CN101095691A - Application of phillyrin in the preparing of medicine for treating or preventing acute and chronic liver injury and hepar fibrosis - Google Patents
Application of phillyrin in the preparing of medicine for treating or preventing acute and chronic liver injury and hepar fibrosis Download PDFInfo
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Abstract
The invention provides the application of phillyrin in preparing medicine that prevents and treats acute or chronic liver injury and liver fibrosis. It can be produced into oral preparation or injection preparation. The dose for injection is 25-800mg, and for oral is 50 -1500mg.
Description
Technical field
The present invention relates to a kind of medicine that is used for the treatment of hepatopathy, be specifically related to phillyrin in prevention or the due to illness application in poison, chemical substance, drug-induced acute and chronic liver injury and the hepatic fibrosis medicines of treatment.
Background technology
Hepatitis refers to the liver inflammation.Many pathogenic microorganisms all may cause the liver inflammation as virus, antibacterial, fungus, rickettsia, spirillum and some protozoon and parasitic infection; The poisoning of various poisonous substances (as arsenicum), toxin (the interior extracellular toxin of antibacterial), chemical substance (ethanol etc.) and some drugs (as isoniazid, indometacin, chlorpromazine etc.) all can cause toxic hepatitis.Be called drug induced hepatitis by what drug intoxication caused; The hepatitis that is caused by chemical substance is called chemical hepatitis; The hepatitis that is caused by the virus virus hepatitis of pretending illness, this virus comprises all kinds of hepatitis viruss, herpesvirus, Epstein-Barr virus, cytomegalovirus, chickenpox virus, enterovirus and adenovirus etc.
China is the hotspot of viral hepatitis, and five type viral hepatitis all have generation and popular at home.According to the report of infectious disease of health and epidemic prevention department, the annual morbidity of China's viral hepatitis is 9,50/,100,000, and its sickness rate occupies the 3rd in Notifiable disease, is only second to infectious diarrhea and influenza.And according to the report of infectious disease of the U.S. in 1988, the annual morbidity of its viral hepatitis only is 23.1/10 ten thousand, and the sickness rate of China is more than 41 times of the U.S..Hepatitis makes the patient in life, and social activity is gone to school, and fermentation such as employment are subjected to restriction in various degree, gives family, and society causes great mental burden.The chronic hepatitis course of disease is long, and refractory more repeatedly, and causes the generation of cancer, and patient's physical and mental health burden is very big.
To the treatment of hepatitis, Western medicine has interferon, interferon inducers, nucleoside derivates or the like at present.Interferon is a choice drug, but exists dosage big, the expense height, and toxic and side effects is big, and effective percentage is not high, easy shortcoming such as recurrence after the drug withdrawal.The therapeutic effect of Chinese medicine also can not be satisfactory, and its pharmaceutical effectiveness is imprecise, and the treatment phase is long, and the expense height is taken for a long time and can be had side effects, and impairs the health of health.Press for the treatment hepatitis active drug that provides new.
Hepatic fibrosis is a chronic hepatopathy important pathological feature.The causes of disease such as virus, ethanol, autoimmune disease all can cause hepatic necrosis, regeneration and persistence fibroplasia, finally cause liver cirrhosis.Confirmed that now hepatic fibrosis is reversible pathological changes, liver cirrhosis then is irreversible.Therefore, in the therapeutic process of chronic hepatopathy, the control of hepatic fibrosis occupies critical role.
The inventor is by a large amount of experimentatioies, invented the application in the medicine of phillyrin prevention and treatment acute and chronic liver injury and hepatic fibrosis.
Summary of the invention
The invention provides the application of phillyrin in the medicine of prevention and treatment acute and chronic liver injury and hepatic fibrosis.
The invention provides the application of phillyrin in the medicine of prevention and treatment acute liver damage.
The invention provides the application of phillyrin in the medicine of prevention and treatment chronic hepatic injury.
The invention provides the application of phillyrin in the medicine of prevention and treatment hepatic fibrosis.
Phillyrin provided by the invention is when being used for above-mentioned arbitrary purposes, and its injection using dosage scope is 25mg~800mg, and the preferred dose scope is 25mg~400mg; It orally uses dosage range is 50mg~1500mg, and the preferred dose scope is 50mg~750mg.
Medicine provided by the invention can add corresponding adjuvant according to the preparation needs, exists with forms such as injection, tablet, pill, granule, capsule, syrup, is preferably freeze-dried powder and capsule.Various dosage form provided by the invention all can adopt the pharmacy conventional method to be prepared from.
The inventor has obtained this anti-acute and chronic liver injury and hepatic fibrosis medicines and has confirmed that this medicine has anti-hepatitis, hepatic fibrosis by following embodiment, prevention and due to illness poison, chemical substance, drug-induced hepatic injury of treatment, the following examples are used for more detailed description the present invention, but and do not mean that the present invention only limits to this.
The specific embodiment:
The preparation of embodiment 1 phillyrin freeze-dried powder
The material therefor phillyrin can prepare (" natural medicinal ingredients extraction separation and preparation ", Sun Wenji chief editor, November in 1999 the 1st edition, the 277th page) by literature method among the present invention.Get phillyrin 20.0g, add injection water 2000ml and make its dissolving,, with mannitol 8g, stirring and dissolving, ultrafiltration obtains apyrogenic clear liquor, pours in the 10ml cillin bottle, 2ml/ only presses the lyophilizing of freeze-dried powder technology, makes every freeze-dried powder that contains phillyrin 20.0mg.
Embodiment 2 phillyrin preparation tablets
Prescription:
Phillyrin 100.0g
Icing Sugar 35.0g
Lactose 40.0g
Carboxymethyl starch sodium 23.0g
3%PVP
K30Aqueous solution is an amount of
Magnesium stearate 2.0g
Make 1000 altogether
Operation: cross 100 mesh sieves after taking by weighing the abundant mix homogeneously of phillyrin, Icing Sugar, lactose and carboxymethyl starch sodium of recipe quantity, add 3%PVP
K30Aqueous solution is made soft material in right amount, and 20 mesh sieves are granulated, 60 ℃ of dryings 3 hours, and 18 mesh sieve granulate add the magnesium stearate of recipe quantity, scrobicula stamping behind the mix homogeneously, the heavily about 200mg of adjustment sheet, promptly.
Test example 1: phillyrin causes the influence of chmice acute hepatic injury to carbon tetrachloride
1.1 material
Carbon tetrachloride (analytical pure, Yantai three and chemical reagents corporation, lot number: 050122); (Shandong Province's natural drug Engineering Technical Research Centre provides phillyrin, content 95%, lot number: 051012); Bifendate (drop pill, Beijing consonance pharmaceutical factory, specification: 1.5mg, lot number: 050512); ALT/GPT test kit (Zhongsheng Beikong Biological Science ﹠ Technology Co., Ltd., lot number 060281); ASP/GOT test kit (Zhongsheng Beikong Biological Science ﹠ Technology Co., Ltd., lot number 060201)
Automatic clinical chemistry analyzer (Italy)
Kunming mouse, body weight 18-22g, Shandong Province's natural drug Engineering Technical Research Centre Experimental Animal Center provides, the quality certification number: 200203005.The male and female dual-purpose.
1.2 method
130 of mices, be divided into 13 groups at random, it is the normal control group, model group, bifendate is irritated stomach 10mg/kg group, phillyrin intravenous injection 2.5mg/kg group, phillyrin intravenous injection 5mg/kg group, phillyrin intravenous injection 25mg/kg group, phillyrin intravenous injection 100mg/kg group, phillyrin intravenous injection 200mg/kg group, phillyrin is irritated stomach 5mg/kg group, phillyrin is irritated stomach 10mg/kg group, phillyrin is irritated stomach 50mg/kg group, phillyrin is irritated stomach 100mg/kg group, phillyrin is irritated stomach 300mg/kg group, each intravenously administrable group successive administration 3 days, each gastric infusion group successive administration 7 days, each organized the carbon tetrachloride oil solution lumbar injection with 0.2% except that matched group in preceding 16 hours in the last administration, volume injected: 0.25ml/ only, fasting immediately 16 hours, last administration posterior orbit blood sampling in 1 hour, centrifugal (4000rpm, 10min), collect serum, detect ALT/GPT with medicine box, the ASP/GOT activity.Data are used with data
Expression is carried out statistical procedures with t check between group.
1.3 result
The result is as shown in table 1, phillyrin intravenous injection 5mg/kg group, phillyrin intravenous injection 25mg/kg group, phillyrin intravenous injection 75mg/kg group, phillyrin intravenous injection 150mg/kg group, phillyrin irritate stomach 10mg/kg group, phillyrin irritate stomach 50mg/kg group, phillyrin irritate stomach 150mg/kg group, phillyrin irritate stomach 300mg/kg group obviously reduce HA, LN, PcIII, HYP level (with model control group relatively, p<0.05 or 0.01).The stomach 150mg/kg group of irritating phillyrin reduces HA, LN, PcIII, HYP level and phillyrin and irritates stomach 300mg/kg group relatively, there was no significant difference; Phillyrin intravenous injection 75mg/kg group reduces HA, LN, PcIII, HYP level and phillyrin intravenous injection 150mg/kg group relatively, there was no significant difference.
Table 1 phillyrin is to CCL
4The GOT of hepatic injury mice, the influence of GPT
Group | Dosage (mg/kg) | ASP/GOT enzyme (U/L) alive | ALT/GPT enzyme (U/L) alive |
The normal control group | --- | 176±33 | 68±13 |
Model group | NS | 1407±261 | 1082±201 |
The bifendate group | 10 | 876±254 | 676±234 |
Phillyrin intravenous injection group | 2.5 | 1231±229 | 947±176 |
5 | 1137±158 * | 874±122 | |
25 | 1037±153 ** | 775±154 ** | |
75 | 837±153 ** | 573±216 ** | |
150 | 823±158 ** | 553±232 ** | |
Phillyrin is irritated the stomach group | 5 | 1231±229 | 957±171 |
10 | 1165±158 * | 870±125 * | |
50 | 1087±159 ** | 796±154 ** | |
150 | 937±173 ** | 623±219 ** | |
300 | 923±178 ** | 609±264 ** |
Compare with model group
*P<0.05,
*P<0.01,
Test example 2: the present composition causes the protective effect of mouse liver injury to D-galactosamine
2.1 material
Carbon tetrachloride (analytical pure, Yantai three and chemical reagents corporation, lot number: 050122); (Shandong Province's natural drug Engineering Technical Research Centre provides phillyrin, content 95%, lot number: 051012); Bifendate (drop pill, Beijing consonance pharmaceutical factory, specification: 1.5mg, lot number: 050512); ALT/GPT test kit (Zhongsheng Beikong Biological Science ﹠ Technology Co., Ltd., lot number 060281); ASP/GOT test kit (Zhongsheng Beikong Biological Science ﹠ Technology Co., Ltd., lot number 060201); D-galactosamine (production of SIGMA company).Automatic clinical chemistry analyzer (Italy)
Kunming mouse, body weight 18-22g, Shandong Province's natural drug Engineering Technical Research Centre Experimental Animal Center provides, the quality certification number: 200203005.The male and female dual-purpose.
2.2 method
130 of mices, be divided into 13 groups at random, it is the normal control group, model group, bifendate is irritated stomach 10mg/kg group, phillyrin intravenous injection 2.5mg/kg group, phillyrin intravenous injection 5mg/kg group, phillyrin intravenous injection 25mg/kg group, phillyrin intravenous injection 100mg/kg group, phillyrin intravenous injection 200mg/kg group, phillyrin is irritated stomach 5mg/kg group, phillyrin is irritated stomach 10mg/kg group, phillyrin is irritated stomach 50mg/kg group, phillyrin is irritated stomach 100mg/kg group, phillyrin is irritated stomach 300mg/kg group, each intravenously administrable group successive administration 3 days, each gastric infusion group successive administration 7 days, each organizes the D-galactosamine modeling with 150mg/kg except that matched group behind the last administration 1h, the blood sampling of fasting 16h posterior orbit, centrifugal (4000rpm, 10min), collect serum, detect ALT/GPT with medicine box, the ASP/GOT activity.Data are used with data
Expression is carried out statistical procedures with t check between group.
2.3 result
As shown in table 2, phillyrin intravenous injection 5mg/kg organizes, phillyrin intravenous injection 25mg/kg organizes, phillyrin intravenous injection 75mg/kg organizes, phillyrin intravenous injection 150mg/kg organizes, phillyrin filling stomach 10mg/kg organizes, phillyrin filling stomach 50mg/kg organizes, phillyrin filling stomach 150mg/kg organizes, phillyrin filling stomach 300mg/kg organizes obvious reduction GOT, GPT level (comparing p<0.05 or 0.01 with model control group).The stomach 150mg/kg group of irritating phillyrin reduces GOT, GPT level and phillyrin and irritates stomach 300mg/kg group relatively, there was no significant difference; Phillyrin intravenous injection 75mg/kg group reduces GOT, GPT level and phillyrin intravenous injection 150mg/kg group relatively, there was no significant difference.
Table 2 phillyrin causes the GOT of hepatic injury mice, the influence of GPT to D-galactosamine
Group | Dosage (mg/kg) | ASP/GOT enzyme (U/L) alive | ALT/GPT enzyme (U/L) alive |
The normal control group | --- | 162±33 | 75±23 |
Model group | NS | 1446±233 | 1112±180 |
The bifendate group | 10 | 836±233 | 666±244 |
Phillyrin intravenous injection group | 2.5 | 1262±205 | 970±157 |
5 | 1191±156 * | 912±120 * | |
25 | 980±153 ** | 795±154 ** | |
75 | 807±153 ** | 643±216 ** | |
150 | 783±158 ** | 623±232 ** | |
Phillyrin is irritated the stomach group | 5 | 1251±213 | 986±171 |
10 | 1185±258 * | 900±125 * | |
50 | 1056±155 ** | 807±154 ** | |
150 | 967±173 ** | 723±219 ** | |
300 | 943±178 ** | 709±264 ** |
Compare with model group
*P<0.05,
*P<0.01,
Test example 3: phillyrin is to the influence of rat chronic hepatic injury
3.1 medicine and reagent
(Shandong Province's natural drug Engineering Technical Research Centre provides phillyrin, content 95%, lot number: 051012); Bifendate (drop pill, Beijing consonance pharmaceutical factory, specification: 1.5mg, lot number: 050512); ALT/GPT test kit (Zhongsheng Beikong Biological Science ﹠ Technology Co., Ltd., lot number 060281): ASP/GOT test kit (Zhongsheng Beikong Biological Science ﹠ Technology Co., Ltd., lot number 060201); Ethanol (analytical pure, Yantai three and chemical reagents corporation, lot number: 0503251.
Laboratory animal regular grade Wistar rat, male, body weight 150-200g, the SD rat, Shandong greenery natural drug Societe Principia Research Development Experimental Animal Center provides qualified number: SYXK (Shandong) 20030020.
3.2 experimental technique:
130 of rats, be divided into 13 groups at random, be that normal control group, model group, bifendate group are irritated stomach 5mg/kg group, phillyrin intravenous injection 1mg/kg group, phillyrin intravenous injection 2.5mg/kg group, phillyrin intravenous injection 12.5mg/kg group, phillyrin intravenous injection 40mg/kg group, phillyrin intravenous injection 80mg/kg group, phillyrin and irritated stomach 2.5mg/kg group, phillyrin and irritate stomach 5mg/kg group, phillyrin and irritate that stomach 25mg/kg group, phillyrin are irritated stomach 75mg/kg group, phillyrin is irritated stomach 150mg/kg group, 10 every group.Except that normal group, each group gives sc carbon tetrachloride stock solution 5ml/kg body weight first, 2 sc 25% carbon tetrachloride solutions (olive oil is released) 2ml/kg body weight weekly later on, continuous 20 weeks.Except that the normal control group, all the other prepare the chronic hepatic injury model as stated above, during the 8th week, begin administration, 12 weeks of successive administration in experiment, administration finishes back with 20% urethane solution intraperitoneal injection of anesthesia, dissect, hepatic tissue is left and taken in the ventral aorta blood sampling, part is fixed with 10% neutral formalin solution, system paraffin mass in the 24-48h.HE dyeing is adopted in the liver histopathology inspection, change is marked to chronic hepatic injury rat histopathology, the liver cytoplasm puffing is divided into the 0-3 level, hepatocyte fat variation is the 0-3 level, hepatic necrosis is divided into the 0-3 level, liver interstitial fibers hypertrophy is divided into the 0-3 level, the rat histopathology is changed mark carry out rank test.Blood sample is centrifugal, and (4000rpm 10min), collects serum, detects ALT/GPT, ASP/GOT activity with medicine box.Data are used with data
Expression is carried out statistical procedures with t check between group.
3.3 experimental result
As shown in table 3, phillyrin intravenous injection 2.5mg/kg organizes, phillyrin intravenous injection 12.5mg/kg organizes, phillyrin intravenous injection 40mg/kg organizes, phillyrin intravenous injection 80mg/kg organizes, phillyrin filling stomach 5mg/kg organizes, phillyrin filling stomach 25mg/kg organizes, phillyrin filling stomach 75mg/kg organizes, phillyrin filling stomach 150mg/kg organizes obvious reduction GOT, GPT level and liver index (comparing p<0.05 or 0.01 with model control group).The stomach 75mg/kg group of irritating phillyrin reduces GOT, GPT level and liver index and phillyrin filling stomach 150mg/kg organizes relatively there was no significant difference; Phillyrin intravenous injection 40mg/kg group reduces GOT, GPT level and liver index and phillyrin intravenous injection 80mg/kg group compares there was no significant difference.
Hepatic tissue pathology changes: the result shows, the chronic liver damage of CCl4 group rat, and the normal hepatocytes leaflet structure destroys, and steatosis is widely arranged, hepatic necrosis and interstitial fibers hypertrophy in various degree, through the rat of phillyrin treatment, damaging pathological change obviously alleviates.
As shown in table 4, phillyrin intravenous injection 2.5mg/kg group, phillyrin intravenous injection 12.5mg/kg group, phillyrin intravenous injection 40mg/kg group, phillyrin intravenous injection 80mg/kg group, phillyrin irritate stomach 5mg/kg group, phillyrin irritate stomach 25mg/kg group, phillyrin irritate stomach 75mg/kg group, phillyrin irritate stomach 150mg/kg group obviously reduce liver cytoplasm puffing, the change of hepatocyte fat, hepatic necrosis and liver interstitial fibers hypertrophy (with model control group relatively, p<0.05 or 0.01).The stomach 75mg/kg group of irritating phillyrin reduces liver cytoplasm puffing, the change of hepatocyte fat, hepatic necrosis and liver interstitial fibers hypertrophy and phillyrin is irritated stomach 150mg/kg group relatively, there was no significant difference; Phillyrin intravenous injection 40mg/kg group liver cytoplasm puffing, the change of hepatocyte fat, hepatic necrosis and liver interstitial fibers hypertrophy and phillyrin intravenous injection 80mg/kg group compare there was no significant difference.
Table 3 phillyrin is to rat GOT, GPT level and the influence of liver index of chronic hepatic injury
Group | Dosage (mg/kg) | The liver index | ASP/GOT enzyme (U/L) alive | ALT/GPT enzyme (U/L) alive |
The normal control group | --- | 2.42±0.07 | 262±33 | 275±23 |
Model group | NS | 2.86±0.08 | 1319±245 | 1199±223 |
The bifendate group | 10 | 2.65±0.10 | 766±233 | 636±244 |
Phillyrin intravenous injection group | 2.5 | 2.79±0.07 | 1212±198 | 1017±207 |
5 | 2.76±0.06 * | 1089±207 * | 926±245 * | |
25 | 2.70±0.07 ** | 880±163 ** | 850±263 ** | |
75 | 2.66±0.08 ** | 767±153 ** | 743±216 ** | |
150 | 2.65±0.07 ** | 743±158 ** | 723±232 ** | |
Phillyrin is irritated the stomach group | 5 | 2.81±0.07 | 1212±198 | 1017±207 |
10 | 2.75±0.07 * | 1085±217 * | 920±249 * | |
50 | 2.72±0.07 ** | 890±183 ** | 870±233 ** | |
150 | 2.70±0.08 ** | 797±173 ** | 763±216 ** | |
300 | 2.69±0.07 ** | 773±168 ** | 743±232 ** |
Compare with model group
*P<0.05,
*P<0.01
Table 4 phillyrin is to the influence of the rat histopathology change of chronic hepatic injury
Group | Dosage (mg/kg) | The liver cytoplasm puffing | Hepatocyte fat becomes | Hepatic necrosis | Liver interstitial fibers hypertrophy |
The normal control group | --- | 0 | 0 | 0 | 0 |
Model group | NS | 2.7±0.5 | 2.6±0.5 | 2.8±0.4 | 2.7±0.5 |
The bifendate group | 10 | 1.7±0.7 ** | 1.6±0.7 ** | 1.7±0.5 ** | 1.7±0.6 ** |
Phillyrin intravenous injection group | 2.5 | 2.1±0.9 | 2.0±0.9 | 2.2±0.9 | 2.1±0.8 |
5 | 2.0±0.8 * | 1.9±0.8 * | 2.0±0.8 * | 2.0±0.8 | |
25 | 1.8±0.8 ** | 1.7±0.8 ** | 1.9±0.8 ** | 1.8±0.7 ** | |
75 | 1.7±0.7 ** | 1.6±0.7 ** | 1.8±0.7 ** | 1.7±0.7 ** | |
150 | 1.6±0.5 ** | 1.6±0.5 ** | 1.7±0.5 ** | 1.6±0.5 ** | |
Phillyrin is irritated the stomach group | 5 | 2.1±0.9 | 2.0±0.9 | 2.2±0.8 | 2.1±0.9 |
10 | 2.0±0.8 * | 1.9±0.7 * | 2.0±0.8 * | 2.0±0.8 * | |
50 | 1.8±0.8 ** | 1.7±0.8 ** | 1.9±0.8 ** | 1.8±0.8 ** | |
150 | 1.7±0.7 ** | 1.6±0.7 ** | 1.8±0.7 ** | 1.7±0.7 ** | |
300 | 1.7±0.5 ** | 1.6±0.5 ** | 1.8±0.5 ** | 1.7±0.5 ** |
Compare with model group
*P<0.05,
*P<0.01
Test example 4: phillyrin is to the influence of hepatic fibrosis
4.1 medicine and reagent
Phillyrin is provided by Shandong Province's natural drug Engineering Technical Research Centre, and content is more than 95%, lot number: 041205; Avandia (rosiglitazone maleate sheet, Glaxo SmithKline company, lot number 051023) HA (hyaluronic acid), LN (laminin) and PcIII (III Collagen Type VI) radioimmunological kit are bought in Shang Haihai and are ground the medical center; The hydroxyproline detection kit is built up bio-engineering research institute available from Nanjing.
Laboratory animal regular grade Wistar rat, male, body weight 150-200g, the SD rat, Shandong greenery natural drug Societe Principia Research Development Experimental Animal Center provides qualified number: SYXK (Shandong) 20030020.
4.2 experimental technique:
130 of rats, be divided into 13 groups at random, be that normal control group, model group, rosiglitazone group are irritated stomach 8mg/kg group, phillyrin intravenous injection 1mg/kg group, phillyrin intravenous injection 2.5mg/kg group, phillyrin intravenous injection 12.5mg/kg group, phillyrin intravenous injection 40mg/kg group, phillyrin intravenous injection 80mg/kg group, phillyrin and irritated stomach 2.5mg/kg group, phillyrin and irritate stomach 5mg/kg group, phillyrin and irritate that stomach 25mg/kg group, phillyrin are irritated stomach 75mg/kg group, phillyrin is irritated stomach 150mg/kg group, 10 every group.The rat liver fibrosis model copy reaches and respectively organizes method of disposal: with reference to the superfine method [Wu Mengchao that duplicates the rat liver fibrosis model of Wu Meng, Yang Guangshun. the research of rats'liver cirrhosis model copy. Chinese experimental surgery magazine, 1984,1 (4): 145-147], except that the normal control group, each organizes the every 100g body weight of every 3d subcutaneous injection 40% carbon tetrachloride oil solution 0.3ml, first dosage doubles, the every 3d subcutaneous injection of rats in normal control group oil solution 0.3ml/100g body weight, after 6 weeks, each group beginning administration, 6 weeks of successive administration, administration finishes back with 20% urethane solution intraperitoneal injection of anesthesia, dissect, hepatic tissue is left and taken in the ventral aorta blood sampling, part is fixed with 10% neutral formalin solution, system paraffin mass in the 24-48h.HE dyeing is adopted in the liver histopathology inspection, the fibroplasia degree be divided into the 0-4 level [Li Kun, Zhao Yuzhen, Zhu Qiushuan etc. ligustrazine is to the influence of the aged mouse heart, liver superoxide dismutase activity. Heilungkiang medical science, 1998; 21:4-5], to HA in the serum (hyaluronic acid), LN (laminin) and PcIII (III Collagen Type VI), and liver in HYP (hydroxyproline) measure, HA, LN, PcIII, HYP measure by the detection kit assay method.
4.3 experimental result
Pathological examination: the rats in normal control group liver structure is normal; Tangible fibrosis all appears in 12 weeks of model group rat liver; Fibrosis is all light than model group in each group of phillyrin.
Om observation: HE normal dyeing and VG collagen staining hepatic tissue section show, visible hepatic cell fattydegeneration in the Liver Fibrosis Model control rats hepatic tissue, necrosis, cell infiltration; Collagen fiber deposition in the portal area, Henny manages hypertrophy; The fibrous connective tissue hypertrophy is obvious, and the fibrous septum increases slightly, and has typical pseudolobuli to form.Phillyrin treatment group liver tissues of rats fibrous connective tissue hyperplasia degree alleviates, and the fibrous septum attenuates, and pseudolobuli forms not obvious.Each group fibroplasia degree score value is carried out rank test.The results are shown in Table 1, phillyrin intravenous injection 2.5mg/kg organizes, phillyrin intravenous injection 12.5mg/kg organizes, phillyrin intravenous injection 40mg/kg organizes, phillyrin intravenous injection 80mg/kg organizes, phillyrin filling stomach 5mg/kg organizes, phillyrin filling stomach 25mg/kg organizes, phillyrin filling stomach 75mg/kg organizes, phillyrin filling stomach 150mg/kg organizes obvious reduction fibroplasia degree (comparing p<0.05 or 0.01 with model control group).
Electron microscopic observation: closely link to each other between the rats in normal control group hepatocyte, the interior various organelles of cell distribute regular, structure typical case.The blood sinus marshalling, the visible fat-storing cells of liver of Disse intracavity has fat to drip in the Cytoplasm.Typical hepatocyte injury structure then appears in the model control group liver tissues of rats, the gap broadening of adjacent hepatocyte, and the hepatocellular degeneration necrosis, karyopycnosis, the irregular fat that occurs in the Cytoplasm differing in size, distributing drips.The fibrosis lesion that exists weight not wait in the hepatic tissue.The sinus hepaticus blood capillaryization, visible more fibroblast (activatory fat-storing cells of liver) in the Disse gap, and a large amount of collagen fiber depositions are arranged on every side.A large amount of collagen fiber can appear in the portal area.In the phillyrin treatment group, hepatocyte injury has alleviating in various degree, and the hepatocyte gap is tightr, and lipid droplet reduces in the Cytoplasm, and cell inner structure trend is normal.The hepatic fibrosis pathological changes is not obvious, and collagen fiber deposition and fibroblast-like cells quantity reduce in hepatic sinusoid and the Disse gap.
Each group HA, LN, PcIII, HYP are carried out the T check.The results are shown in Table 6, phillyrin intravenous injection 2.5mg/kg group, phillyrin intravenous injection 12.5mg/kg group, phillyrin intravenous injection 40mg/kg group, phillyrin intravenous injection 80mg/kg group, phillyrin irritate stomach 5mg/kg group, phillyrin irritate stomach 25mg/kg group, phillyrin irritate stomach 75mg/kg group, phillyrin irritate stomach 150mg/kg group obviously reduce HA, LN, PcIII, HYP level (with model control group relatively, p<0.05 or 0.01).The stomach 75mg/kg group of irritating phillyrin reduces HA, LN, PcIII, HYP level and phillyrin and irritates stomach 150mg/kg group relatively, there was no significant difference; Phillyrin intravenous injection 40mg/kg group reduces HA, LN, PcIII, HYP level and phillyrin intravenous injection 80mg/kg group relatively, there was no significant difference.
Table 5 phillyrin is to the influence of rat liver fibrosis pathomorphism
Group | Dosage (mg/kg) | 0 | I | II | III | IV | T |
Normal group model group Rosiglitazone group forsythin intravenous injection group forsythin gavage group | --- NS 8 1 2.5 12.5 40 80 2.5 5 25 75 150 | 10 0 0 0 0 0 0 0 0 0 0 0 0 | 0 0 3 1 1 2 3 3 1 1 3 3 2 | 0 1 4 2 2 3 2 4 2 2 2 4 5 | 0 4 3 3 6 4 5 3 3 7 5 3 2 | 0 5 0 4 1 1 0 0 4 0 0 0 1 | -- --- 66 ▲▲ 95 81.5 ▲ 76 ▲ 71 ▲▲ 66 ▲▲ 95 77 ▲ 71 ▲▲ 66 ▲▲ 66 ▲▲ |
Compare with model group,
▲P<0.05;
▲ ▲P<0.01.
Table 6 phillyrin is to the influence of hepatic fibrosis rats hepatic tissue HYP content and serum HA, LN and PCIII content
Group | Dosage (mg/kg) | HYP (μg/L) | PCIII (μg/L) | HA (μg/L) | LN (μg/L) |
The normal control group | --- | 760±90 | 14.2±2.8 | 40.7±7.5 | 31.3±6.9 |
Model group | NS | 1769±130 | 42.6±8.5 | 130.4±24.1 | 87.6±19.4 |
The rosiglitazone group | 8 | 1259±153 ▲▲ | 26.5±9.6 ▲▲ | 88.9±20.5 ▲▲ | 63.6±16.8 ▲▲ |
Phillyrin intravenous injection group | 1 | 1704±124 | 38.2±7.8 | 115.2±24.1 | 79.6±19.0 |
2.5 | 1630±110 ▲ | 34.2±7.6 ▲ | 106.3±23.4 ▲ | 68.3±17.9 ▲ | |
12.5 | 1578±113 ▲▲ | 31.4±7.8 ▲▲ | 97.5±23.6 ▲▲ | 62.0±20.0 ▲▲ | |
40 | 1278±121 ▲▲ | 26.5±9.1 ▲▲ | 77.9±20.7 ▲▲ | 57.6±16.8 ▲▲ | |
80 | 1217±143 ▲▲ | 25.7±7.8 ▲▲ | 74.6±18.9 ▲▲ | 55.3±14.6 ▲▲ | |
Phillyrin is irritated the stomach group | 2.5 | 1724±121 | 38.0±7.5 | 113.8±24.8 | 79.1±19.4 |
5 | 1614±121 ▲ | 33.7±7.3 ▲ | 104.3±26.4 ▲ | 69.3±16.9 ▲ | |
25 | 1535±125 ▲▲ | 31.6±7.2 ▲▲ | 97.0±24.6 ▲▲ | 61.0±20.6 ▲▲ | |
75 | 1299±153 ▲▲ | 27.5±9.6 ▲▲ | 84.9±20.5 ▲▲ | 59.6±16.8 ▲▲ | |
150 | 1250±174 ▲▲ | 26.9±10.5 ▲▲ | 80.7±18.6 ▲▲ | 57.3±18.6 ▲▲ |
Compare with model group,
▲P<0.05;
▲ ▲P<0.01.
Claims (5)
1. the application of phillyrin in the medicine of preparation treatment or prophylaxis of acute hepatic injury.
2. the application of phillyrin in the medicine of preparation treatment or prevention chronic hepatic injury.
3. the application of phillyrin in the medicine of preparation treatment or prevention hepatic fibrosis.
4. according to the arbitrary described application of claim 1-3, its drug administration by injection dosage is 25-800mg, and oral administration dosage is 50-1500mg.
5. application according to claim 4, drug administration by injection preferred dose are 25-400mg, and the oral administration preferred dose is 50-750mg.
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