CN1899367B - Carpet bugle extract, its preparing method, use and compound preparation - Google Patents
Carpet bugle extract, its preparing method, use and compound preparation Download PDFInfo
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- CN1899367B CN1899367B CN 200510085017 CN200510085017A CN1899367B CN 1899367 B CN1899367 B CN 1899367B CN 200510085017 CN200510085017 CN 200510085017 CN 200510085017 A CN200510085017 A CN 200510085017A CN 1899367 B CN1899367 B CN 1899367B
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Landscapes
- Medicines Containing Plant Substances (AREA)
Abstract
The present invention discloses a kind of carpet bugle extract, and its use in preparing medicine for hysteromyoma and hyperplasia of mammary glands and compound preparation. The carpet bugle extract and its compound preparation have obvious curative effect on hysteromyoma and hyperplasia of mammary glands and no obvious toxic side effect. The carpet bugle extract has main components of 8-acetyl harpagide and harpagide.
Description
Technical field
The present invention relates to Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.) extract, in more detail, the present invention relates to be used for the treatment of the Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.) extract of hysteromyoma or cyclomastopathy.
Background technology
Carpet bugle preparation mainly contains: the muscles and bones blade (ministry standard, WS3-B-1446-93) and capsule (ministry standard WS3-B-3704-98), act as heat-clearing and toxic substances removing, eliminates the phlegm cough-relieving.The property of medicine hardship that Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.) is put down in writing in traditional Chinese medicine is sweet, and is cold; Supplement to the Herbal record sweet in the mouth is flat, nontoxic; " detailed outline is picked up any lost article from the road " record is cold in nature, bitter in the mouth; " book on Chinese herbal medicine is new again " record is returned through " going into lung meridian ".Has clearing away lung-heat to relieve cough, promoting the function of the gallbladder to alleviate jaundice, cool liver endogenous wind stopping, the effect of hard masses softening and resolving.Cure mainly tracheitis, spit blood epistaxis, bloody dysentery, gonorrhea, laryngopharynx swelling and pain, furuncle, carbuncle, traumatic injury.
Existing carpet bugle preparation (sheet and capsule), heat-clearing and toxic substances removing, cough-relieving is eliminated the phlegm, and relievings asthma, and is used for acute and chronic bronchitis, pulmonary abscess.In these products, be the extract that obtains with ethanol extraction, and make tablet and capsule after mixing with the herb coarse crushing, without any qualitative and quantitative index control its quality.The quality of existing product all has instability, and dose is big, poor solubility, and bioavailability is low, and all there are many defectives in no specificity quality control criterion on Technology and quality control.
The muscles and bones blade is 77 editions kinds of recording of Chinese Pharmacopoeia, be the Herb of Labiatae Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.) Ajugadecumbens Thunb.. according to Min Zhida et al, Chem Pharm Bull, 1990,38 (11): 3167Y TAKEDA, S TSUCHIDA and T FUJITA.Phytochemistry, 1987,26 (8): 2303 record, the main chemical compositions in the Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.) are iridoids, Diterpenes, flavonoid and phenethyl alcohol glycosides etc.Wherein iridoids has 8-acetyl group Harpagide (8-O-acetylharpagide), Harpagide (Harpagide), the general glycosides of Lay (Reptoside), ajugoside A, B, C, D (decumboside A, B, C, D) and ajugasterone (decumbesterone) etc.
In sum, up to the present, do not see about the relevant report of Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.) extract effective part group or document openly, it is open not see that also Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.) is used for the treatment of the report or the document of hysteromyoma and cyclomastopathy.
Hysteromyoma and cyclomastopathy are commonly encountered diseases and the frequently-occurring diseases that threatens WomanHealth, also are the difficult disease that domestic and international medical circle is being studied.Modern study confirms that the pathogeny of these two kinds of diseases is all long-term in tension relevant with spirit.In today that rhythm of life is accelerated day by day, its sickness rate is in rising trend.Chinese and western medicine does not all have effective medicine so far, and the excision uterus is final Therapeutic Method, and uterectomy can bring new body, pained hardship to the patient, especially for the period of duration women.Therefore, and development toxic and side effects little medicine definite to such curative effect of disease will be benefited the patient.
Summary of the invention
Based on the narration of above-mentioned background technology part, press for for a long time and develop for hysteromyoma or cyclomastopathy is evident in efficacy and toxic and side effects is little medicine.The inventor finds to adopt Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.) to make raw material through years of researches and a large amount of test, adopts the specific extract that extracting method obtained, and can treat hysteromyoma or cyclomastopathy effectively, and the toxic and side effects that produces is very little.
The technical problem to be solved in the present invention provides a kind of Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.) extract that is used for the treatment of hysteromyoma or cyclomastopathy.Another technical problem that the present invention will solve provides this preparation method of extract.Another technical problem that the present invention will solve provides the purposes that this extract is used to prepare the medicine for the treatment of hysteromyoma or cyclomastopathy.Another technical problem that the present invention will solve provides the compound preparation that contains this extract.
Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.) extract of the present invention is one of by the following method preparation:
(1). as raw material, water or concentration are lower than 80% ethanol with the Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.) coarse powder, at 30-90 ℃, preferably carry out heating extraction at 45-70 ℃, perhaps carry out percolation, it is 1.0-1.3 that extracting solution is concentrated into proportion, preferably to 1.12-1.16, filter, handle through macroporous adsorbent resin, after impurity is removed in washing, alcoholic solution eluting resin to effective ingredient with 30%-95% washes out fully, reclaim solvent, drying obtains the said extracted thing;
Perhaps (2). as raw material, is 40%-95% ethanol extraction with concentration with the Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.) coarse powder, and it is 1.0-1.3 that extracting solution is concentrated into proportion, preferably to 1.12-1.16, the alcoholic solution of water or 5%-30% returns moltenly then, and dissolution fluid is filtered, reclaim solvent, drying obtains the said extracted thing.
The effective part group of extract of the present invention is 8-acetyl group Harpagide (8-O-acetylharpagide) and Harpagide (Harpagide); their content in extract is 50-99%, and the proportion of Harpagide and 8-acetyl group Harpagide is about 1: in the 2-4 scope.
Compound preparation of the present invention contains said extracted thing and invigorating blood circulation (breaking) stasis of blood, promoting blood flow to regulate menstruation, heat clearing and damp drying, heat-clearing and toxic substances removing, clearing away heat and cooling blood, regulating QI to relieve pain, enrich blood and suppressing liver-YANG class Chinese medicine at least a.Wherein invigorating blood circulation (breaking) stasis of blood class Chinese medicine is selected from least a in Rhizoma Chuanxiong, Olibanum, Myrrha, Rhizoma Curcumae Longae, the Radix Curcumae; Promoting blood flow to regulate menstruation class Chinese medicine is selected from least a in Herba Leonuri, Semen Persicae, Flos Carthami, the Radix Salviae Miltiorrhizae; Heat clearing and damp drying class Chinese medicine is selected from least a in Spica Prunellae, Radix Sophorae Flavescentis, Radix Scutellariae, the Radix Gentianae; Antipyretic and antidotal type Chinese medicine is selected from least a in Herba Patriniae, Rhizoma Osmundae, Herba Houttuyniae, Flos Chrysanthemi Indici, Herba Euphorbiae Humifusae, Herba Lobeliae Chinensis, Rhizoma Bistortae, Herba Hedyotidis Diffusae, Indigo Naturalis, Pseudobulbus Cremastrae Seu Pleiones, Radix Rhapontici, the Folium Eucalypti Robustae; Clearing away heat and cooling blood class Chinese medicine is selected from least a in the Radix Rehmanniae, Radix Scrophulariae, Radix Arnebiae (Radix Lithospermi), Cortex Moutan, the Radix Paeoniae Rubra; Regulating QI to relieve pain class Chinese medicine is selected from least a in Rhizoma Cyperi, Fructus Citri Sarcodactylis, Flos Rosae Rugosae, Lignum Santali Albi, the Radix Linderae, the Semen Litchi; Hematonic class Chinese medicine is selected from least a in the Radix Paeoniae Alba, Radix Rehmanniae Preparata, the Radix Polygoni Multiflori; Suppressing liver-YANG class Chinese medicine is selected from Concha Ostreae.
The common process that compound preparation of the present invention can adopt pharmaceutical field to prepare compound preparation is prepared, for example, the various pharmaceutic adjuvants (cellulose family, starch based, dextrin class, magnesium stearate, lactose, micropowder silica gel etc.) that extract of the present invention and field of medicaments is commonly used mix preparations shaping; Perhaps with extract of the present invention, above-mentioned invigorating blood circulation (breaking) stasis of blood, promoting blood flow to regulate menstruation, heat clearing and damp drying, heat-clearing and toxic substances removing, clearing away heat and cooling blood, regulating QI to relieve pain, enrich blood and at least a drug powder of suppressing liver-YANG class Chinese medicine or its extract and above-mentioned various pharmaceutic adjuvant mix preparations shaping; Perhaps also Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.) can be extracted with at least a back of mixing of above-mentioned invigorating blood circulation (breaking) stasis of blood, regulating QI to relieve pain and antipyretic and antidotal type Chinese medicine, then extract be mixed preparations shaping with above-mentioned various pharmaceutic adjuvants.
Extract of the present invention and compound preparation thereof can be made the various regular dosage forms of field of medicaments; for example; various common dosage forms such as tablet, pill, capsule, gel, powder spray, aerosol, suspensoid, Emulsion, syrup, aseptic injection; also can be the rapid release or the preparation long-acting or site-specific delivery of drugs or release of above-mentioned various dosage forms; wherein the used technology of durative action preparation is to utilize pH to rely on the controlled release technique for packing, or colonic enzyme degraded controlled release technique for packing is made micron grain or nanoparticle and obtained.
Above-described extract of the present invention or compound preparation, can pass through various administrations commonly used, comprise oral, mucosa, percutaneous, subcutaneous, intravenous and intramuscular injection administration, according to body weight that gives object and symptom, give dosage with usually in the scope in 10-500 milligram (extract)/sky.
Extract of the present invention and compound preparation thereof prove through the inventor's a large amount of pharmacodynamicss and toxicology test, have significant curative effect for treatment hysteromyoma or cyclomastopathy, and life-time service do not have obvious toxic-side effects.For the ease of being well understood to the present invention more; this description with the lower part, the inventor makes further description to the present invention by specific embodiment, still; and the non exhaustive this specific embodiment, protection scope of the present invention is not construed as limiting.
The specific embodiment
Embodiment 1-4
Prepare the extract of embodiment 1-4 according to following arbitrary extracting method, the concrete technological parameter that is adopted is referring to table 1:
(1) with the Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.) coarse powder as raw material, water or ethanol carry out heating extraction, perhaps carry out percolation, extracting solution concentrates, filter, handle, after impurity is removed in washing, wash out fully with alcoholic solution eluting resin to effective ingredient through macroporous adsorbent resin, reclaim solvent, drying obtains the said extracted thing;
Perhaps (2) as raw material, use ethanol extraction with the Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.) coarse powder, concentrated extracting solution, and water or alcoholic solution return moltenly then, and dissolution fluid is filtered, and reclaim solvent, and drying obtains the said extracted thing.
Table 1 Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.) extract technological parameter
The physical and chemical parameter of effective site and experimental basis thereof in the extract of the present invention
According to experimental analysis; the effective part group of extract of the present invention is 8-acetyl group Harpagide (8-O-acetylharpagide) and Harpagide (Harpagide); their content in extract is 50-99%, and the proportion of Harpagide and 8-acetyl group Harpagide is about 1: in the 2-4 scope.
Harpagide has the structure of following general formula I, be to find and be reported in [Biological analysis ofHarpagophytum procumbens D.C.II.Pharmacological analysis of the effects ofharpagoside from Harpagophytum procumbens plant first by Fontaine J etc. in 1981, harpagide and harpagogenine on the isolated guinea-pig ileum, J PharmBelg., 1981 Sep-Oct; 36 (5): 321-4]; 8-acetyl group Harpagide has the structure of following general formula I I, be that Breschi MC etc. finds and be reported in [Vasoconstrictor activityof 8-O-acetylharpagide from Ajuga reptans., J.Nat.Prod.1992 first from Ajuga reptans plant; Aug; 55 (8): 1145-8].
General formula I: general formula I I:
The structural analysis of Harpagide:
Maximum absorption wavelength is 197nm, and the two keys of molecular structure neither one are described; IR provide following signal 3381 →-OH, 1655 → C=C, 1237,1075 →-C-O-C-, 947 → cis-CH=CH-;
1H-NMR (DMSO-d6) shows: and angular methyl signal δ 1.23 (3H, s), five saccharic subsignal δ 3.21-3.89, sugared terminal hydrogen signal δ 4.56 (1H, d, J=7.8Hz), two alkene hydrogen signal δ 4.94 (1H, d, J=6.3Hz) and 6.30 (1H, d, J=6.3Hz);
13C-NMR (DMSO-d6) shows 16 carbon signals altogether, removes six the carbon signal δ 99.4 (d) on the glucose, 74.5 (d), and 78.1 (d), 71.7 (d), 77.5 (d), outside 62.8 (t), also surplus 10 carbon signals prompt for the monoterpenes chemical compound;
13C-NMR shows two olefinic carbon signal δ 142.6 (d) and 108.5 (d), and an acetal carbon δ 93.2 (d), this chemical compound are iridoid glycoside.Compare with chemical compound 1, chemical compound 2 except that having lacked an acetoxyl group, other information basically identicals; FAB-MS has also verified this point: the molecular weight of chemical compound 2 is 364, compares with the molecular weight 406 of chemical compound 1, just in time differs 42 (COCH
3); Therefore infer that chemical compound 2 is harpagide.Will according to DEPT, HMQC and HMBC spectrum
1H-NMR and
13The C-NMR data belong to.
The structure of Harpagide is identified:
UV λ: 197nm; IR v
Max KBr: 3381,2930,1655,1379,1237,1075,947cm
-1FAB-MS (m/z): 387[M+Na]
+, 347[M-OH], 274,207,167 (100%), 145,115;
1H-NMR (300Hz, DMSO) δ: 1.23 (3H, s, H-10), 1.78 (1H, dd, J=3.9,14.1Hz, 7 α-H), 1.90 (1H, dd, J=4.5,13.5Hz, 7 β-H), 2.53 (1H, brs, H-9), 3.21 (1H, d, J=7.8Hz, H-2 '), (3.26 1H, m, H-4 '), 3.29 (1H, m, H-3 '), 3.40 (1H, m, H-5 '), 3.63 (1H, d, J=5.4Hz, H-6), 3.68 (1H, m, H1-6 '), 3.89 (1H, dd, J=1.8,10.2Hz, H
2-6 '), 4.56 (1H, d, J=7.8Hz, H-1 '), 4.94 (1H, d, J=6.3Hz, H-4), 5.73 (1H, d, J=1.2Hz, H-1), 6.30 (1H, d, J=6.3Hz, H-3);
13The C-NMR data see Table.
The structural analysis of 8-acetyl group Harpagide:
Maximum absorption wavelength is 197nm, and illustrating does not have conjugated double bond in the molecular structure; IR shows following functional group: 3440 →-OH, 1711 → C=O, 1652 → C=C, 1238,1075 →-C-O-C-, 960 → cis-CH=CH-;
1H-NMR (DMSO-d
6) show: angular methyl signal δ 1.35 (3H, s), acetoxyl group signal δ 1.92 (3H, s), six saccharic subsignal δ 2.98-3.68, sugared terminal hydrogen signal δ 4.38 (1H, d, J=7.8Hz), two cis alkene hydrogen signal δ 4.87 (1H, d, J=6.3Hz) and 6.35 (1H, d, J=6.3Hz);
13C-NMR (DMSO) shows 16 carbon signals altogether, remove an acetoxyl group signal 22.0 (q), 170.1 (s) and glucose on six carbon signal δ 97.3 (d), 73.0 (d), 77.1 (d), 70.2 (d), 75.7 (d), 61.6 (t), also surplus 9 carbon signals prompt for the monoterpenes chemical compound;
13C-NMR shows two olefinic carbon signal δ 141.2,107.4 and acetal carbon signal 92.4 (d), is illustrated as iridoid.Will
13The literature value of C-NMR data and 8-acetylharpagide
[4]Relatively, the two is identical substantially, therefore, determines that this chemical compound is 8-acetylharpagide.Will according to DEPT, HMQC and HMBC spectrum
1H-NMR and
13The C-NMR data belong to.
The structure of 8-acetyl group Harpagide is identified:
UVλ：197nm；IR?v
max KBr：3440，2912，1711，1652，1375，1238，1075，960；FAB-MS(m/z)：429[M+Na]
+，407[M+H]
+，369，329(100％)，311，277，241，209；
1H-NMR(DMSO-d6)δ：1.35(3H，s，10-CH
3)，1.92(3H，s，-COCH
3)，1.77(1H，dd，J＝4.5，14.7Hz，7α-H)，2.05(1H，dd，J＝3.9，12.9Hz，7β-H)，2.64(1H，brs，H-9)，2.98(1H，d，J＝6Hz，H-2’)，3.06(1H，m，H-5’)，3.10(1H，m，H-4’)，3.14(1H，m，H-3’)，3.46(1H，d，J＝1.2Hz，H
1-6’)，3.56(1H，brs，H-6)，3.68(1H，dd，J＝6.6Hz，H
2-6’)，4.38(1H，d，J＝7.8Hz，H-1’)，4.87(1H，d，J＝6.3Hz，H-4)，5.86(1H，d，J＝1.2Hz，H-1)，6.35(1H，d，J＝6.3Hz，H-3)。
The assay of extract
Method: measure according to high performance liquid chromatography (appendix VID of Chinese Pharmacopoeia version in 2000).Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica; Acetonitrile-water (10: 90) is a mobile phase; The detection wavelength is 197nm; 30 ℃ of column temperatures.
The preparation of reference substance solution: precision takes by weighing Harpagide and acetyl Harpagide reference substance is an amount of, and dissolve with methanol is mixed with the reference substance solution of 0.088mg/ml and 0.124mg/ml respectively.
The preparation of need testing solution: the accurate title of extract 0.1g of getting preparation according to the method described above is fixed, put in the conical flask, precision adds 20% ethanol 100ml, close plug, weigh, supersound process 10min is put coldly, weighs, supply the weight that subtracts mistake with 20% ethanol, shake up, filter with microporous filter membrane (0.45 μ m), promptly.
Algoscopy: accurate respectively reference substance solution 5 μ l and the need testing solution 5 μ l of drawing, inject chromatograph of liquid, measure, promptly.
The result: the mensuration of 10 batch samples is all at 50-70%.The measurement result of its response rate is as follows.
Table 2 acetyl Harpagide determination of recovery rates result
The determination of recovery rates result of table 3 Harpagide
Referring to this Figure of description, that represent among the figure is the high performance liquid chromatogram figure of Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.) extract assay of the present invention.
Embodiment 5-12
Contain the preparation of the Chinese medicinal compound extract of carpet bugle
According to the arbitrary compatibility combination among the embodiment 5-12, with mix application after common process that the Chinese medicinal compound extract of Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.) extract compatibility can adopt pharmaceutical field to prepare compound preparation is prepared, perhaps also can with carpet bugle with extract after at least a medicine among the embodiment 5-12 mixes, then extract is mixed preparations shaping with above-mentioned various pharmaceutic adjuvants. The concrete compatibe drug that adopts is referring to table 2:
The medicine that table 4 and Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.) extract compatibility are used
Embodiment 13
Active component is to the pharmacodynamics test data of rat mammary gland model of hyperplasia in the Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.) extract
The rat mammary gland model of hyperplasia following pathological change occurs as the sign of model success take the breast tissue of model group rat: the lobule of mammary gland number increases, acinus increases in the leaflet, leaflet is dispersivity and increases, even mutually merge, the leaflet form is irregular, distortion, or lose leaflet structure, profile is unclear, but still keeps the characteristics of lobular hyperplasia. The obvious hyperplasia of leaflet ductal epithelium of individual animal, the low film of the base of part envelope obviously thickens, and has vitreous fibre sample secretion or slurries to ooze out in the envelope, and the slight hyperplasia of connective tissue in indivedual leaflets has a large amount of lymphocytic infiltrations around the leaflet.
Curative effect determinate standard is used the pharmacology statistical software and is added up with the sxemiquantitative grade scale of above-mentioned Histopathologic change, relatively has significant difference to be as the criterion with model group.
1. test material
1.1 medicine: Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.) extract: every gram contains 8-O-Acetylharpagide 700mg. The breast addiction disappears: Liaoning Province Heng Ren medicine company Co., Ltd, lot number: 02042; Estradiol benzoate injection: 1mg/ml, Shanghai the 9th pharmaceutical factory produces, lot number: 001102. Progesterone injection: 10mg/ml, Shanghai the 9th pharmaceutical factory produces, lot number 020115. The short folliculus of serum ripe plain (hFSH), estradiol (E2), serum luteinizing principle (LH) radioimmunoassay kit: all available from Beijing Fu Rui bio-engineering corporation, lot number: 0109.
1.2 animal: SD kind rat, female, 200-250 gram, available from dimension tonneau China animal used as test Co., Ltd, the quality certification number: SCXK (capital) 2002-0003.
1.3 instrument: FG-630 microcomputer multiple tracks γ analyzer, Beijing 262 factories make; The SAKUPA automatic dehydrator, Japan produces; The Leitz rotary microtom, Germany produces; SAKURA RSH-100 automatic staining machine, Japan produces; The Nikon light microscope, Japan produces; The biological automatically microphotograph system of DLYMPUS BH-2, Japan produces.
2. method
Get SD kind rat, be divided at random 6 groups according to body weight, 10 every group, except the blank group, all the other animal muscle injection oestradiol benzoate 0.5mg/Kg, continuous 25 days, use intramuscular injection progesterone 4mg/Kg instead, every day 1 time, continuous 5 days afterwards at every day 1 time. Moulding simultaneously with Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.) extract according to 40,20,10mg/Kg gastric infusion 30 days, the positive control drug breast addiction continuous gastric infusion of 2.4g/Kg 30 days (quite 30 times of clinical dosage) that disappears. The 31st day, animal is anaesthetized with 3% amobarbital, abdominal aortic blood, centrifugal, get determination of serum estradiol (E2), short folliculus ripe plain (hFSH), luteinizing principle (LH); Visual inspection mammary gland situation; Get the 2nd, 3 pair of breast with the 8mm card punch and weigh, 10% formalin is fixed, paraffin section, HE dyeing, light microscopy checking; Get ovary and weigh in the uterus. Compare group difference with the t check.
3. result
3.1 the impact to the rat mammary gland model of hyperplasia
3.1.1 the impact to the breast general form
Visually observe demonstration, the 2nd, the 3 pair of breast of model group rat is all obviously red and swollen, and nipple increases, increases, and the disappear breast redness of group and the large, medium and small dosage group of administration rat of positive drug breast addiction obviously alleviates, and nipple increases, increases not obvious.
3.1.2 the impact to breast wt
The result shows that the 2nd, the 3 pair of breast wt of model group rat all obviously increases, and be remarkable with the control group comparing difference; With model group relatively, the disappear breast wt of group and each dosage group rat of administration of positive drug breast addiction obviously reduces (seeing Table 1).
3.1.3 the impact to the breast tissue form
Observe under the light microscopic, the mammary gland of rats in normal control group has no obvious hyperplasia, and structure is normal. The lobule of mammary gland number of model group rat increases, and acinus increases in the leaflet, and leaflet is dispersivity and increases, even mutually merges, and the leaflet form is irregular, distortion, or lose leaflet structure, profile is unclear, but still keeps the characteristics of lobular hyperplasia. The obvious hyperplasia of leaflet ductal epithelium of individual animal, the low film of the base of part envelope obviously thickens, and has vitreous fibre sample secretion or slurries to ooze out in the envelope, and the slight hyperplasia of connective tissue in indivedual leaflets has a large amount of lymphocytic infiltrations around the leaflet. Each group of administration and the breast tissue pathology of positive drug control group all have in various degree improvement than model group, acinus increases, increases, the glandular tube epithelium thickens, ooze out in the glandular tube, inflammatory infiltration degree around the acinus all obviously alleviates than model group, and the large, medium and small dosage group of administration is dose-effect relationship to the effect of breast tissue with the increase of its dosage.
3.1.4 the impact to the uterus coefficient
The result shows that the uterus weight of model group rat increases, and the uterus coefficient increases, and is remarkable with the control group comparing difference; With model group relatively, the uterus weight of the heavy dose of group of positive drug and administration rat alleviates, the uterus coefficient reduces, significant difference is in the administration, the uterus coefficient of small dose group rat has reduction trend, but there was no significant difference (seeing Table 5).
3.2 the impact to hormonal readiness
The result shows that the estradiol of model group rat (E2) and serum luteinizing principle (LH) obviously raise, and be remarkable with blank group comparing difference; Compare with model group, each group of positive drug and administration can reduce the E2 level, with model group comparing difference remarkable (P＜0.05); To short folliculus ripe plain (hFSH) and the influential trend of luteinizing principle (LH), but there was no significant difference (P＞0.05) (seeing Table 4).
4. brief summary
Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.) extract with 40,20,10mg (extract)/Kg dosage gastric infusion, with the positive contrast medicine of RUPIXIAO electuary 2.4g/Kg (quite 30 times of clinical dosage), can resist rat experiment hyperplasia of mammary gland model due to female, the progestogen, reduce the degree and the breast wt of its cyclomastopathy, reduce estradiol level, reduce the uterus coefficient, remarkable with the model group comparing difference.
Influence (X ± the S of table 1. pair rat breast weight; N=10)
Annotate: compare with the blank group:
#P＜0.05;
##P＜0.01; Compare with model group:
*P＜0.05;
*P＜0.01 (down together).
Influence (X ± the S of table 2. pair rat breast tissue morphology; N=10)
Annotate: continuous 3 visuals field under 10 * 10 times of mirrors;
The acinus number is the mean of the maximum persons of acinus number in every visual field.
Influence (the X of table 3. pair rat mammary gland hyperplasia degree
±S; N=10)
Annotate: the grade scale of cyclomastopathy:
+++severe: inflammatory cell infiltration and epithelial proliferation have connective tissue individually than disperse.
++ moderate: inflammatory cell infiltration and epithelial proliferation be limitation, involves a plurality of lobules.
+ slight: inflammatory cell infiltration and epithelial proliferation are dispersed in the form of sheets.
-normal: there are not obvious hypertrophy and inflammatory cell infiltration.
Influence (X ± the S of table 4. pair hormonal readiness; N=8)
Influence (X ± the S of table 5. pair rat uterus coefficient; N=10)
Embodiment 14
Effective site is to the pharmacodynamics test data of animal uterus muscular tumor model in the Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.) extract
Animal uterus muscular tumor model increases with the uterus weight of model group animal, estrogen level raises, uterine smooth muscle thickness increases and the sign that following pathological change is the model success appears in uterine cancer cell: subangle uterus root smooth muscle layer is obviously inhomogeneous thickening, the smooth muscle cell arrangement disorder, show that the smooth muscle strand is main, orientation is vortex, nucleus is elongated rod shape, rounded or the polygon of indivedual smooth muscle cell is arranged, matter has obviously hemorrhage between the uterus muscle of part animal, myometrium has red degeneration, and the infiltration of slight inflammatory cell arranged, based on lymphocyte, a small amount of neutrophilic granulocyte is arranged.
Curative effect determinate standard is used the pharmacology statistical software and is added up with the variation of These parameters and the sxemiquantitative grade scale of pathological tissue, relatively has significant difference to be as the criterion with model group.
1. material
1.1 animal Cavia porcellus: female, body weight 300-350g; Rat: the SD kind, female, body weight 200-250 gram, the SPF level, available from dimension tonneau China laboratory animal company limited, the quality certification number: SCXK (capital) 2002-0003.Rabbit: female, New Zealand's kind, 2-2.5Kg all cultures factory's (capital is moving is betrothed to 2000 No. 010 total No. 55) available from Beijing tonneau.Mice: the Kunming kind, male and female half and half, body weight 18-20g is available from factory that zooscopy is bred of the Chinese Academy of Medical Sciences (quality certification number: SCXK 11-00-0006).
1.2 medicine and reagent Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.) extract: every gram contains acetyl Harpagide 700mg.Ramulus Cinnamomi Poria pill: Jin Ding pharmaceutcal corporation, Ltd in Chengdu produces, lot number: 0020627.Estradiol benzoate injection: 1mg/ml, Shanghai the 9th pharmaceutical factory produces, lot number: 991102.Progesterone injection: 10mg/ml, Shanghai the 9th pharmaceutical factory produces, lot number 980201.The short folliculus of serum ripe plain (hFSH), estradiol (E2), serum lutropin (LH) radioimmunoassay kit: all available from Beijing Fu Rui bio-engineering corporation, lot number: 0009.
1.3 instrument BIOPACSY STEM eight road physiology monitors: Americanized.FG-630 microcomputer multiple tracks γ analyzer: Beijing 262 factories make.
2. method and result
2.1 influence to the experimental leiomyoma of uterus of Cavia porcellus
Select 60 of adult unpregnancy Cavia porcelluss for use, be divided into normal control group, model control group group, positive drug control group, the large, medium and small dosage group of Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.) extract at random, 10 every group.The intramuscular injection estradiol benzoate is respectively organized in model group and administration, 0.2mg/ only, 3 times/week, inject 3 months continuously after, add a Progesterone 1.5mg/ intramuscular injection, 2 times/week, continuous 1 month.In moulding simultaneously, each dosage group oral administration every day of Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.), model group and normal control group such as are given every day at dosage water.After 4 months, behind all animals administer 0.5h, 3% pentobarbital intraperitoneal injection of anesthesia (0.1ml/100g) is weighed, and abdominal aortic blood is centrifugal, gets serum and surveys estradiol (E2), the short folliculus of serum ripe plain (hFSH), serum lutropin (LH); Cut open the belly and observe the uterus general form,, weigh, calculate the uterus coefficient, (uterus weight/body weight) along clip uterus, bladder disjunctor place, uterus; Measure the above and subangle uterus root transverse diameter of cervix uteri; Fixing in 20% neutral formalin, the above same area crosscut of the uterus subangle 0.5cm that draws materials, 3 of every side-draw materials, paraffin embedding, HE dyeing, om observation uterine cancer cell form, 5 positions are chosen in every section, under 10 * 10 mirrors, measure smooth muscle thickness with micro-micrometer, average, with t check comparable group differences.
2.1.1 the uterus weight that influences the model group animal to uterus weight increases, and is remarkable with the matched group comparing difference.Each group of administration and relatively weight saving of model group, significant difference (P＜0.05).See Table 1.
2.1.2 to the uterus transverse diameter influence under the model group animal uterus subangle and subangle root transverse diameter increases slightly than matched group, significant difference, administration is respectively organized transverse diameter all less than model group, significant difference (P＜0.05).See Table 1.
2.1.3 the influence to uterine smooth muscle thickness is a thickness unit with the little lattice number of eyepiece micrometer, the normal matched group of model group animal uterus smooth muscle thickness obviously thickens (P＜0.001), each group of administration is than the obvious attenuation of model group, with model group comparing difference remarkable (P＜0.001).See Table 2.
Table 1. pair hysteromyoma Cavia porcellus uterus heavily reaches the influence (X ± S of uterus transverse diameter; N=10)
Annotate: compare * P＜0.05 with model group; * P＜0.01 (down together)
Influence (X ± the S of table 2. pair hysteromyoma Cavia porcellus uterine smooth muscle thickness; N=10)
2.1.4 to hormonal readiness influence model group animal serum E2 and the LH level obviously raises, each group of administration all can reduce the E2 level to some extent, with model group comparing difference significantly (P＜0.05); To hFSH and the influential trend of LH, but there is not significant difference (P＞0.05).See table 2 for details.
Influence (X ± the S of table 2. pair hysteromyoma Cavia porcellus hormonal readiness; N=10)
2.1.5 the morphological change mirror of uterine cancer cell is observed down, normal control treated animal Uterine mucosa body of gland belongs to the secretory phase, and smooth muscle flesh layer does not see and obviously thicken that a matter is not seen the infiltration of hemorrhage and inflammatory cell.Model components silver coin palace root smooth muscle layer is obviously inhomogeneous thickening, the smooth muscle cell arrangement disorder, show that the smooth muscle strand is main, orientation is vortex, and nucleus is elongated rod shape, and the rounded or polygon of indivedual smooth muscle cell is arranged, matter has obviously hemorrhage, myometrium that red degeneration is arranged between the uterus muscle of part animal, and the infiltration of slight inflammatory cell is arranged, based on lymphocyte, a small amount of neutrophilic granulocyte is arranged.The uterine smooth muscle layer of each treated animal of administration all is thinner than model group to some extent, arranges regularly, and inflammatory infiltration is not seen in big or middle dosage treated animal uterus, and matter does not see have obviously hemorrhagely between uterus muscle, and the small dose group individual animal is seen slight inflammatory infiltration.
2.2 to the leiomyomatous influence in rat experiment temper palace
Select 60 of adult not pregnant rats for use, be divided into normal control group, model group, positive controls, the large, medium and small dosage group of Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.) extract at random, 10 every group.Intramuscular injection estradiol benzoate 0.5mg/Kg is respectively organized in model group and administration, 3 times/week, inject 3 months continuously after, add Progesterone 5mg/Kg intramuscular injection, 2 times/week, continuous 1 month.In moulding simultaneously, each dosage group oral administration every day of Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.), model group and normal control group such as are given every day at dosage water.After 4 months, behind all animals administer 0.5h, 3% pentobarbital intraperitoneal injection of anesthesia (0.1ml/100g) is weighed, and abdominal aortic blood is centrifugal, gets serum and surveys estradiol (E2); Cut open the belly and observe the uterus general form,, weigh, calculate uterus coefficient (uterus weight/body weight) along clip uterus, bladder disjunctor place, uterus; Measure the above and subangle uterus root transverse diameter of cervix uteri; Fixing in 20% neutral formalin, the above same area crosscut of the uterus subangle 0.5cm that draws materials, 3 of every side-draw materials, paraffin embedding, HE dyeing, om observation uterine cancer cell form, 5 positions are chosen in every section, under 10 * 10 mirrors, measure smooth muscle thickness with micro-micrometer, average, with t check comparable group differences.
2.2.1 the model group the weight of animals that influences to body weight, uterus and ovary weight descends, uterus weight increases, and ovary weight reduces, and is remarkable with the matched group comparing difference.The body weight of each treated animal of administration and ovary weight all have to some extent to be increased, and uterus weight all has decline to some extent, and is remarkable with the model group comparing difference.See table 3 for details.
Table 3, to the influence of hysteromyoma rat body weight and uterus, ovary coefficient (n=10, X ± S)
2.2.2 to the atrophy of thymus gland that influences the model group animal of immune organ, weight descends, spleen weight increases, and is remarkable with normal control group comparing difference.The thymus of each treated animal of administration and body weight all have to some extent to be increased, and spleen weight all has decline to some extent, and is remarkable with the model group comparing difference.See Table 4.
Table 4, to the influence of hysteromyoma rat immunity organ (n=10, X ± S)
2.2.3 to the uterus root thickness influence model group animal uterus subangle root vertically the footpath, diameter all increases slightly than matched group under footpath and the subangle root anyhow, remarkable with normal control group comparing difference, the uterus root diameter (RD) of each treated animal of administration is all less than model group, with model group comparing difference remarkable (P＜0.05).See Table 5.
Table 5, to the influence of hysteromyoma rat uterus root thickness (n=10, X ± S)
2.2.4 the estradiol that influences the model group animal (E2) to hormonal readiness obviously raises, each group of administration all can reduce the E2 level to some extent, with model group comparing difference remarkable (P＜0.05).See Table 6.
Table 6, to the influence (X ± S of hysteromyoma rat estrogen level; N=10)
2.2.5 the morphological change mirror of uterine cancer cell is observed down, normal control treated animal myometrium is made up of smooth muscle, and with the connective tissue layering, the layering of flesh layer is not obvious between muscle bundle, does not see to thicken, and does not see the infiltration of hemorrhage and inflammatory cell.The model group uterine smooth muscle obviously thickens, and nucleus is long shuttle shape, dense arrangement, nuclear mostly is elongated rod shape, the blunt circle in two ends, and chromatin is very thin, endochylema pinkiness, smooth muscle interfascicular are a spot of fiber vascular tissue and slight inflammatory cell infiltration, based on neutral leaflet nuclear.The degree that the uterine smooth muscle of each treated animal of administration thickens and inflammatory cell is contaminated all has to some extent than model group and alleviates.See Table 7,8.
Table 7, to the influence (X ± S of hysteromyoma rat uterus smooth muscle thickness; N=10)
Annotate: (being to measure under 16 * 16 times of light microscopics)
Table 8, to the influence (n=10) of uterus lesion tissue degree
Annotate: rank test: compare with model group
*P＜0.05;
*P＜0.01
Grade scale:
"-": myometrium does not see and thickens that not seeing has inflammatory infiltration, and structure is normal.
"+": myometrium thickens not obvious, and inflammatory infiltration is light.
" ++ ": myometrium slightly thickens, and inflammatory cell infiltration is more obvious, based on neutral leaflet nuclear.
" +++": myometrium obviously thickens, and inflammatory cell infiltration is heavier.
" ++ ++ ": myometrium obviously thickens, myocyte's arrangement disorder, diffuse inflammation cellular infiltration.
2.3 to the influence of rabbit in the body uterus
Rabbit faces upward the position and fixes through auricular vein injection pentobarbital sodium 30mg/Kgb.w anesthesia, and the hypogastric region cropping is made a median incision in hypogastric region, the about 4-5cm of length.Open the abdominal cavity, put into an air bag from cervix uteri and vagina intersection to an Aconitum carmichaeli Debx. palace, air bag is connected with a silica gel tube, drain the air in the air bag, and allow and be full of water in the air bag, silica gel tube links to each other with pressure transducer, with polygraph monitoring uterine activity situation.When postoperative treats that uterine activity is constant (operation back 30min approximately), write down one section normal contraction curve, then through duodenal administration, behind the record medicine 30,60 and 90min uterine activity curve, calculate area under uterine contraction amplitude, contraction frequency and the shrinkage curve with BIOPAC System Acknowledgement3.5 software for calculation.
Statistical method: respectively with behind every animals administer 30,60 and uterine contraction amplitude, 4min number of contractions and the per minute shrinkage curve of 90min record below integration do not deduct analog value before this animals administer, draw the difference of administration front and back, i.e. uterine contraction amplitude of variation value, contraction frequency changing value and area under curve changing value.Total data is all represented with mean ± standard deviation, checks the difference that compares between each administration group and model control group with t-.
The result: the Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.) heavy dose can increase 30min-90min after the administration; Low dose of can increase that the 30min-60min rabbit is at the shrinkage amplitude in body uterus after the administration, two dosage are to number of contractions and not influence of area under curve.See Table 9.
Table 9. Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.) extract is to the influence (X ± S of rabbit at the body uterine smooth muscle; N=10)
3, conclusion
Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.) extract has the obvious suppression effect to the experimental hysteromyoma model of rat due to female, the progestogen and Cavia porcellus, and can reduce the uterus weight that model causes increases, and makes under the subangle of uterus, subangle root transverse diameter and uterine smooth muscle less thick; Reduce estrogen (estradiol) level; Suppressing the congested swelling of animal uterus and the pathologic of uterine cancer cell changes; Increase the shrinkage amplitude of rabbit in the body uterus; Suppress the swollen and mice ear of rat granuloma; Suppress the pain reaction that oxytocin, chemical stimulation and thermostimulation cause mice, remarkable with the model group comparing difference.
Embodiment 15
The safety testing of Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.) extract
1, acute toxicity test
Under maximum administration capacity and maximum administration concentration condition, mouse stomach give Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.) 25g extract/kg (be equivalent to the back of 750g crude drug/kg) mostly animal show the movable phenomenon that reduces, gradually recover normal subsequently.Animal does not have death.After about 24 hours, behavior, movable basic recovery are normally after the administration.Body weight gain is normal in 14 days observation period afterwards, shows no obvious abnormalities symptom.
Under maximum administration capacity and maximum administration concentration condition, rat oral gavage gives Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.) 10g extract/kg, and (after being equivalent to 300g crude drug/kg), animal shows spontaneous activity and reduces mostly, and the motionless phenomenon of often lying prostrate is gradually recovered normal subsequently.Animal does not have death.After about 24 hours, behavior, movable basic recovery are normally after the administration.Body weight gain is normal in observation period afterwards, shows no obvious abnormalities symptom.
2, long term toxicity test
Summary: the large, medium and small dosage 1200mg/kg of Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.) extract, 220mg/kg, 40mg/kg, continuously to 25 weeks of rat oral gavage administration.The result shows that the general state of each administration group rat, hematology, blood biochemical learn index and the main organs tissue shows no obvious abnormalities.
Test objective
Observe Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.) extract SD kind female rats was gavaged for 25 weeks continuously, the issuable toxic and side effects of animal body and the order of severity thereof are to determine the safe dose scope of this product, for people's data for clinical drug use provides foundation.
Test material
Be subjected to the reagent thing: Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.) extract: every gram extract contains crude drug 3.6 grams, is provided by the Drug Manufacturing Room of China Academy Of Traditional Chinese Medicine Traditional Chinese Medicine Research Institute.Adding distil water is made into corresponding concentration before using.
Test kit: T-CHOL test kit: Zhongsheng Beikong Biological Science ﹠ Technology Co., Ltd. produces, and all the other 9 blood biochemicals are learned the index determining test kit and produced by the safe clinical reagent company limited of Beijing northization.Urine check reagent paper (8N all events) is produced by Chinese Suzhou first pharmaceutical factory.
Animal: SD kind rat, female, body weight 95+5 gram, available from Beijing dimension tonneau China laboratory animal company limited, the quality certification number: SCXK (capital) 2002-0003.
Instrument: the full-automatic blood cell monitor of MEK6318K type, Hitachi, Ltd produces; HUMALYZER2000 biochemical measurement instrument, Germany produces.
Animal feed: rat feed, Chaoyang District Beijing Jiujiang mouth feed factory are produced [capital is moving is betrothed to total No. 052 (2000) No. 007].Main component: coarse ash 8.0%, Sal 0.54%, crude protein 26.7%, crude fat 6.8%, crude fibre 3.7%, calcium 1.4%, total phosphorus 0.92%.
Animal feeding condition: three grades of animal breeding plants, room temperature: 22-24 ℃, relative humidity 45-60%.
Test method
Grouping of animal and dosage
5 in animal per cage is raised with full nutrition feed, freely drinks water, and is divided into 4 groups at random, 40 every group after first adaptability is fed a week before the experiment.Heavy dose of group 1200mg (extract)/kg, middle dosage group 220mg (extract)/kg, small dose group 40mg (extract)/kg, the administration volume is 1ml/100g, and the normal control group gavages with volume 0.5%CMC-Na.Continuously 25 weeks of gastric infusion, administration is 6 days weekly.Weigh on every Mondays and food-intake, adjust dosage according to body weight.
Test item and method
Observe the general state of animal every day, i.e. the mental status, behavioral activity, hair color and urine just wait situation.In 12 weeks of administration, 25 weeks, get 10 of each treated animals, 20 respectively, eye socket is got hematometry hemoglobin (HB), erythrocyte sum (RBC), total white blood cells (WBC) and classification, platelet hematological indices such as (PLT), measures clotting time; Femoral artery is got blood centrifuging and taking serum, and automatic biochemistry analyzer is measured asparagine based transferase (GOP), alanine aminotransferase (GPT), alkali phosphatase (ALP), blood urea nitrogen (BUN), flesh liver (Crea), total protein (TP), albumin (ALb), blood glucose (Glu), total bilirubin (T-Bili), T-CHOL biochemical indicators such as (T-CHO); Dissection is cored, liver, spleen, lung, kidney, adrenal gland, brain (brain, cerebellum), thyroid, thymus, pancreas, hypophysis, optic nerve, stomach, duodenum, colon, jejunum, ileum, uterus, ovary, bladder, breastbone, mammary gland are weighed, and calculates organ coefficient; Do the histopathologic examination of internal organs.Result of the test is carried out statistical procedures, do T check between group, the comparable group differences.10 animals of each group residue are cooked above-mentioned inspection after the drug withdrawal Later Zhou Dynasty, one of the Five Dynasties 5, observation index is the same.
Result of the test
Influence to animal general state and body weight
The animal general state: after 12 weeks of administration, 25 weeks and 5 weeks of drug withdrawal, it is normal that each organizes activities in rats, and the mental status is good, hair color is glossy, and two is just normal, and routine urianlysis shows no obvious abnormalities (seeing Table 5), do not see that other is obviously unusual, each treated animal does not all occur dead.
The weight of animals and food-intake: after 12 weeks of administration, 25 weeks and 5 weeks of drug withdrawal, each body weight and food-intake of organizing rat is normal, does not see significant difference (seeing Table 1,2) with the blank group.
Rat blood is learned the influence of index
Hematological measurement result shows, after 12 weeks of rat administration, 25 weeks and 5 weeks of drug withdrawal, big or middle, medicine is after 5 weeks, and general state, hematology, the blood biochemical of comparing each administration group rat with the blank group learned index and main organs and organized and do not see that the significance relevant with medicine influences.Little three dosage indexs that group is surveyed and matched group relatively do not have statistical significant difference (seeing Table 3-1,3-2,6).
Influence to blood parameters
The measurement result of blood parameters shows that after 25 weeks of rat administration, three dosage indexs that group is surveyed all fluctuate in normal range, relatively do not have statistical significant difference (seeing Table 4-1,4-2) with matched group.
Influence to rat main organs coefficient
After 12 weeks of administration, 25 weeks and 5 weeks of drug withdrawal, dissect rat, with the naked eye the gross examination of skeletal muscle internal organs of respectively organizing rat do not see that obvious adhesion, degeneration etc. are unusual, and administration three each organ coefficient of dosage group and matched group relatively do not have statistical significant difference (seeing Table 7-1,7-2).
To the histological influence of main organs
Pathological examination results shows that after 12 weeks of this product administration, 25 weeks and 5 weeks of drug withdrawal, the main organs of each administration group rat is organized and do not seen the obviously pathologic damage relevant with being tried thing, sees pathologic finding report and photo for details.
Conclusion
Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.) extract 1200mg/kg, 310mg/kg, 80mg/kg, histology's procuratorial work that 5 weeks after 12 weeks of rat oral gavage administration, 25 weeks and the drug withdrawal are learned index and main organs to general state, hematology, the blood biochemical of rat does not see that the pathologic relevant with medicine changes continuously.
Table 1,25 weeks of administration are to the influence (X ± SD of female rats body weight; N=40; G)
Table 2,25 weeks of administration are to the influence (X ± SD of female rats food-intake; N=40; G/100g)
Table 3-1,25 weeks of administration are to the influence (X ± SD of female Mus blood routine index; N=20)
Table 3-2,25 weeks of administration are to the influence (X ± SD of female Mus blood routine index; N=20)
Table 4-1,25 weeks of administration are to the influence (X ± SD of female Mus serum biochemistry index; N=20)
Table 4-2,25 weeks of administration are to the influence (X ± SD of female Mus serum biochemistry index; N=20)
Annotate: compare with matched group
*P＜0.05,
*P＜0.01
Table 5,25 weeks of administration are to the influence (n=20) of rat routine urinalysis
Annotate: * is the weak positive; # X ± SD
Influence (X ± the SD of table 6 pair clotting time; N=20; Sec)
Table 7-1,25 weeks of administration are to female rats organ coefficient (X ± SD; N=20; G/100g)
Table 7-2,25 weeks of administration are to female rats organ coefficient (X ± SD; N=20; G/100g)
Claims (7)
1. the Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.) extract that is used for the treatment of hysteromyoma or cyclomastopathy is characterized in that this extract prepares by the following method:
With the Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.) coarse powder as raw material, water or concentration are lower than 80% ethanol, carry out heating extraction at 30-90 ℃, perhaps carry out percolation, it is 1.0-1.3 that extracting solution is concentrated into proportion, filter, handle through macroporous adsorbent resin, after impurity is removed in washing, alcoholic solution eluting resin to effective ingredient with 30%-95% washes out fully, reclaim solvent, drying obtains the said extracted thing
2. the extract of claim 1, wherein the temperature of heating extraction is 45-70 ℃, it is 1.12-1.16 that extracting solution is concentrated into proportion.
3. the extract of claim 1, it contains 8-acetyl group Harpagide and the Harpagide of 50-99%.
4. the extract of claim 1, the ratio of Harpagide that it is contained and 8-acetyl group Harpagide is 1: 2-4.
5. the preparation method of extract of one of claim 1-4 is characterized in that this method is:
With the Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.) coarse powder as raw material, water or concentration are lower than 80% ethanol, carry out heating extraction at 30-90 ℃, perhaps carry out percolation, it is 1.0-1.3 that extracting solution is concentrated into proportion, filter, handle through macroporous adsorbent resin, after impurity is removed in washing, alcoholic solution eluting resin to effective ingredient with 30%-95% washes out fully, reclaim solvent, drying obtains the said extracted thing.
6. the method for claim 5, wherein the temperature of heating extraction is 45-70 ℃, it is 1.12-1.16 that extracting solution is concentrated into proportion.
7. the purposes of the Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.) extract of one of claim 1-4 is characterized in that being used to prepare the medicine for the treatment of hysteromyoma or cyclomastopathy.
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| CN102397305B (en) * | 2010-09-16 | 2013-06-05 | 石永仓 | Preparation method of medicament for treating arthralgia and myalgia |
| CN102603826A (en) * | 2011-01-20 | 2012-07-25 | 中国中医科学院中药研究所 | Method for extracting 8-acetylharpagide from decumbent bugle herb plant |
| CN102399250B (en) * | 2011-12-15 | 2014-05-21 | 成都普思生物科技有限公司 | High-efficiency preparation method for acetyl harpagide reference standard product |
| CN102558269B (en) * | 2011-12-29 | 2014-01-22 | 浙江惠松制药有限公司 | Method for extracting ecdysone from decumbent bugle herb |
| CN102727673B (en) * | 2012-02-24 | 2014-04-30 | 广州加原医药科技有限公司 | Chinese medicine composition for treating hysteromyoma and preparation method thereof |
| CN102600278A (en) * | 2012-03-05 | 2012-07-25 | 丛月英 | Chinese medicament for treating uterine fibroid |
| CN103656530B (en) * | 2013-12-23 | 2015-08-19 | 刘永秋 | A kind of Chinese medicine composition for the treatment of cyclomastopathy |
| CN105726620A (en) * | 2015-09-17 | 2016-07-06 | 黄勇 | Application of Abyssinian erythrina indica leaf extract in preparation of medicine for treating uterine myoma and ovarian cyst |
| CN106138242A (en) * | 2016-08-23 | 2016-11-23 | 郑景蒲 | Medicine for the treatment of hysteromyoma and preparation method thereof |
| TWI726730B (en) * | 2019-05-23 | 2021-05-01 | 國立陽明大學 | A method for treatment of cellular senescence |
| CN110755475A (en) * | 2019-11-27 | 2020-02-07 | 贵州泰尔医药研究所 | External preparation for treating cervicitis and preparation method thereof |
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