizoma Rhei 150-300 part.

Further, it is the preparation being prepared from by the crude drug of following weight proportion:

400 parts of Cortex Magnoliae Officinalis, 288 parts of Fructus Aurantii Immaturuss, 200 parts of Radix Et Rhizoma Rhei;

Or, 500 parts of Cortex Magnoliae Officinalis, 360 parts of Fructus Aurantii Immaturuss, 250 parts of Radix Et Rhizoma Rhei;

Or, 400 parts of Cortex Magnoliae Officinalis, 360 parts of Fructus Aurantii Immaturuss, 150 parts of Radix Et Rhizoma Rhei;

Or, 300 parts of Cortex Magnoliae Officinalis, 300 parts of Fructus Aurantii Immaturuss, 150 parts of Radix Et Rhizoma Rhei;

Or, 300 parts of Cortex Magnoliae Officinalis, 300 parts of Fructus Aurantii Immaturuss, 300 parts of Radix Et Rhizoma Rhei.

Be preferably, it is the preparation being prepared from by the crude drug of following weight proportion: 400 parts of Cortex Magnoliae Officinalis, 288 parts of Fructus Aurantii Immaturuss, 200 parts of Radix Et Rhizoma Rhei.The present invention finds through long-term experimental observation, this prescription proportioning therapeutical effect the best to functional dyspepsia, and body is had no side effect, be applicable to long-term taking.

Wherein, it is taking the medicated powder of described crude drug or the water of crude drug or extractive with organic solvent as active component, adds the preparation that pharmaceutically conventional adjuvant or complementary composition are prepared from.

Wherein, described preparation is oral formulations.Oral formulations of the present invention refers to through gastrointestinal absorption preparation, and certainly, unexpected except oral formulations, other can all be applicable to the present invention through the dosage form of gastrointestinal absorption.

Further, described oral formulations is capsule, tablet, powder, granule, pill or oral liquid.

The present invention also provides the preparation method of above-mentioned pharmaceutical composition, and it comprises following operating procedure:

(1) weighting raw materials by weight ratio;

(2) crude drug is pulverized, added water or 60-90%v/v ethanol extraction, after extracting solution is concentrated, add the preparation that pharmaceutically conventional adjuvant or complementary composition are prepared from.

Further, the concentration of described ethanol is 75%v/v.

Further, the concrete operations of step (2) are as follows: get crude drug and be ground into coarse powder, decoct with water three times, each 10 times of amounts, extract collecting decoction 1 hour, filter, be concentrated into 60 DEG C of clear paste that record relative density 1.2,60 DEG C of high-pressure dryings, add the preparation that pharmaceutically conventional adjuvant or complementary composition are prepared from.

The present invention also provides the preparation method of above-mentioned pharmaceutical composition, and it comprises following operating procedure:

(1) weighting raw materials by weight ratio;

(2) get Cortex Magnoliae Officinalis, Fructus Aurantii Immaturus, extract as extracting solvent taking water or 60-90%v/v ethanol, obtain extract A;

(3) get Radix Et Rhizoma Rhei, extract as extracting solvent taking water or 60-90%v/v ethanol, obtain extract B; Wherein, step (2) is different from the extraction solvent of step (3);

(4) united extraction thing A and B, adds the preparation that pharmaceutically conventional adjuvant or complementary composition are prepared from.

The present invention also provides the above-mentioned pharmaceutical composition purposes in the medicine of preparation treatment functional dyspepsia.

Further, described medicine is to promote that gastrointestinal tract is emptying, suppress gastric juice and pepsin discharges, the medicine of increase intestinal tube muscular tension.

Medicine of the present invention is taking Cortex Magnoliae Officinalis as monarch drug, and its nature and flavor toil, temperature, return spleen, stomach, large intestine channel.Cure mainly stagnation of QI due to dyspepsia, abdominal distention constipation, retention of dampness in middle-JIAO, dirty painful abdominal mass vomiting and diarrhoea etc." book on Chinese herbal medicine converges and says " cloud: " Cortex Magnoliae Officinalis, alleviating distention in middle-JIAOization is stagnant, the medicine of flat gastric qi is also ".Materia Medica of Decoction cloud: " herbal classic " cloud Cortex Magnoliae Officinalis is controlled apoplexy, cold headache, warming middle-JIAO QI invigorating, the expectorant therapeutic method to keep the adverse QI flowing downwards, thick the intestines and stomach, removes distention and fullness in the abdomen.If fruit is lost heart, fruit QI invigorating and long-pending real, the same use of Radix Et Rhizoma Rhei, can let out real full ... "." Records of Tradition Chinese and Western Medicine in Combination ": Cortex Magnoliae Officinalis, control adverse rising of stomach-QI, feeling sick vomits trembles, and gastric qi pent-up distension pain, is the key medicine of warming the middle warmer and descending qi.

Long-pending real nature and flavor toil, tepor, return spleen, stomach, liver, heart channel, cure mainly in stagnant stop, feeling of fullness distending pain, constipation etc.Materia Medica of Decoction cloud: " long-pending real, dispelling the stagnated QI help with Radix Et Rhizoma Rhei, lead a cow, Natrii Sulfas; This " herbal classic " multiple speech disappears painful abdominal mass also so say QI invigorating.Non-long-pending reality can not be removed painful abdominal mass." " medicine justice " cloud: " amass in fact and specially let out excess of the stomach, convince hard knot by patient analysis, Gu Zhuzhong is dirty to control blood system, treats the interventral reality of umbilicus completely ... by dyspepsia, broken blocked-up chest, relieving constipation is closed, non-this can not be also.For the gas medicine in blood system, only this claims "." Bencao Jingshu " cloud: " it is long-pending real ... the special food stagnation removing of this property of medicine, dispelling the stagnated QI damages true ... therefore the medicine of the strengthening the spleen stomach of meaning, outside non-food stagnation removing, has the merit of tonification also again ".

Radix Et Rhizoma Rhei bitterness is cold, returns spleen, stomach, large intestine, Liver Channel.Cure mainly excess-heat constipation, the accumulation of heat feeling of stuffiness in chest, damp-heat dysentery etc.Materia Medica of Decoction cloud: " Radix Et Rhizoma Rhei, the yin aspect of yin medicine are let out fullly, push away Chen Zhixin, remove old dirt and settling five organs, and meaning as survey disastrous disorder so that peace is as good as, so there is general's name "." modality " cloud: " the main tonneau of Radix Et Rhizoma Rhei is tied poison also, thus can control breast, abdominal distention, stomachache and just close, dysuria, jaundice addiction hematoma pus is controlled on side "." Records of Tradition Chinese and Western Medicine in Combination " cloud: " Radix Et Rhizoma Rhei ... its power is heavy and floating, and to attack certainly as use, lower all disease tumors are gathered ... the intestines and stomach heat is fallen in fact to lead to dryness accumulated in the stomach and intestine.”

Medicine of the present invention is made up of Cortex Magnoliae Officinalis, Radix Et Rhizoma Rhei, Fructus Aurantii Immaturus, reasonable recipe, compatibility are forbidden, evident in efficacy, use amount is little, it is clear and definite to cure mainly syndrome, have no side effect, there is circulation of qi promoting except full merit, be applicable to the card of the interior-excess stagnation of QI, can promote that gastrointestinal tract is emptying, suppress gastric juice and pepsin discharges, the medicine of increase intestinal tube muscular tension, be used for the treatment of functional dyspepsia.

Brief description of the drawings

The impact of Fig. 1 HPWL on normal rabbit duodenum motion

The impact of Fig. 2 HPWL on the pretreated rabbit duodenum motion of atropine

The impact of Fig. 3 HPWL on the pretreated rabbit duodenum motion of dopamine

The impact of Fig. 4 HPWL on the pretreated rabbit duodenum motion of phenylephrine

The impact of Fig. 5 HPWL on the pretreated rabbit duodenum motion of isoproterenol

The impact of Fig. 6 HPWL on the motion of normal rabbit jejunum

The impact of Fig. 7 HPWL on the pretreated rabbit jejunum motion of atropine

The impact of Fig. 8 HPWL on the pretreated rabbit jejunum motion of dopamine

The impact of Fig. 9 HPWL on the pretreated rabbit jejunum motion of phenylephrine

The impact of Figure 10 HPWL on the pretreated rabbit jejunum motion of isoproterenol

The impact of Figure 11 HPWL on normal rabbit Ileum activity

The impact of Figure 12 HPWL on the pretreated rabbit Ileum activity of atropine

The impact of Figure 13 HPWL on the pretreated rabbit Ileum activity of dopamine

The impact of Figure 14 HPWL on the pretreated rabbit Ileum activity of phenylephrine

The impact of Figure 15 HPWL on the pretreated rabbit Ileum activity of isoproterenol

Figure 16 HPWL acute toxicity test in mice body weight

Figure 17 HPWL rat chronic toxicity test body weight (♂)

Figure 18 HPWL rat is for a long time to property test body weight (♀)

Detailed description of the invention

The preparation of embodiment 1 medicine of the present invention

Cortex Magnoliae Officinalis 400g Fructus Aurantii Immaturus 288g Radix Et Rhizoma Rhei 200g

Above three taste raw medicinal materials are made 1000 of capsules altogether.

Above three tastes, are ground into coarse powder, decoct with water three times, and each 10 times of amounts are extracted 1 hour, and collecting decoction filters, and is concentrated into relative density 1.2(60 DEG C survey) clear paste.60 DEG C of high-pressure dryings.60 mesh sieves of granulating after dried cream powder is broken, filling capsule, makes 1000, to obtain final product.

The preparation of embodiment 2 medicines of the present invention

Cortex Magnoliae Officinalis 500g Fructus Aurantii Immaturus 360g Radix Et Rhizoma Rhei 250g

Above three tastes, are ground into coarse powder and add 75% alcohol reflux three times, and each 10 times of amounts are extracted 1 hour, and merge extractive liquid, filters, and is evaporated to relative density 1.2(60 DEG C survey) clear paste.60 DEG C of high-pressure dryings.60 mesh sieves of granulating after dried cream powder is broken, filling capsule, makes 1000, to obtain final product.

The preparation of embodiment 3 medicines of the present invention

Cortex Magnoliae Officinalis 400g Fructus Aurantii Immaturus 360g Radix Et Rhizoma Rhei 150g

Above three tastes, are ground into coarse powder, and Cortex Magnoliae Officinalis, Fructus Aurantii Immaturus add 75% ethanol extraction three times, and each 10 times of amounts, extract 1 hour, and merge extractive liquid, filters, and is evaporated to relative density 1.2(60 DEG C survey) clear paste.Radix Et Rhizoma Rhei decocts with water three times, and each 10 times of amounts are extracted 1 hour, and collecting decoction filters, and is concentrated into relative density 1.2(60 DEG C survey) clear paste.Merge two kinds of extractum, add medicinal micropowder silica gel, mix, 60 DEG C of drying under reduced pressure.Dried cream powder is broken, granulate, cross 60 mesh sieves, filling capsule, makes 1000.

The preparation of embodiment 4 medicines of the present invention

Cortex Magnoliae Officinalis 300g Fructus Aurantii Immaturus 300g Radix Et Rhizoma Rhei 150g

Above three tastes, are ground into coarse powder, and Cortex Magnoliae Officinalis, Fructus Aurantii Immaturus decoct with water three times, and each 10 times of amounts are extracted 1 hour, and collecting decoction filters, and is concentrated into relative density 1.2(60 DEG C survey) clear paste.Radix Et Rhizoma Rhei adds 75% ethanol extraction three times, and each 10 times of amounts, extract 1 hour, and merge extractive liquid, filters, and is evaporated to relative density 1.2(60 DEG C survey) clear paste.Merge two kinds of extractum, mix 60 drying under reduced pressure.Crushed after being dried, crosses 60 mesh sieves, adds magnesium stearate, and tabletting, makes 1000.

The preparation of embodiment 5 medicines of the present invention

Cortex Magnoliae Officinalis 300g Fructus Aurantii Immaturus 300g Radix Et Rhizoma Rhei 300g

Be prepared into capsule by embodiment 1 method.

Illustrate beneficial effect of the present invention by test example below.In following test, described HPWL is pharmaceutical composition of the present invention, is all to prepare according to embodiment 1.

Test example 1 efficiency evaluation research

1 experiment material

1.1 laboratory animal

KM kind mice, male and female half and half, body weight 18～22g, SPF level, is provided the quality certification number: SCXK(river by Sichuan Provincial Academy of Traditional Chinese Medicine (Traditional Chinese Medicine Research Institute, Sichuan Province) Experimental Animal Center) 2008-19

SD rat, male and female half and half, body weight 180～220g, SPF level, is provided the quality certification number: SCXK(river by Sichuan Provincial Academy of Traditional Chinese Medicine (Traditional Chinese Medicine Research Institute, Sichuan Province) Experimental Animal Center) 2008-19

Japan large ear rabbit, male and female dual-purpose, body weight 2.0～2.5kg, regular grade, is provided the quality certification number: SCXK(river by plant of laboratory animal special commission of Sichuan Province) 2008-14.

1.2 medicines and reagent

Test agent in HPWL, is brown granular, has specificity fragrance, and every g is equivalent to crude drug in whole 4.07g, lot number: 110727, provided by Sichuan Provincial Academy of Traditional Chinese Medicine medicine institute

Itopride Hydrochloride glue (HARBIN PHARMACEUTICAL GROUP CO., LTD. General Pharm. Factory, the accurate word of traditional Chinese medicines: H20030327, lot number: A100621002)

Omeprazole enteric-coated capsules (Harbin Pharmaceutical Group Sanjing Nuojie Prarmaceutical Co., Ltd..The accurate word of traditional Chinese medicines: H20064032)

Charcoal end gum tragacanth (gum tragacanth 3%, activated carbon powder 5%)

Atropine sulfate injection (Taiji Group Xinan Pharmaceutical Co., Ltd., the accurate word of traditional Chinese medicines: H50020044, lot number: 100401)

Dopamine hydrochloride inj (Changzhou Yabang Pharmaceutical & Chemical Co., Ltd., the accurate word of traditional Chinese medicines: H32023366, lot number: 100821)

Adrenalin hydrochloride injection (Tianjin KingYork Amino Acid Co., Ltd., the accurate word of traditional Chinese medicines: H12020526, lot number: 1007071)

Phenylephrine hydrochloride inj (Shanghai Hefeng Pharmaceutical Co., Ltd., the accurate word of traditional Chinese medicines: H31021175, lot number: 101101)

Isoproterenol hydrochloride inj (Shanghai Hefeng Pharmaceutical Co., Ltd., the accurate word of traditional Chinese medicines: H31021344, lot number: 100501)

Methyl orange indicator (Chengdu Ke Long chemical reagent factory, lot number: 20101016)

Phenolphthalein (Chengdu Ke Long chemical reagent factory, lot number: 20101102).

1.3 key instrument

PB-10 acidometer (German Sai Duolisi)

ALLEGRAX-22R High speed refrigerated centrifuge (Beckman Coulter Inc. of the U.S.)

Japan's UV-730 spectrophotometer (Japanese Shimadzu company)

HV-4 in vitro tissue organ constant temperature perfusion system, BL-420S biological function experimental system (Chengdu TME Technology Co., Ltd.).

2 experimental techniques and result

2.1 impacts on Mouse Stomach air emptying function

2.1.1 the impact emptying on normal Mouse Stomach

2.1.1.1 experimental technique

60 of KM kind mices, male and female half and half, by body weight be divided at random Normal group, 3 dosage groups of tested medicine (1.38,2.76,5.52g crude drug in whole kg ^-1bW), positive controls (Itopride Hydrochloride capsule).Not isoconcentration gastric infusion 3d of each dosage group equal-volume, Normal group is filled with in same volume distilled water, gavage volume 0.1ml10g ^-1.Fasting (can't help water) 16 hours before experiment, 20min after last administration, respectively organizes the equal gavage of mice and only (for getting rid of the impact of former gastric thing contrast color, all establishes 2 contrast Mus not to methyl orange for each group) to 0.1% methyl orange 0.2mL/, after 15min, mice is put to death in cervical vertebra dislocation, fast open abdomen exposes full stomach, after ligation cardia and pylorus, stomach is taken out, and cuts off along greater gastric curvature side, gastric content is fully washed in distilled water, pour graduated centrifuge tube into, water is supplied 10ml, 3000rmin ^-1centrifugal 10min, gets supernatant, in 470nm place colorimetric, measures the optical density of solution, deducts this group contrast Mus record average with measured value, calculates methyl orange residual rate by following formula.Result compares between organizing with t inspection.

(preparation of standard pipe reagent: 0.1% methyl orange 0.2mL adds 10mL normal saline to shake up).

2.1.1.2 experimental result

From table 1, HPWL1.38g(crude drug in whole) kg ^-1bW group gastric methyl orange residual rate is lower than Normal group, and statistical discrepancy is (p<0.05) significantly; HPWL5.52,2.76g(crude drug in whole) kg ^-1bW and Normal group relatively have effect trend, but not remarkable (p>0.05) of statistical discrepancy.Therefore can think, HPWL is in trial dosage range, and only low dosage has the effect that promotes gastric emptying.

The table 1HPWL impact emptying on normal Mouse Stomach

Note: with Normal group comparison, ^*p<0.05, ^*p<0.01

2.1.2 the impact on atropine sulfate induced mice gastrointestinal motility Disorder Model gastric emptying

2.1.2.1 experimental technique

72 of KM kind mices, male and female half and half, by body weight be divided at random Normal group, model control group, 3 dosage groups of tested medicine (1.38,2.76,5.52g crude drug in whole kg ^-1bW), positive controls (Itopride Hydrochloride capsule).The same 2.1.1.1 of medication, last administration pneumoretroperitoneum injection atropine sulfate 0.3mgkg ^-1, after modeling, 15min gives methyl orange, the same 2.1.1.1 of all the other methods.

1.2.2 experimental result

From table 2, HPWL1.38,2.76,5.52g(crude drug in whole) kg ^-1bW group gastric methyl orange residual rate all has the trend lower than model control group, but not remarkable (p>0.05) of statistical discrepancy.Therefore can think, HPWL has the effect trend that promotes atropine sulfate induced mice gastrointestinal motility Disorder Model gastric emptying in trial dosage range.

The impact of table 2HPWL on atropine induced mice gastrointestinal motility obstacle mould gastric emptying

Note: with model control group comparison, ^*p<0.05, ^*p<0.01

2.1.3 the impact on adrenalin hydrochloride induced mice gastrointestinal motility Disorder Model gastric emptying

2.1.3.1 experimental technique

72 of KM kind mices, male and female half and half, by body weight be divided at random Normal group, model control group, 3 dosage groups of tested medicine (1.38,2.76,5.52g crude drug in whole kg ^-1bW), positive controls (Itopride Hydrochloride capsule).The same 2.1.1.1 of medication, last administration pneumoretroperitoneum injection adrenalin hydrochloride 0.3mgkg ^-1, after modeling, 15min gives methyl orange, the same 2.1.1.1 of all the other methods.

2.1.3.2 experimental result

From table 3, HPWL1.38,2.76g(crude drug in whole) kg ^-1bW group gastric methyl orange residual rate is all lower than model control group, and statistical discrepancy is (p<0.01) significantly.Therefore can think, HPWL has the effect of obvious promotion adrenalin hydrochloride induced mice gastrointestinal motility Disorder Model gastric emptying in trial dosage range.

The impact of table 3HPWL on epinephrine induced mice gastrointestinal motility obstacle mould gastric emptying

Note: with model control group comparison, ^*p<0.05, ^*p<0.01

2.1.4 the impact on dopamine hydrochloride induced mice gastrointestinal motility Disorder Model gastric emptying

2.1.4.1 experimental technique

72 of KM kind mices, male and female half and half, by body weight be divided at random Normal group, model control group, 3 dosage groups of tested medicine (1.38,2.76,5.52g crude drug in whole kg ^-1bW), positive controls (Itopride Hydrochloride capsule).The same 2.1.1.1 of medication, last administration pneumoretroperitoneum injection dopamine hydrochloride 0.45mgkg ^-1, give methyl orange, the same 2.1.1.1 of all the other methods simultaneously.

2.1.4.2 experimental result

From table 4, HPWL1.38,2.76,5.52g(crude drug in whole) kg ^-1bW group, with model control group comparison, gastric methyl orange residual rate changes all not obvious, and significant difference is remarkable (p>0.05) not.Result demonstration, HPWL has no obvious impact at trial dosage range to dopamine hydrochloride induced mice gastrointestinal motility Disorder Model gastric emptying.

The impact of table 4HPWL on dopamine induced mice gastrointestinal motility obstacle mould gastric emptying

Note: with model control group comparison, ^*p<0.05, ^*p<0.01

2.2 impacts on mouse small intestine propulsion functions

2.2.1 the impact on small intestine movement of mice propulsion functions

2.2.1.1 experimental technique

50 of KM kind mices, male and female half and half, by body weight be divided at random Normal group, 3 dosage groups of tested medicine (1.38,2.76,5.52g crude drug in whole kg ^-1bW), positive controls (Itopride Hydrochloride capsule).Not isoconcentration gastric infusion 3d of each dosage group equal-volume, Normal group is filled with in same volume distilled water, gavage volume 0.1ml10g ^-1.Fasting (can't help water) 16 hours before experiment, 20min after last administration, respectively organizes the equal gavage of mice and gives black charcoal end gum tragacanth suspension, every 0.6ml.After 15min, cervical vertebra dislocation is put to death, and takes out rapidly small intestinal, and small intestinal is pulled into straight line, measures pylorus to the small intestinal total length of ileocecus and pylorus to the distance in forward position, charcoal end, is calculated as follows intestinal propulsion rate.Result compares between organizing with t inspection.

2.1.2.2 experimental result

From table 5, HPWL2.76,5.52g(crude drug in whole) kg ^-1bW group intestinal propulsion rate has the trend higher than Normal group, and statistical discrepancy is remarkable (p>0.05) not.Therefore think, HPWL has the trend that promotes intestinal motility in trial dosage range.

The impact of table 5HPWL on small intestine movement of mice propelling rate

Note: with Normal group comparison, ^*p<0.05, ^*p<0.01

2.2.2 impact atropine sulfate induced mice gastrointestinal motility Disorder Model intestinal being advanced

2.2.2.1 experimental technique

60 of KM kind mices, male and female half and half, by body weight be divided at random Normal group, model control group, 3 dosage groups of tested medicine (1.38,2.76,5.52g crude drug in whole kg ^-1bW), positive controls (Itopride Hydrochloride capsule).The same 2.2.1.1 of medication, last administration pneumoretroperitoneum injection atropine sulfate 0.3mgkg ^-1, after modeling 15min, the equal gavage of each group mice gives charcoal end gum tragacanth suspension, the same 2.2.1.1 of all the other methods.

2.2.2.2 experimental result

From table 6, HPWL1.38,2.76,5.52g(crude drug in whole) kg ^-1bW group intestinal propulsion rate is all higher than model control group, and statistical discrepancy is (p<0.05) significantly.Therefore can think, HPWL has the effect of obvious promotion atropine sulfate induced mice gastrointestinal motility Disorder Model intestinal propulsion in trial dosage range.

The impact of table 6HPWL on atropine induced mice gastrointestinal motility obstacle mould intestinal propulsion

Note: with model control group comparison, ^*p<0.05, ^*p<0.01

2.2.3 impact adrenalin hydrochloride induced mice gastrointestinal motility Disorder Model intestinal being advanced

2.2.3.1 experimental technique

60 of KM kind mices, male and female half and half, by body weight be divided at random Normal group, model control group, 3 dosage groups of tested medicine (1.38,2.76,5.52g crude drug in whole kg ^-1bW), positive controls (Itopride Hydrochloride capsule).The same 2.2.1.1 of medication, last administration pneumoretroperitoneum injection adrenalin hydrochloride 0.3mgkg ^-1, after modeling 15min, the equal gavage of each group mice gives charcoal end gum tragacanth suspension, the same 2.2.1.1 of all the other methods.

2.2.3.2 experimental result

From table 7, HPWL2.76g(crude drug in whole) kg ^-1bW group intestinal propulsion rate is higher than model control group, and statistical discrepancy is (p<0.05) significantly; HPWL1.38,5.52g(crude drug in whole) kg ^-1bW and model control group relatively have effect trend, but not remarkable (p>0.05) of statistical discrepancy.Therefore can think, HPWL is in trial dosage range, and only middle dosage has the effect of obvious promotion adrenalin hydrochloride induced mice gastrointestinal motility Disorder Model intestinal propulsion.

The impact of table 7HPWL on epinephrine induced mice gastrointestinal motility obstacle mould intestinal propulsion

Note: with model control group comparison, ^*p<0.05, ^*p<0.01

2.2.4 impact dopamine hydrochloride induced mice gastrointestinal motility Disorder Model intestinal being advanced

2.2.4.1 experimental technique

60 of KM kind mices, male and female half and half, by body weight be divided at random Normal group, model control group, 3 dosage groups of tested medicine (1.38,2.76,5.52g crude drug in whole kg ^-1bW), positive controls (Itopride Hydrochloride capsule).The same 2.2.1.1 of medication, last administration pneumoretroperitoneum injection dopamine hydrochloride 0.45mgkg ^-1, the equal gavage of each group mice gives charcoal end gum tragacanth suspension, the same 2.2.1.1 of all the other methods simultaneously.

2.2.4.2 experimental result

From table 8, HPWL2.76,5.52g(crude drug in whole) kg ^-1bW group intestinal propulsion rate is higher than model control group, and statistical discrepancy is (p<0.05) significantly; HPWL1.38g(crude drug in whole) kg ^-1bW and model control group relatively have effect trend, but not remarkable (p>0.05) of statistical discrepancy.Therefore can think, HPWL, in trial dosage range, has the effect that promotes dopamine hydrochloride induced mice gastrointestinal motility Disorder Model intestinal propulsion.

The impact of table 8HPWL on dopamine induced mice gastrointestinal motility obstacle mould intestinal propulsion

Note: with model control group comparison, ^*p<0.05, ^*p<0.01

2.3 impacts that normal rat stomach liquid is secreted

2.3.1 experimental technique

60 of SD rats, male and female half and half, by body weight be divided at random Normal group, 3 dosage groups of tested medicine (1.15,2.30,4.60g crude drug in whole kg ^-1bW), positive controls (omeprazole).Not isoconcentration gastric infusion 7d of each dosage group equal-volume, Normal group is filled with in same volume distilled water, gavage volume 1ml100g ^-1.After last administration, water 24h is can't help in fasting, when experiment, under chloral hydrate anesthesia, opens abdominal cavity, ligation pylorus, give to sew up abdominal part after Isodose medicine 1 time via duodenum, fasting is put to death animal after prohibiting water 5h, opens abdominal cavity, ligation cardia, takes out stomach and collects gastric juice, in 3000rmin ^-1centrifugal 15min, draws supernatant, is total gastric juice amount.Gastric acidity determination, with the pH value of acidometer measurement gastric juice.Pepsic mensuration, gets gastric juice 500 μ l and puts into the plastics centrifuge tube with cover of 10mL, adds 0.05molL ^-1hydrochloric acid 7.0mL, shakes up, and puts into two of protein pipe, builds bottleneck, in 37 DEG C of calorstats, hatches 24h, takes out protein pipe, by the length of vernier caliper measurement protein pipe two ends transparent part, averages with the value of four ends.Ask pepsin activity unit=meansigma methods ²× 16, pepsin output=pepsin activity unit × gastric juice amount/5.Result compares between organizing with t inspection.

2.3.2 experimental result

From table 9, HPWL1.15g(crude drug in whole) kg ^-1total gastric juice amount of BW group is lower than Normal group and gastric juice pH value higher than Normal group, and statistical discrepancy is (p<0.05 or 0.01) significantly, HPWL2.30,4.60g(crude drug in whole) kg ^-1bW group relatively has effect trend with Normal group, but not remarkable (p>0.05) of statistical discrepancy.HPWL2.30g(crude drug in whole) kg ^-1bW group pepsin activity is higher than Normal group, and statistical discrepancy is (p<0.05) significantly, HPWL1.15,4.60g(crude drug in whole) kg ^-1bW group relatively has effect trend with Normal group, but not remarkable (p>0.05) of statistical discrepancy.HPWL1.15g(crude drug in whole) kg ^-1total pepsin output of BW group,, statistical discrepancy is (p<0.01) significantly, HPWL2.30,4.60g(crude drug in whole lower than Normal group) kg ^-1bW group relatively has effect trend with Normal group, but not remarkable (p>0.05) of statistical discrepancy.Therefore can think, HPWL low dose has the total gastric juice amount of the pylorus ligation rat of inhibition, pepsin output, the effect of rising gastric juice pH.

The impact of table 9HPWL on normal rat stomach liquid secretion

Note: with Normal group comparison, ^*p<0.05, ^*p<0.01

2.4 impacts on rabbits infestines smooth muscle

2.4.1 the impact on rabbits' isolated duodenum intestinal tube

2.4.1.1 Isolated Duodenum intestinal tube preparation

Healthy Japan large ear rabbit, body weight 1.5～2.0kg, male and female are regardless of, and before experiment, animal fasting be can't help water 24 hours.The head of fiercelying attack causes dusk, takes out rapidly duodenum intestinal tube, is positioned over (NaCL:6.9g, KCL:0.35g, MgSO in the culture dish that contains Kreb ' s liquid ₄7H ₂o:0.29g, K ₂h ₂pO ₄: 0.16g, NaHCO ₃: 2.1g, CaCL ₂: 0.28g, anhydrous glucose: 2g, is mixed with the solution of 1000ml), cut the duodenum intestinal tube of long 10mm, hook in myenteron with metal hanger, one end is placed in the constant temperature perfusion flesh groove containing 37 DEG C of Kreb ' s liquid, one end is connected on tonotransducer, gives 1.0g preload.Every 20min changes 1 Kreb ' s liquid (37 DEG C), and incubation balance 1h tests after muscle specimen activity is stable.

2.4.1.2 grouping and administration

Adopt accumulation method for dosing medicine, dosing interval 2min, accumulation dosing dosage is 2 × 10 ^-5, 4 × 10 ^-5, 8 × 10 ^-5g(crude drug in whole) ml ^-1.Or before dosing, first use atropine (1 × 10 ^-8moll ^-1), dopamine (4 × 10 ^-7moll ^-1), phenylephrine (4 × 10 ^-7moll ^-1), isoproterenol (1 × 10 ^-8moll ^-1) pretreatment adds medicinal liquid again.

2.4.1.3 observation index

Record before administration and the tension force (g) of administration metaduodenum intestinal tube, contraction wave mean amplitude of tide (g), frequency (beat/min) be observation index.Be calculated as follows tension force and amplitude change rate, result adopts administration front and back paired t-test, and the tension force before administration and amplitude change rate are with 0 note.

2.4.1.4 experimental result

2.4.1.4.1 the impact on normal rabbits' isolated duodenum intestinal tube

From table 10, Fig. 1, HPWL is at 2 × 10- ⁵, 8 × 10- ⁵g(crude drug in whole) ml ^-1time, rabbits' isolated duodenum intestinal tube amplitude change rate is all higher than before administration, and significant difference is (p<0.05) significantly; At 4 × 10- ⁵g(crude drug in whole) ml ^-1time have effect trend, but do not there is significant difference (p>0.05).HPWL is at 4 × 10- ⁵g(crude drug in whole) ml ^-1time, rabbits' isolated duodenum intestinal tube muscular tension rate of change higher than administration before, have significant difference (p<0.01); At 2 × 10- ⁵, 8 × 10- ⁵g(crude drug in whole) ml ^-1time have effect trend, but do not there is significant difference (p>0.05), Isolated Duodenum intestinal tube frequency is not affected to (p>0.05).Therefore can think, HPWL, in trial dosage range, has the effect that promotes the motion of rabbits' isolated duodenum intestinal tube.

The impact of table 10HPWL on normal rabbit duodenum motion

Note: with comparison before administration, ^*p<0.05, ^*p<0.01

2.4.1.4.2 on rabbits' isolated duodenum intestinal tube through the pretreated impact of atropine sulfate

From table 11, Fig. 2, HPWL is at 2 × 10- ⁵, 4 × 10- ⁵, 8 × 10- ⁵g(crude drug in whole) ml ^-1time, with the comparison of atropine sulfate group, rabbits' isolated duodenum intestinal tube amplitude change rate, muscular tension rate of change, frequency all do not have significant change, and significant difference is remarkable (p>0.05) not.Therefore can think, HPWL is in trial dosage range, on having no obvious impact through the pretreated rabbits' isolated duodenum intestinal tube of atropine sulfate.

The impact of table 11HPWL on the pretreated rabbit duodenum motion of atropine

Note: with atropine sulfate comparison, ^*p<0.05, ^*p<0.01

2.4.1.4.3 on rabbits' isolated duodenum intestinal tube through the pretreated impact of dopamine hydrochloride

From table 12, Fig. 3, HPWL is at 2 × 10- ⁵, 4 × 10- ⁵, 8 × 10- ⁵g(crude drug in whole) ml ^-1time, rabbits' isolated duodenum intestinal tube amplitude change rate, muscular tension rate of change are all lower than dopamine hydrochloride group, and rabbits' isolated duodenum intestinal tube frequency has the trend higher than dopamine hydrochloride group, but not remarkable (p>0.05) of significant difference.Therefore can think, HPWL, in trial dosage range, has the rabbits' isolated duodenum of inhibition intestinal tube through the pretreated motion effect of dopamine hydrochloride trend.

The impact of table 12HPWL on the pretreated rabbit duodenum motion of dopamine

Note: with dopamine hydrochloride comparison, ^*p<0.05, ^*p<0.01

2.4.1.4.4 on rabbits' isolated duodenum intestinal tube through the pretreated impact of phenylephrine hydrochloride

From table 13, Fig. 4, HPWL is at 2 × 10- ⁵g(crude drug in whole) ml ^-1time, rabbits' isolated duodenum intestinal tube amplitude change rate, muscular tension rate of change all have the trend lower than phenylephrine group, and at 4 × 10- ⁵, 8 × 10- ⁵g(crude drug in whole) ml ^-1there is the trend higher than phenylephrine group, but not remarkable (p>0.05) of significant difference; And rabbits' isolated duodenum intestinal tube frequency has the trend (p>0.05) higher than phenylephrine group.Therefore can think, HPWL, in trial dosage range, has and first promotes to suppress afterwards rabbits' isolated duodenum intestinal tube through the pretreated motion effect of phenylephrine hydrochloride trend.

The impact of table 13HPWL on the pretreated rabbit duodenum motion of phenylephrine

Note: with phenylephrine comparison, ^*p<0.05, ^*p<0.01

2.4.1.4.5 on rabbits' isolated duodenum intestinal tube through the pretreated impact of isoprenaline

By table 14, the visible HPWL of Fig. 5 at 8 × 10- ⁵g(crude drug in whole) ml ^-1time, rabbits' isolated duodenum intestinal tube amplitude change rate, muscular tension rate of change are all lower than isoproterenol group, at 4 × 10- ⁵g(crude drug in whole) ml ^-1time rabbits' isolated duodenum intestinal tube amplitude change rate lower than isoproterenol group, significant difference is (p<0.05) significantly.At 2 × 10- ⁵g(crude drug in whole) ml ^-1time, rabbits' isolated duodenum intestinal tube amplitude change rate, muscular tension rate of change all have the trend lower than isoproterenol group, but not remarkable (p>0.05) of significant difference; To rabbits' isolated duodenum intestinal tube frequency do not have a significant effect (p>0.05).Therefore can think, HPWL, in trial dosage range, has the effect that rabbits' isolated duodenum intestinal tube moves after isoprenaline pretreatment that suppresses.

The impact of table 14HPWL on the pretreated rabbit duodenum motion of isoproterenol

Note: with isoproterenol comparison, ^*p<0.05, ^*p<0.01

2.4.2 the impact on the in vitro jejunum intestinal tube of rabbit

2.4.2.1 in vitro jejunum intestinal tube is prepared in descendant duodenum and intercepts jejunum intestinal tube, the same 2.4.1.1 of all the other methods.

2.4.2.2 grouping and administration, same to 2.4.1.2

2.4.2.3 observation index, same to 2.4.1.3

2.4.2.4 experimental result

2.4.2.4.1 on the impact of the in vitro jejunum intestinal tube of normal rabbit

From table 15, Fig. 6, HPWL is at 2 × 10- ⁵, 4 × 10- ⁵, 8 × 10- ⁵g(crude drug in whole) ml ^-1time, the in vitro jejunum intestinal tube of rabbit muscular tension rate of change is all higher than before administration, at 2 × 10- ⁵g(crude drug in whole) ml ^-1intestinal tube muscular tension rate of change is all higher than before administration, and significant difference is (p<0.05) significantly; At 4 × 10- ⁵, 8 × 10- ⁵g(crude drug in whole) ml ^-1time have effect trend, but not significantly (p>0.05) of significant difference; To the in vitro jejunum intestinal tube of rabbit frequency do not have a significant effect (p>0.05).Therefore can think, HPWL, in trial dosage range, has the effect that promotes the in vitro jejunum intestinal tube motion of rabbit.

The impact of table 15HPWL on the motion of normal rabbit jejunum

Note: with comparison before administration, ^*p<0.05, ^*p<0.01

2.4.2.4.2 on the in vitro jejunum intestinal tube of rabbit through the pretreated impact of atropine sulfate

From table 16, Fig. 7, HPWL is at 2 × 10- ⁵, 4 × 10- ⁵, 8 × 10- ⁵g(crude drug in whole) ml ^-1time, with the comparison of atropine sulfate group, the in vitro jejunum intestinal tube of rabbit amplitude change rate, muscular tension rate of change, frequency all do not have significant change, and significant difference is remarkable (p>0.05) not.Therefore can think, HPWL is in trial dosage range, on having no obvious impact through the in vitro jejunum intestinal tube of the pretreated rabbit of atropine sulfate.

The impact of table 16HPWL on the pretreated rabbit jejunum motion of atropine

Note: with atropine sulfate comparison, ^*p<0.05, ^*p<0.01

2.4.2.4.3 on the in vitro jejunum intestinal tube of rabbit through the pretreated impact of dopamine hydrochloride

From table 17, Fig. 8, HPWL is at 2 × 10- ⁵, 4 × 10- ⁵, 8 × 10- ⁵g(crude drug in whole) ml ^-1time, the in vitro jejunum intestinal tube of rabbit amplitude change rate, muscular tension rate of change all have the trend higher than dopamine hydrochloride group, but not remarkable (p>0.05) of significant difference; To the in vitro jejunum intestinal tube of rabbit frequency do not have a significant effect (p>0.05).Therefore can think, HPWL, in trial dosage range, has the in vitro jejunum intestinal tube of the rabbit of promotion through the pretreated motion effect of dopamine hydrochloride trend.

The impact of table 17HPWL on the pretreated rabbit jejunum motion of dopamine

Note: with dopamine hydrochloride comparison, ^*p<0.05, ^*p<0.01

2.4.2.4.4 on the in vitro jejunum intestinal tube of rabbit through the pretreated impact of phenylephrine hydrochloride

From table 18, Fig. 9, HPWL is at 2 × 10- ⁵, 4 × 10- ⁵, 8 × 10- ⁵g(crude drug in whole) ml ^-1time, with the comparison of phenylephrine group, the effect of the in vitro jejunum intestinal tube of rabbit amplitude change rate, muscular tension rate of change, frequency is all not obvious, and significant difference is remarkable (p>0.05) not.Therefore can think, HPWL is in trial dosage range, on having no obvious impact through the in vitro empty duodenum 12 intestinal tube of the pretreated rabbit of phenylephrine hydrochloride.

The impact of table 18HPWL on the pretreated rabbit jejunum motion of phenylephrine

Note: with phenylephrine comparison, ^*p<0.05, ^*p<0.01

2.4.2.4.5 on the in vitro jejunum intestinal tube of rabbit through the pretreated impact of isoprenaline

From table 19, Figure 10, HPWL is at 2 × 10- ⁵, 4 × 10- ⁵, 8 × 10- ⁵when g/ml, with the comparison of isoproterenol group, the effect of the in vitro jejunum intestinal tube of rabbit amplitude change rate, muscular tension rate of change, frequency is all not obvious, and significant difference is remarkable (p>0.05) not.Result demonstration, HPWL is in trial dosage range, on having no obvious impact through the in vitro empty duodenum 12 intestinal tube of the pretreated rabbit of isoprenaline.

The impact of table 19HPWL on the pretreated rabbit jejunum motion of isoproterenol

Note: with isoproterenol comparison, ^*p<0.05, ^*p<0.01

2.4.3 the impact on rabbit Ileum From A White intestinal tube

2.4.3.1 Ileum From A White intestinal tube is prepared in ileocecus top and intercepts ileum intestinal tube, the same 2.4.1.1 of all the other methods.

2.4.3.2 grouping and administration, same to 2.4.1.2

2.4.3.3 observation index, same to 2.4.1.3

2.4.3.4 experimental result

2.4.3.4.1 the impact on normal rabbit Ileum From A White intestinal tube

From table 20, Figure 11, HPWL is at 8 × 10- ⁵g(crude drug in whole) ml ^-1time, rabbit Ileum From A White intestinal tube amplitude change rate, intestinal tube muscular tension rate of change are all higher than before administration, at 2 × 10- ⁵g(crude drug in whole) ml ^-1time, rabbit Ileum From A White intestinal tube muscular tension rate of change is all higher than before administration, and significant difference is (p<0.05) significantly; At 4 × 10- ⁵g(crude drug in whole) ml ^-1time intestinal tube amplitude change rate is had to the effect trend of inhibition, and intestinal tube muscular tension rate of change is had to the effect trend of promotion, but not significantly (p>0.05) of significant difference; To rabbit Ileum From A White intestinal tube frequency do not have a significant effect (p>0.05).Therefore can think, HPWL, in trial dosage range, has the effect that increases rabbit Ileum From A White intestinal tube muscular tension.

The impact of table 20HPWL on normal rabbit Ileum activity

Note: with comparison before administration, ^*p<0.05, ^*p<0.01

2.4.3.4.2 on rabbit Ileum From A White intestinal tube through the pretreated impact of atropine sulfate

From table 21, Figure 12, HPWL is at 4 × 10- ⁵, 8 × 10- ⁵g(crude drug in whole) ml ^-1time, rabbit Ileum From A White intestinal tube muscular tension rate of change is higher than atropine sulfate group, and significant difference is (p<0.05) significantly, at 2 × 10- ⁵g(crude drug in whole) ml ^-1time have effect trend, but not significantly (p>0.05) of significant difference; HPWL is at 2 × 10- ⁵, 4 × 10- ⁵, 8 × 10- ⁵g(crude drug in whole) ml ^-1time, rabbit Ileum From A White intestinal tube amplitude change rate all has the trend higher than atropine sulfate group, and rabbit Ileum From A White intestinal tube frequency all has the trend lower than atropine sulfate group, but not remarkable (p>0.05) of significant difference.Therefore can think, HPWL, in trial dosage range, has the effect that increases rabbit Ileum From A White intestinal tube muscular tension after atropine sulfate pretreatment.

The impact of table 21HPWL on the pretreated rabbit Ileum activity of atropine

Note: with atropine sulfate comparison, ^*p<0.05, ^*p<0.01

2.4.3.4.3 on rabbit Ileum From A White intestinal tube through the pretreated impact of dopamine hydrochloride

From table 22, Figure 13, HPWL is at 4 × 10- ⁵, 8 × 10- ⁵g(crude drug in whole) ml ^-1time, rabbit Ileum From A White intestinal tube muscular tension rate of change is higher than dopamine hydrochloride group, and significant difference is (p<0.05) significantly, at 2 × 10- ⁵g(crude drug in whole) ml ^-1time have effect trend, but not significantly (p>0.05) of significant difference; HPWL is at 2 × 10- ⁵, 4 × 10- ⁵, 8 × 10- ⁵g(crude drug in whole) ml ^-1time, rabbit Ileum From A White intestinal tube amplitude change rate is equal, frequency has the trend higher than dopamine hydrochloride group, but not remarkable (p>0.05) of significant difference.Therefore can think, HPWL, in trial dosage range, has the effect that increases rabbit Ileum From A White intestinal tube muscular tension after dopamine hydrochloride pretreatment.

The impact of table 22HPWL on the pretreated rabbit Ileum activity of dopamine

Note: with dopamine hydrochloride comparison, ^*p<0.05, ^*p<0.01

2.4.3.4.4 rabbit is returned to duodenum 12 intestinal tube in vitro through the pretreated impact of phenylephrine hydrochloride

From table 23, Figure 14, HPWL is at 2 × 10- ⁵, 4 × 10- ⁵, 8 × 10- ⁵g(crude drug in whole) ml ^-1time, rabbit Ileum From A White intestinal tube amplitude change rate, muscular tension rate of change are all higher than phenylephrine group, significant difference is (p<0.05 or p<0.01) significantly, and rabbit Ileum From A White intestinal tube frequency all has the trend (p>0.05) lower than phenylephrine group.Therefore can think, HPWL, in trial dosage range, has the effect that promotes that rabbit Ileum From A White intestinal tube moves after phenylephrine hydrochloride pretreatment.

The impact of table 23HPWL on the pretreated rabbit Ileum activity of phenylephrine

Note: with phenylephrine comparison, ^*p<0.05, ^*p<0.01

2.4.3.4.5 on rabbit Ileum From A White intestinal tube through the pretreated impact of isoprenaline

From table 24, Figure 15, HPWL is at 2 × 10- ⁵, 4 × 10- ⁵, 8 × 10- ⁵g(crude drug in whole) ml ^-1time, all not obvious to the effect of rabbit Ileum From A White intestinal tube amplitude change rate, muscular tension rate of change, frequency, significant difference is remarkable (p>0.05) not.Therefore can think, HPWL is in trial dosage range, on having no obvious impact through the pretreated rabbit Ileum From A White of isoprenaline intestinal tube.

The impact of table 24HPWL on the pretreated rabbit Ileum activity of isoproterenol

Note: with isoproterenol comparison, ^*p<0.05, ^*p<0.01

Test example 2 acute toxicity test in mice

1 test material

1.1 experimental animal

40 of KM mices, male and female half and half, body weight 18～22g, SPF level.The quality certification number: SCXK(river is provided by Sichuan Provincial Academy of Traditional Chinese Medicine (Traditional Chinese Medicine Research Institute, Sichuan Province) Experimental Animal Center) 2008-19.

1.2 tested medicines

Test agent in HPWL, is brown granular, has specificity fragrance, and every g is equivalent to crude drug in whole 4.07g, lot number: 110727, provided by Sichuan Provincial Academy of Traditional Chinese Medicine study of pharmacy.

Compound method: take when test and be subject to reagent 15.0g(to be equivalent to crude drug in whole 61.05g), add appropriate distilled water and grind evenly, being advisable by No. 16 syringe needles, be finally settled to 33.1ml, obtaining concentration is 1.85g(crude drug in whole) ml ^-1the suspendible medicinal liquid of (100ml suspendible medicinal liquid is approximately equivalent to crude drug in whole 1850g).

2 test methods and result

2.1 mice maximum dosage-feeding assay methods

40 of KM mices, male and female half and half, body weight 18～22g, is divided into 2 groups at random by body weight, i.e. administration group and normal control, dosage is 73.8g(crude drug in whole) kg ^-1bW, 20 every group.Before test, water 16h is can't help in fasting, and it is 1.85g(crude drug in whole that gavage gives concentration) ml ^-1be subject to reagent and same volume distilled water, administration volume 0.4ml10g ^-1, single-dose in a day.After administration, at once observe, and Continuous Observation 14 days, animal per sky body weight change recorded.Give whole body poisoning manifestations and the death condition of observing animal after tested material, comprise animal appearance, behavioral activity, the mental status, two just, skin, by variations such as hair, nose, eye, oral secretion and breathing, circulation, central nervous system.If there is dead animal to carry out eye anatomy observation, in the time having the visible pathological changes of naked eyes, carry out pathological examination.

2.2 result of the test

HPWL is with 73.8g(crude drug in whole) kg ^-1gavage mice of dosage (gavage volume 0.4ml10g of BW ^-1), after administration, a large amount of animals occur closing one's eyes and the movable symptom reducing, and there is prostrate symptom in few animals, and after lasting 15～20min, appearance activity increases (table 25), continues about 2h.Continuous Observation 14 days later, outward appearance, behavioral activity, the mental status, defecation and the color thereof of animal, quilt hair, the colour of skin, breathing, nose, eye, oral secretion are showed no extremely, do not observe specific tissue, organ or system toxicity performance yet, after test, the 1st day administration group body weight has notable difference with Normal group ratio, may suppress to take food relevant with this medicine.Thereafter Mouse Weight is normal growth state (table 26, Figure 16), after off-test, puts to death and dissects animal, and perusal has no obvious pathological change.

Table 25HPWL acute toxicity test in mice Symptom Spectrum

Body weight change before and after table 26HPWL acute toxicity test in mice

Note: with blank group ratio, ^*p<0.05, ^*p<0.01

Test example 3 rat chronic toxicity tests

1 test material

1.1 experimental animal

SD rat, SPF level, body weight 80～100g, 120, male and female half and half, are provided the quality certification number: SCXK(river by Sichuan Provincial Academy of Traditional Chinese Medicine (Traditional Chinese Medicine Research Institute, Sichuan Province) Experimental Animal Center) 2008-19.

1.2 medicines and reagent

Test agent in HPWL, is brown granular, has specificity fragrance, and every g is equivalent to crude drug in whole 4.07g, lot number: 110727, provided by Sichuan Provincial Academy of Traditional Chinese Medicine study of pharmacy.Compound method and preservation condition: get respectively HPWL226.1g(and be equivalent to 920.2g crude drug in whole), 113.1g(is equivalent to 460.3g crude drug in whole), 56.5g(is equivalent to 223.0g crude drug in whole) adding distil water is ground to 500ml, i.e. HPWL long term toxicity test high dose (18.4g crude drug in whole kg respectively ^-1bW), middle dosage group (9.2g crude drug in whole kg ^-1and low dosage (4.6g crude drug in whole kg BW) ^-1bW) group suspendible medicinal liquid.Make up a prescription weekly 2 times, 4 DEG C of refrigerator cold-storages are preserved, and face 1 hour in advance used time and take out and recover administration after room temperature.

Prothrombin time determination reagent box (lot number: 0711061), partial thromboplastin time is measured test kit (lot number: 0611021), AST(aspartate amino transferase, lot number: 0711051), ALT(alanine aminotransferase, lot number: 0911081), ALP(alkali phosphatase, lot number: 0511031), CK(creatine phosphate creatase, lot number: 0511031), TBIL(total bilirubin, lot number: 0711031), TP(total protein, lot number: 0211011), Alb(albumin, lot number: 0511021), TC(T-CHOL, lot number: 0911061), TG(triglyceride, lot number: 0311021), CREA(creatinine, lot number: 0911101), Urea(carbamide, lot number: 0511031), GLU(blood glucose, lot number: 0511031), reticulocyte (lot number: ZA0072), reticulocyte diluent (lot number: G1303) detection kit, provide by Maike Tech Co., Ltd., Sichuan Prov..

Formaldehyde (analytical pure), ethanol (95% analytical pure), sodium chloride (analytical pure) etc. are commercially available.

1.3 key instrument

EB-3200D electronic balance (d=0.01g, Japanese Shimadzu)

MEK-6318K Automatic Blood Cell Analyzer (Japanese photoelectricity)

Hitachi's 7020 type automatic clinical chemistry analyzers (Hitachi of Amada Co., Ltd. new and high technology)

The clinical electrolyte analyser of HC-9883 type (Hang Chuan armarium company limited of Shenzhen)

The semi-automatic coaglation analyzer of CD4001 (German blue ripple)

TSJ-Q type Full automatic closed tissue processor (Changzhou Texlab Electronic Instrument Co., Ltd.)

BMJ-III type embedding machine and pathologic tissue packing freezing stage (Changzhou Texlab Electronic Instrument Co., Ltd.)

LEICA RM2135 microtome

PHY-III type pathological tissue floats and dries instrument (Changzhou Texlab Electronic Instrument Co., Ltd.)

BA400 microscope (Motic)

Image analysis software (Motic Images Advanced)

2 test methods and result

2.1 grouping and administrations

120 of SD rats, in half and half, 5～6 week age of male and female, body weight 80～100g, observes after one week at laboratory rearing, is divided at random 4 groups by body weight and sex: high, medium and low 3 the dosage groups of HPWL, dosage is respectively 18.4g, 9.2g, 4.6g(crude drug in whole) kg ^-1bW and 1 matched group, 30 every group.Special messenger every morning, administration set time, adopts isometric(al) variable concentrations gastric infusion (Normal group is to isometric(al) distilled water), administration volume 1ml100g ^-1, administration 6 days weekly, successive administration 3 months (13 weeks).

2.2 the test period

This research cures mainly according to its function and medicine feature determines that this long term toxicity test cycle is 13 weeks.Restorative observation 2 weeks.

2.3 Reversible observe

In administration, after 13 weeks, each group leaves 1/3 animal not to tested medicine, continues to observe 2 weeks, to understand the degree of reversibility of toxic reaction and the retardance toxicity that may occur.

2.4 observation index

2.4.1 generally performance

The outward appearance sign of every animal of the each group of administration every day fore-and-aft observing, behavioral activity, glandular secretion, breathes, two just situations, each natural hole has or not abnormal secretion thing etc.Before administration, weigh 2 times, administration and drug withdrawal viewing duration record weekly body weight and food-intake 1 time.

2.4.2 hematological indices

After administration, 3 months (13 weeks) and drug withdrawal are observed 2 weeks, only get respectively 2/3(20 for each group), 1/3(10 is only) animal is with 10% chloral hydrate 0.3ml/100g(600mg/kg) abdominal aortic blood after ip anesthesia, Automatic Blood Cell Analyzer is measured WBC(leukocyte), RBC (erythrocyte), HGB (hemoglobin), HCT (packed cell volume), MCV (mean corpuscular volume (MCV)), MCH (mean corpuscular hemoglobin), MCHC (mean corpuscular hemoglobin concentration (MCHC)), RDW-SD (Erythrocyte hemoglobin distribution width-standard deviation), RDW-CV(Erythrocyte hemoglobin distribution width-coefficient of variation), PLT (platelet count), MPV (mean platelet volume), PCT(thrombocytocrit), PDW (the volume of platelets dispersion of distribution), the large platelet ratio of P-LCR(), RET%(Reticulocyte ratio), NEUT%(neutrophilic granulocyte ratio), LY%(lymphocyte ratio), MO%(mononuclear cell ratio), EO%(eosinophilic granulocyte ratio), BASO%(basophilic granulocyte ratio).Semi-automatic coaglation analyzer is measured PT(plasma prothrombin time), APTT(activated partial thromboplastin time).

2.4.3 blood biochemical is learned index

With 2.4.2 method abdominal aortic blood, conventional separation of serum, automatic clinical chemistry analyzer detects ALT (alanine aminotransferase), AST (AST), TP (total protein), ALB (albumin), TBIL (total bilirubin), ALP(alkali phosphatase), GLU (blood glucose), BUN (blood urea nitrogen), CREA (creatinine), TC (T-CHOL), TG (triglyceride), CK (creatine phosphokinase), GLOB(globulin), A/G(albumins/globulins).Electrolyte analyser is measured Na ⁺, K ⁺, Cl ^-.

2.4.4 system becomes celestial and histopathologic examination

Get after blood sacrificed by decapitation animal rapidly by 2.4.2 method, carry out comprehensive system by this laboratory " experimental animal carcass dissection rule of operation " and become celestial.Every animal is carried out to comprehensive system obduction, perusal.Core, liver, spleen, lung, kidney, brain, adrenal gland, thymus, uterus, ovary, testis, epididymis, 13 kinds of substantial visceras such as prostate are weighed, calculate organ coefficient, and rapidly by the heart, liver, spleen, lung, kidney, brain (brain, cerebellum), hypophysis, spinal cord (cervical part of esophagus, breast section, waist section), salivary gland (submaxillary gland), sciatic nerve, aorta, esophagus, trachea, uterus, ovary, mammary gland, testis, epididymis, prostate, thyroid, thymus, pancreas, adrenal gland, breast bone, stomach, duodenum, return, colon, bladder, the internal organs such as lymph node (administration regional nodes and mesenteric lymph node) or tissue are placed in 10% formalin solution and fix, first high dose group and matched group are carried out to routine paraffin wax section, the dyeing of haematoxylin-Yihong, under light microscopic, make histopathological examination, if high dose group is found pathological change, centering, low dose group corresponding organs is carried out histopathological examination.

2.4.5 the index observing time

General status and observation of symptoms are carried out day by day.Record weekly body weight and food-intake 1 time.Administration 13 weeks and drug withdrawal are observed and after 2 weeks, are respectively carried out one time indices complete detection.

2.4.6 statistical procedures

Measurement data is used

represent, between organizing with t or t' inspection, compare between two.Counting index X ²inspection or definite probabilistic method compare between organizing between two.Inspection level α=0.05.Adopt PEMS3.1 statistical package to carry out statistical analysis.

2.5 result of the test

2.5.1 generally performance

HPWL18.4g(crude drug in whole) kg ^-1there is sialorrhea symptom in the each administration of BW, continues about 20 minutes after 2～5 minutes.HPWL18.4g, 9.2g(crude drug in whole) kg ^-1there is loose stool phenomenon in BW buck, jenny is not obvious after 8 weeks in administration.From table 27,28, each administration group is compared with matched group, and food consumption total amount has no notable difference weekly.Visible, HPWL18.4g, 9.2g, 4.6g(crude drug in whole) kg ^-1bW gastric infusion 13 weeks and drug withdrawal recover to observe 2 weeks, and rats eating amount is had no significant effect.

From table 29, Figure 17, gastric infusion 13 weeks and drug withdrawal recover to observe 2 weeks, and each administration group and matched group buck (♂) body weight are all growth state.HPWL high dose group (18.4g crude drug in whole kg ^-1bW) buck recovered to observe the 1st week body weight all lower than matched group (p<0.05 or p<0.01) at 1st～13 weeks with drug withdrawal.(the 9.2g crude drug in whole kg of dosage group in HPWL ^-1bW) buck 3rd～13 weeks body weight lower than matched group (p<0.05 or p<0.01).

From table 30, Figure 18, gastric infusion 13 weeks and drug withdrawal recover to observe 2 weeks, and each administration group and matched group jenny (♀) body weight are all growth state, and compare obviously significant difference of nothing with matched group.

Therefore can think that HPWL high dose and middle dosage group can cause male rat body weight gain amplitude and slow down, body weight is lower than concurrent control treated animal, and jenny has no same symptom, occurs obvious sex difference.Analyzing its reason may be relevant on digestive and absorptive functions impact with the each component drug of HPWL itself.

Table 27HPWL rat chronic toxicity test food ration (♂, g/kg/d)

Table 28HPWL rat chronic toxicity test food ration (♀, g/kg/d)

Table 29HPWL rat chronic toxicity test body weight

Note: with matched group comparison, ^*p<0.05, ^*p<0.01

Table 30HPWL rat chronic toxicity test body weight

Note: with matched group comparison, ^*p<0.05, ^*p<0.01

2.5.2 the blood cytology index of animal

From table 31, HPWL is 13 weeks high dose group (18.4g crude drug in whole kg after administration ^-1bW) HCT, RDW, PLT, PCT, NEUT are higher than matched group (p<0.05), and PT is lower than matched group (p<0.05); Middle dosage group (9.2g crude drug in whole kg ^-1bW) RET, APTT are higher than matched group (p<0.05), and MCHC, PDW, EO, PT are lower than matched group (p<0.05); Low dose group (4.6g crude drug in whole kg ^-1bW) NEUT, RET higher than matched group (p<0.05) LY lower than matched group (p<0.05).

From table 32, HPWL is high dose group (18.4g crude drug in whole kg after drug withdrawal recovers 2 weeks ^-1bW) NEUT, HCT be higher than matched group (p<0.05), MPV, PDW, P-LCR, LY, APTT low with matched group (p<0.05); Middle dosage group PCT, PLT, MPV, PDW, P-LCR are lower than matched group (p<0.05).

In conjunction with this laboratory intact animal blood cytology data refer value range analysis, above-mentioned difference index and administration time, dosage is all without obvious dependency, and has no the index that is associated and change, still think that above-mentioned hematological indices changes without obvious biological significance.

13 weeks blood cytology testing results of table 31HPWL rat chronic toxicity test administration

Note: with matched group comparison, ^*p<0.05, ^*p<0.01

The drug withdrawal of table 32HPWL rat chronic toxicity test recovers 2 weeks blood cytology testing results

Note: with matched group comparison, ^*p<0.05, ^*p<0.01

2.5.3 the blood biochemical of animal is learned index

From table 33, after administration 13 weeks, HPWL high dose group (18.4g crude drug in whole kg ^-1bW) K ⁺ion is higher than matched group (p<0.05); (the 9.2g crude drug in whole kg of dosage group in HPWL ^-1bW) AST, CREA are lower than matched group (p<0.05), K ⁺, Na ⁺ion is higher than matched group (p<0.05); HPWL low dose group (4.6g crude drug in whole kg ^-1bW) BUN is lower than matched group (p<0.05), TC, Na ⁺ion is higher than matched group (p<0.05).

From table 34, drug withdrawal recovers 2 weeks, HPWL high dose group (18.4g crude drug in whole kg ^-1bW) CK is higher than in matched group (p<0.01); (the 9.2g crude drug in whole kg of dosage group in HPWL ^-1bW) AST, GLU, GREA, CK are lower than matched group (p<0.05), Na ⁺ion is higher than matched group (p<0.05); HPWL low dose group (4.6g crude drug in whole kg ^-1bW) AST, CK are lower than matched group (p<0.05), Na ⁺ion is higher than matched group (p<0.05).

Learn data refer value scope and zoobiology mutation analysis, administration group AST, BUN, GLU, GREA, CK, K in conjunction with this laboratory intact animal blood biochemical ⁺, Na ⁺index variation and administration time, dosage is all without obvious relation, and has no the index that is associated and change, without obvious biological significance.

The 13rd week blood biochemical of table 33HPWL rat chronic toxicity test learned testing result

Note: with matched group comparison, ^*p<0.05, ^*p<0.01

The drug withdrawal of table 34HPWL long term toxicity test recovers the 2nd week blood biochemical and learns testing result

Note: with matched group comparison, ^*p<0.05, ^*p<0.01

2.5.4 system obduction

Recover after 2 weeks respectively at administration 13 weeks and drug withdrawal, high dose group, middle dosage group, low dose group and all animals of matched group are dissected.The high, medium and low dosage group of HPWL and the each natural animal of matched group hole key, outward appearance sign no abnormality seen.Subcutaneous without the abnormal phenomena such as lump, xanthochromia.The tissue such as each animal thoracic cavity cardiopulmonary is arranged normal, and thoracic cavity is without hydrops.Abdominal cavity dissect the tissues such as liver,spleen,kidney, pancreas arrange normal, without adhesion without abnormal secretions.Each internal organs are all abnormal as seen without naked eyes, and chromaticness is normal.

From table 35, organ coefficient and Normal group comparison are weighed, calculated to the high, medium and low dosage group of HPWL capsule, HPWL high dose group (18.4g crude drug in whole kg to 14 kinds of substantial visceras such as the heart, liver, spleen, lung, kidney, brain, adrenal gland, thymus, thyroid, uterus, ovary, testis, epididymis, prostate on the 13rd week in administration ^-1bW) heart, lung, kidney, brain, adrenal gland, testis, prostatic organ coefficient are all higher than matched group (p<0.05 or p<0.01), and thymus is lower than matched group (p<0.05); (the 9.2g crude drug in whole kg of dosage group in HPWL ^-1bW) lung, kidney, brain, adrenal gland, testis, epididymis are all higher than matched group (p<0.05 or p<0.01); HPWL low dose group (4.6g crude drug in whole kg ^-1bW) lung is higher than matched group (p<0.01).

From table 36, the high, medium and low dosage group of HPWL capsule is recovered organ coefficient and Normal group comparison were weighed, calculated to 14 kinds of substantial visceras such as the heart, liver, spleen, lung, kidney, brain, adrenal gland, thymus, thyroid, uterus, ovary, testis, epididymis, prostate, (the 9.2g crude drug in whole kg of dosage group in HPWL in the 2nd week in drug withdrawal ^-1bW) thymus is higher than matched group (p<0.05).

From table 37, in the impact of buck organ coefficient, administration the 13rd week and Normal group comparison, HPWL high dose group (18.4g crude drug in whole kg ^-1bW) heart, lung, kidney, brain, adrenal gland, testis, prostate are all higher than matched group (p<0.05 or p<0.01), and thymus is lower than matched group (p<0.05); (the 9.2g crude drug in whole kg of dosage group in HPWL ^-1bW) lung, kidney, brain, adrenal gland, testis, epididymis are all higher than matched group (p<0.05 or p<0.01), and thymus is lower than matched group (p<0.05); HPWL low dose group (4.6g crude drug in whole kg ^-1bW) lung is higher than matched group (p<0.01); Drug withdrawal recovers the 2nd week and Normal group comparison, HPWL high dose group (18.4g crude drug in whole kg ^-1bW) liver is higher than matched group (p<0.05), (the 9.2g crude drug in whole kg of dosage group in HPWL ^-1bW) lung, thymus are higher than matched group (p<0.05).

From table 38, in the impact of jenny organ coefficient, administration the 13rd week and Normal group comparison, HPWL high dose group (18.4g crude drug in whole kg ^-1bW) heart, liver, kidney are higher than matched group (p<0.05 or p<0.01); (the 9.2g crude drug in whole kg of dosage group in HPWL ^-1bW) liver, kidney are higher than matched group (p<0.01), and thymus is lower than matched group (p<0.05); Drug withdrawal recovers the 2nd week and Normal group comparison, HPWL high dose group (18.4g crude drug in whole kg ^-1bW), adrenal gland is lower than matched group (p<0.05); (the 9.2g crude drug in whole kg of dosage group in HPWL ^-1bW) liver, adrenal gland are lower than matched group (p<0.05).

Therefore can think, HPWL administration 13 Zhou Hougao, middle dosage liver, lung, kidney, brain, adrenal gland, testis are all higher than Normal group, wherein buck lung, kidney, brain, adrenal gland, testis show more obvious, and the performance of jenny liver, kidney is more obvious, may to be starkly lower than matched group relevant with its body weight.Thymus show as administration after 13 weeks lower than matched group, and recover after 2 weeks higher than matched group, more obvious with middle dosage performance, may reduce and then recover relevant with its immunity.

The 13rd week organ coefficient (internal organs g/100g body weight) of table 35HPWL rat chronic toxicity test

Note: with matched group comparison, ^*p<0.05, ^*p<0.01

The 13rd week organ coefficient (internal organs g/100g body weight) of continued 35HPWL rat chronic toxicity test

Note: with matched group comparison, ^*p<0.05, ^*p<0.01

The drug withdrawal of table 36HPWL rat chronic toxicity test recovers the 2nd week organ coefficient (internal organs g/100g body weight)

Note: with matched group comparison, ^*p<0.05, ^*p<0.01

Table 37HPWL rat chronic toxicity test the 13rd week and drug withdrawal recover the 2nd week organ coefficient (internal organs g/100g body weight)

Note: with matched group comparison, ^*p<0.05, ^*p<0.01

Continued 37HPWL rat chronic toxicity test the 13rd week and drug withdrawal recover the 2nd week organ coefficient (internal organs g/100g body weight)

Note: with matched group comparison, ^*p<0.05, ^*p<0.01

Table 38HPWL rat chronic toxicity test the 13rd week and drug withdrawal recover the 2nd week organ coefficient (internal organs g/100g body weight)

Note: with matched group comparison, ^*p<0.05, ^*p<0.01

Continued 38HPWL rat chronic toxicity test the 13rd week and drug withdrawal recover the 2nd week organ coefficient (internal organs g/100g body weight)

Note: with matched group comparison, ^*p<0.05, ^*p<0.01

2.5.5 histopathological examination

(1) heart: visceral pericardium is complete, has no proliferation of fibrous tissue; Flesh layer muscle fiber attenuates without loose atrophy, and without the fine fracture of muscle, wave degeneration, myocardial cell is without water sample, cavity, steatosis, and nucleus is placed in the middle, clear in structure, muscle fiber has no necrosis and scar tissue forms; Have no cell infiltration and fibrous connective tissue hypertrophy, endocardial endothelial cell is intact.

(2) liver: 90 days matched group 2(2/20 of administration) only, high dose group 1(1/20), convalescent period matched group 1(1/10) and high dose group 2(2/10) an animal liver portal area cell infiltration.All the other animal liver leaflet structures are complete, have no hypertrophy and pseudolobuli and form, and lobule central vein has no congestion, and hepatocyte has no degeneration and necrosis; Also have no liver cell proliferation, fibrosis and canceration, in hepatocyte and anacholia alluvial in tiny bile duct, have no various types of cells and infiltrate, portal area is without obviously expanding and fibrous connective tissue hypertrophy.Interlobular bile duct is without expansion and hypertrophy, and tunicle is complete, has no and thickens and ooze out.

(3) kidney: 90 days high doses of administration 1 (1/20), visible a little cell infiltration of 1 (1/20) animal interstitial of convalescent period high dose group.All the other animal kidney tunicles are complete, have no connective tissue proliferation and inflammatory exudation; Cortex internal glomerulus has no blood vessel hyperplasia and fibroatrophy, also without degeneration, necrosis; Kidney convoluted tubule, without cloudy swelling degeneration, vitreous degeneration and necrosis, has no cell and protein cast in medullary loop and collecting tubule; Interstitial is without congested and all kinds of cell infiltration; Mucous membrane of renal pelvis is complete, has no degeneration, necrosis, comes off.

(4) spleen: tunicle and spleen trabeculae fibrous connective tissue have no hypertrophy, therebetween without cell infiltration, in white pulp marginal zone, T cell and B cellular regions inner cell quantity have no minimizing, also without atrophy, splenic nodule anergy hypertrophy.

(5) lungs: 90 days high dose group 1(1/20 of administration) only reach matched group 1(1/20) only, convalescent period matched group 1(1/10) and high dose group 2(2/10) animal interstitial pneumonia. all the other animal lung visceral pleuras without connective tissue proliferation, thicken, have no inflammatory exudation; In bronchial lumens at different levels and in alveolar, have no and ooze out edematous fluid, hemorrhage and cell infiltration, bronchial mucosa pseudostratified ciliated columnar epithelium comes off without hypertrophy, atrophy, degeneration, necrosis.

(6) brain (brain, cerebellum): cranial nerve cell has no degeneration, necrosis, glial cell is also without neuronophagia and satellitosis, and interstitial blood vessel is without congested, hemorrhage, gap broadening around and lymphocyte bustle pipe phenomenon etc.

(7) hypophysis: neurohypophysis and adenohypophysis part have no degeneration, necrosis, hemorrhage.

(8) spinal cord (cervical part of esophagus, breast section, waist section): cinereum matter structure is clear, grey matter neuronal structure distribution no abnormality seen, neurogliocyte has no hypertrophy, and white matter nerve fiber has no variation, necrosis, and cell infiltration.

(9) thyroid: tunicle is made up of thin layer fibrous tissue, without hypertrophy, thicken and cell infiltration, thyroid follicle forms, in the same size, and have no hypertrophy and nipple and form, colloid pinkiness in folliculus, uniformity, has no degeneration, necrosis, hemorrhage.

(10) parathyroid gland: the rounded or polygon of chief cell, core circle, is positioned at cell central authorities, and kytoplasm is painted shallow; Oxyphil cell is single or be distributed in groups between chief cell, cell more greatly, the little engrain of core, kytoplasm acidophilia.Have no degeneration, necrosis, hemorrhage.

(11) thymus: tunicle fibrous connective tissue is complete, has no hypertrophy and inflammatory exudation, and cortex endolymph cell has no atrophy and lymphopenia, has no special abnormality in medullary substance.

(12) pancreas: tunicle is made up of thin layer fibrous tissue, without thickening and cell infiltration, mucus and serous acinus have no hypertrophy and increase, and atrophy, degeneration, necrosis, in acinar parenchyma, have no hemorrhage, cell infiltration.

(13) adrenal gland: tunicle is complete, has no proliferation of fibrous tissue and inflammatory exudation, and glomerular zone, zona fasciculata and reticular zone structure are intact in cortex, has no and in the de-mistake of lipid and hypertrophy, atrophy, medullary substance, has no hemorrhage, necrosis and cell infiltration.

(14) ovary: ovary primordial follicle, growing follicle and mature follicle form and quantity are normal, without atrophy, degeneration and necrosis, also without cell infiltration.

(15) uterus: endometrium is complete, has no hypertrophy, atrophy, congestion and edema and degeneration necrosis, sees a small amount of cell infiltration, placenta percreta no abnormality seen in flesh layer.

(16) prostate: tunicle connective tissue stretches in gland and is separated into many lobules, and acinus is envelope shape, without degeneration, hemorrhage, downright bad, also without cell infiltration.

(17) testis: in convoluted seminiferous tubule, spermatogenic cells at different stages quantity has no minimizing, in its tube chamber, sperm also has no minimizing, and interstitial is without congestion and edema, cell infiltration and fibrous connective tissue hypertrophy.

(18) epididymis: tube wall is made up of pseudostratified columnar epithelium, cell is high column, and there is fine quiet hair on surface, has secretory granule in Cytoplasm, accidental pigment, visible sperm in epididymis, efferent duct, epididymal duct etc. are without degeneration, hemorrhage, downright bad, also without cell infiltration.

(19) mammary gland: a little mammary gland tissue in connective tissue, acinus rareness in lobule, alveolar lumen is little, is resting mammary gland.

(20) trachea: tube wall three-decker is clear, has no epithelial cell degeneration, cilium lodging, the hyperemia of Submucosa edema and cell infiltration.

(21) esophagus: tube wall four-layer structure is clear, has no stratified squamous epithelium hypertrophy, parakeratosis or hyperkeratosis, and all the other each layer has no congestion and edema and cell infiltration.

(22) stomach: mucosa simple columnar epithelium, lamina propria and muscular layer of mucosa structure are intact, have no degeneration and inflammatory exudation, also come off without necrosis, and without hypertrophy intestinal and squamous metaplasia, tela submucosa has no congestion and edema.Flesh layer and serous coat are also without cell infiltration.

(23) duodenum, colon, ileum: mucosa simple columnar epithelium, lamina propria and muscular layer of mucosa structure are intact, have no degeneration and inflammatory exudation, also come off without necrosis, and without hypertrophy intestinal and squamous metaplasia, tela submucosa has no congestion and edema.Flesh layer and serous coat are also without cell infiltration.

(24) bladder: mucosa, flesh layer, three layers, serous coat are intact, have no degeneration, necrosis and cell infiltration.

(25) sciatic nerve: nerve fiber structure is complete, without fracture, visible medullary cord, around medullary cord, nerve, has no hemorrhage and downright bad, no abnormality seen hyperplasia, cell infiltration.

(26) aorta: inner membrance is made up of endothelium, subendothelial layer, internal elastic membrane.Subendothelial layer is positioned at outside endothelium, is thinner loose connective tissue, includes a small amount of smooth muscle fiber.Internal elastic membrane is made up of elastin laminin, has many apertures in elastica, each layer of structural integrity, and endothelium is without hypertrophy and come off, and lamina propria blood vessel has no congested expansion, has no foam cell and forms.

(27) salivary gland (submandibular gland): acinus structural integrity, have no hypertrophy and atrophy, have no hyperemia and cell infiltration, have no myoepithelial cell and softening sample tissue, lymph foilicie hyperplasia.

(28) lymph node (under jaw, mesentery): tunicle is complete, lymphatic nodule anergy hypertrophy.

(29) breastbone: breastbone is dense, and bone structure is clear, arrange normally bone trabecula likeness in form sponge rack, visible hemocyte, macrophage, adipose cell or mesenchymal cell in different developmental phases therebetween, and containing abundant blood sinus, three is that cellular morphology and the nothing that distributes are abnormal.

This experimental section rat heart, liver, kidney, lung, prostate, the visible pathological change of bladder, but lesion degree is lighter, and each group all has generation, is the common spontaneous pathological changes of rat, irrelevant with tested material.

Claims (10)

1. a pharmaceutical composition for the treatment of functional dyspepsia, is characterized in that: it is the preparation being prepared from by the crude drug of following weight proportion:

Cortex Magnoliae Officinalis 300-500 part, Fructus Aurantii Immaturus 288-360 part, Radix Et Rhizoma Rhei 150-300 part.

2. pharmaceutical composition according to claim 1, is characterized in that: it is the preparation being prepared from by the crude drug of following weight proportion:

400 parts of Cortex Magnoliae Officinalis, 288 parts of Fructus Aurantii Immaturuss, 200 parts of Radix Et Rhizoma Rhei;

Or, 500 parts of Cortex Magnoliae Officinalis, 360 parts of Fructus Aurantii Immaturuss, 250 parts of Radix Et Rhizoma Rhei;

Or, 400 parts of Cortex Magnoliae Officinalis, 360 parts of Fructus Aurantii Immaturuss, 150 parts of Radix Et Rhizoma Rhei;

Or, 300 parts of Cortex Magnoliae Officinalis, 300 parts of Fructus Aurantii Immaturuss, 150 parts of Radix Et Rhizoma Rhei;

Or, 300 parts of Cortex Magnoliae Officinalis, 300 parts of Fructus Aurantii Immaturuss, 300 parts of Radix Et Rhizoma Rhei.

3. pharmaceutical composition according to claim 1 and 2, is characterized in that: it is taking the medicated powder of described crude drug or the water of crude drug or extractive with organic solvent as active component, adds the preparation that pharmaceutically conventional adjuvant or complementary composition are prepared from.

4. according to the pharmaceutical composition described in claim 1-3 any one, it is characterized in that: described preparation is oral formulations.

5. the preparation method of the pharmaceutical composition described in claim 1-4 any one, is characterized in that: it comprises following operating procedure:

(1) weighting raw materials by weight ratio;

(2) crude drug is pulverized, added water or 60-90%v/v ethanol extraction, after extracting solution is concentrated, add the preparation that pharmaceutically conventional adjuvant or complementary composition are prepared from.

6. preparation method according to claim 5, is characterized in that: the concentration of described ethanol is 75%v/v.

7. preparation method according to claim 5, it is characterized in that: the concrete operations of step (2) are as follows: get crude drug and be ground into coarse powder, decoct with water three times, each 10 times of amounts, extract collecting decoction 1 hour, filter, be concentrated into 60 DEG C of clear paste that record relative density 1.2,60 DEG C of high-pressure dryings, add the preparation that pharmaceutically conventional adjuvant or complementary composition are prepared from.

8. the preparation method of the pharmaceutical composition described in claim 1-4 any one, is characterized in that: it comprises following operating procedure:

(1) weighting raw materials by weight ratio;

(2) get Cortex Magnoliae Officinalis, Fructus Aurantii Immaturus, extract as extracting solvent taking water or 60-90%v/v ethanol, obtain extract A;

(3) get Radix Et Rhizoma Rhei, extract as extracting solvent taking water or 60-90%v/v ethanol, obtain extract B; Wherein, step (2) is different from the extraction solvent of step (3);

(4) united extraction thing A and B, adds the preparation that pharmaceutically conventional adjuvant or complementary composition are prepared from.

9. the purposes of the pharmaceutical composition described in claim 1-4 any one in the medicine of preparation treatment functional dyspepsia.

10. purposes according to claim 9, is characterized in that: described medicine is to promote that gastrointestinal tract is emptying, suppress gastric juice and pepsin discharges, the medicine of increase intestinal tube muscular tension.

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