CN103585240B - One treats leukemic pharmaceutical composition and preparation method thereof - Google Patents
One treats leukemic pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN103585240B CN103585240B CN201310525385.9A CN201310525385A CN103585240B CN 103585240 B CN103585240 B CN 103585240B CN 201310525385 A CN201310525385 A CN 201310525385A CN 103585240 B CN103585240 B CN 103585240B
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Abstract
The present invention relates to one and treat leukemic pharmaceutical composition and preparation method thereof, it is characterized in that: this pharmaceutical composition is made up of following crude drug by weight: Herba Elephantopi Mollis 1-3 part, Altay Heteropappus hispidus (Thunb.) Less.-Aster hispidus Thunb． 3-5, Flos et Folium Eritrichii Rupestris 2-4 part, the sub-1-2 part of salon, lazurite 4-6 part.Above-mentioned each crude drug pulverized 80 order-200 mesh sieves, made pill etc., or formed through Hydrolysis kinetics.Pharmaceutical composition of the present invention can improve NCK, IL-2, IL-6, IFN-gamma activity, has good using value to treatment leukemia.
Description
Technical field
The invention belongs to field of medicaments, relate to one and treat leukemic pharmaceutical composition and preparation method thereof.
Background technology
Leukemia (Leukemia) is a kind of malignant tumor of hemopoietic system, it is characterized by leukocyte and juvenile cell also has erythroneocytosis or megalokaryocyte (i.e. leukaemia) Progressive symmetric erythrokeratodermia, runaway paraplasm in bone marrow or other hemopoietic tissue, infiltrate the various tissue of whole body and internal organs, and enter in peripheral blood.According to degree and the leukemic natural process of leukaemia's maturation, leukemia mainly can be divided into acute leukemia and the large class of chronic leukemia two.Acute leukemia onset is hurried, causes anemia, hemorrhage, the symptom such as secondary infection and heating because of normocytic minimizing.In addition, respectively organize internal organs because leukaemia extensively infiltrates, also cause liver, spleen, lymphadenectasis and other organ dysfunction.Chronic leukemia onset is delayed, and the course of disease is longer, and early stage patient can without clinical symptoms, the subjective symptoms occurred the earliest often weak, low grade fever, hyperhidrosis, night sweat, the hypermetabolic performance such as lose weight, be found when few patients checks more than health check-up or other.
Leukemia is comparatively common, accounts for about 5% of cancer total incidence, especially with child and youth in the majority.In the mortality rate of each age group malignant tumor of China, leukemia accounts for the 6th (male) and the 8th (women), in the crowd of child and less than 35 years old, then account for the 1st.Leukemic distribution is global
The traditional Chinese medical science is without this noun of leukemia, but it is early on the books in symptoms such as the heating of clinical appearance, anemia, hemorrhage, liver spleen and lymphadenectasis to leukemia, belong to the category such as " empty old ", " anxious old ", " heat is old ", owing to there being hemorrhage also belonging to " blood disorder ", and heating is similar to " epidemic febrile disease ".The obvious person of hepatosplenomegaly, can be described as “ mass in the abdomen " (disorder of YIN and YANG, internal organs are weak, and ailment said due to cold or exposure fights it, be think long-pending), lymphadenectasis obvious person can be described as: " sucutaneous nodule ".Illustrate that motherland's medical science be the dynamic disease of deficiency of YIN fire to leukemic understanding is originally inherent deficient, disorder of YIN and YANG, on the basis of internal organs weakness, caused by ailment said due to cold or exposure pyretic toxicity is taken advantage of a weak point, and clinical manifestation to be deficiency and excess hold assorted general performance under the arm.
Modern leukemic treatment means mainly chemotherapy and bone marrow transplantation therapy.In recent years, along with combined chemotherapy is used for tactful perfect gradually of maintenances, after treatment etc. after clinical and complete incidence graph, and new anti-leukemia medicine is as idarubicin (IDA), mitoxantrone (MIT), the appearance of etoposide (VP-16) and cytosine arabinoside (Ara-C), leukemic treatment level has had breakthrough.But because many unsolved problems such as the toxic and side effects of chemotherapeutics and derived from bone marrow difficulty, force people finding new therapeutic strategy always.Chinese medicine leukemia cause for a long time, is basic rule for the treatment of with heat-clearing and toxic substances removing, supplementing QI and nourishing YIN.Recently increasing research shows, Chinese medicine has obvious advantage and characteristic, for leukemic radical cure provides new Research Thinking and clue in cell death inducing, cell differentiation, reverse leukaemia multidrug resistance and immunomodulating etc.Extract from Chinese medicine, have developed more anti-leukemia medicine and preparation, experiment confirms that these Chinese medicines have antileukemie effect really, and its mechanism of action comprises and suppresses leukaemia DNA, RNA synthesis, promotes apoptosis or differentiation-inducing etc.
Folium et Ramulus Cephalotaxi ester: the harringtonine extracted from Folium et Ramulus Cephalotaxi plant and homoharringtonine, can press down
DNA synthesis processed is a kind of cell cycle nonspecific agent (CCNSA).The HA scheme be made up of harringtonine or homoharringtonine and cytosine arabinoside is widely used in the treatment of acute nonlymphocytic leukemia, and curative effect is better.
Hydroxy camptothecin, hydroxy camptothecin is a kind of Alkaloid of separation and Extraction from China's distinctive plant camptotheca acuminata seed.Mainly suppress nucleic acid especially DNA synthesis in vitro, be S phase specific drug, topoisomerase I is its main site of action.Certain curative effect is had to treatment CML.
Paclitaxel, paclitaxel can be combined with microtubule and microtubule stability is strengthened, and suppresses microtubule depolymerization, makes cell cycle arrest in division stage.Have obvious inhibitory action to the propagation of Lymphoma Raji Cells, after paclitaxel (4 μ g/ml) acts on 48 hours, inhibitory rate of cell growth reaches 82.6%, and through morphology and flow cytometry analysis showed, cell is G
2/ M the phase blocks and apoptosis.
Garlicin, along with garlicin concentration and the increase of action time, human leukemia cell line K
562s phase cell content obviously decline, G
2/ M phase cell content has obvious ascendant trend, prompting garlicin effect be by by cell detention in G
2the result of/M phase.
Indigo Naturalis, indirubin, Meisoindigotin, Indigo Naturalis is one of effective ingredient screening discovery one by one on the DANGGUI LUHUI WAN treatment effective basis of CML.Indirubin is isolated effective ingredient from Indigo Naturalis, can obtain through chemosynthesis.Indirubin has inhibitory action in various degree to untreated slow grain immature granulocyte propagation, and its action principle may be suppress it to breed by suppressing leukaemia DNA synthesis.Meisoindigotin is the similar product of synthesis indirubin, and curative effect is higher than indirubin.Nearest research shows, the mechanism of Meisoindigotin treatment CML may be suppressed relevant with apoptosis with Meisoindigotin leukemogenesis cell proliferation.
Arsenicum, Compendium of Material Medica is early on the books: " arsenic is the medicine of the large poison of large heat, and the poison of arsenicum is especially strong ".Arsenicum sablimatum becomes arsenicum through distillation, and the main chemical compositions of arsenicum is arsenic trioxide or arsenious acid.Arsenic trioxide can cell death inducing, and the expression reducing bcl-2 gene in cell may be one of molecular mechanism of its effect.
Radix Puerariae, find the research of kudzu vine root S86019, S86019 can suppress HL-60 cell proliferation, makes cell be the cell that trend is ripe by promyelocyte phasic development, and the increase acted on along with drug level also becomes to strengthening.S86019 is an effective HL-60 cell induction differentiation agent really.
Elemene, the elemene extracted from Rhizoma Curcumae has obvious impact to Primary human megakaryocytic leukemia cell series Himeg cell cycle, and its effect link mainly affects the cell cycle S phase to G
2the transition process of/M phase, is arrested in the S phase by leukaemia, reduce and enter G
2the cell quantity of/M phase, suppresses leukemic cell growth metabolism, reduces its mitosis, and cause affected tumor cell rapid apoptosis.
Fructus Crotonis, someone is broken up and cytotoxic screening experiment HL-60 cell induction by 302 kinds of Chinese medicines, tentative confirmation Fructus Crotonis has more significant inducing leukemia cell and thinks the effect that normal cell breaks up, and in this result prompting Fructus Crotonis, some composition is expected to become the leukemic active drug for the treatment of.
Radix Sophorae Flavescentis, Radix Sophorae Flavescentis has good therapeutical effect to older patients with acute non-lymphocytic leukemia, and its mechanism may be: to the direct killing effect of tumor cell; Directly act on rake DNA and play its antitumor action; Its antitumor action is played by affecting cell cycle; Its antitumor action is played by inducing apoptosis of tumour cell; Synergism is played by induced microparticle cytochrome P450; By the anti-tumor activity etc. of immunologic mechanism enhancing body.
Qinghuang Powder, Qinghuang Powder [Indigo Naturalis, Realgar (As
2s
3)].Have good curative effect with Qinghuang Powder for Treatment CML, after medication, symptom is clearly better or extinction time is 11.4 days, and within average 10.1 days, spleen starts to reduce.Experimentation shows, Qinghuang Powder is to L
615, S
180dNA, RNA synthesis of cell has inhibitory action in various degree, and be characterized in that inhibitory action is fast, namely drug effect reaches peak in 30 minutes in cell; Drug effect amount effect relationship; Obvious inhibitory action is all had to DNA, RNA.Over the course for the treatment of, the experimental technique such as hematopoietic stem cell cultivation is utilized to observe the impact on mice pluripotent stem cell, grain system and the various cell such as CFU-E, tip hemogram of Qinghuang Powder and Busulfan, result shows that Busulfan has obvious inhibitory action to above-mentioned various types of cells, Qinghuang Powder then unrestraint effect, prompting Qinghuang Powder may have selective inhibitory to leukaemia.Carry out ultrastructure to CML Bone Marrow of Patients cell dynamically to observe, the degeneration necrosis that it is feature that discovery leukaemia mainly occurs with karyolysis, karyopycnosis, fragmentation and Combination, show that the curative effect that Qinghuang Powder for Treatment CML produces is relevant with the pharmacological action of its promotion leukaemia degeneration necrosis, namely finally cause leukaemia dead by degeneration.
No. 1, cancer spirit, cancer No. 1, spirit (pyrrole stone, Calomelas) is current China traditional Chinese medical herbal treatment leukemia particularly one of the most effective medicine of promyelocytic leukemia.Its pharmacology principle is the treating the poisonous disease with poisonous drugs effect of the traditional Chinese medical science.Arsenical is traditional poison in Chinese medicine, and Xin Wen is very toxic.Experimentation proves, arsenic compound can combine with the sulfydryl (-SH) in tissue (protein), protein is lost activity, thus inhibits Leukemia Cell Proliferation, serves the leukemic effect for the treatment of.Secondly, to the selective cytotoxicity of cancerous cell.Experimental studies have found that No. 1, cancer spirit is selective between cancerous cell and normal cell, even if long-term prescription is to hemopoietic function of bone marrow also unrestraint, on the contrary hemopoietic function.3rd, there is induction of differentiation.Use arsenic trioxide injection treatment APL, hemogram and the bone marrow smear of observing patient CR are that after the patient treatment of discovery 77.3%, leukocyte rises gradually, peak is reached in 7-20 days, while leukocyte raises, point apoplexy due to endogenous wind promyelocyte ratio of discovery reduces, and in, metamyelocyte can reach 0.12 and 0.15 respectively.4th, have and promote apoptotic effect.Use during arsenic agent treatment leukemia and find, can see granulocyte degenerative change in patient's bone marrow after treatment CR, endochylema and core have vacuolar degeneration, and chromatin pyknosis, coagulation inequality and nucleorhexis-" apoptotic body ", detect visible Apoptotic cell peak with drain cell instrument.
LIUSHEN WAN, LIUSHEN WAN (Margarita powder, Calculus Bovis, Moschus, Venenum Bufonis, Borneolum Syntheticum) has the merit of heat-clearing and toxic substances removing, blood-activating analgetic.Pharmacology proves that the Calculus Bovis in LIUSHEN WAN contains bilirubin, ergosterol, has effects such as promoting erythrocyte new life, calmness, convulsion, heart tonifying; Venenum Bufonis containing Venenum Bufonis dienol, epinephrine, lysergol, catecholamines, has heart tonifying, boosting, the effect such as anticancer; Realgar is containing orpiment, and sulfydryl enzyme system can be suppressed to affect cellular metabolism, thus have inhibitory action to the growth of tumor cell, other still have Margarita, Borneolum Syntheticum, Moschus etc. to have the effects such as antifungal, anti-bacteria, stimulating central nervous system system.LIUSHEN WAN treatment leukemia, for inducer remission, has obvious inhibitory action to granulocytic systen, but then very unobvious to bone marrow depression, and can prevention and therapy oral ulcer, tonsillitis etc.
FUFANG QINGDAI PIAN, FUFANG QINGDAI PIAN (Indigo Naturalis, Radix Pseudostellariae, Radix Salviae Miltiorrhizae, Realgar etc.) experimentation shows, Realgar has induction APL cell (NB4) and the apoptotic effect of HL-60.
The multiple health of blood, multiple health (Indigo Naturalis, Rhizoma Curcumae, the Radix Puerariae etc.) experimentation of blood confirms, the multiple health of blood can suppress K
562growth of Cells also makes it that apoptosis occur.
Herba Elephantopi Mollis is the dry aerial parts of feverfew Herba Elephantopi Mollis (Picris japonica T hunb.).Summer, autumn two gather when season, the flowers are in blossom, and removing impurity, dries.Record in 1998 " Drug Standard of Ministry of Public Health of the Peoples Republic of China mongolian medicine fascicle ".Cool in nature, rough, bitter in the mouth.Kill " gluing ", pain relieving, heat clearing away, detumescence, removing toxic substances.For pestilence, Adam's apple, mastitis, breast twinge, parotitis, battle array twinge.The common drug of the minority areas such as illiteracy is hidden for China.But about the basic research of Herba Elephantopi Mollis is still very limited, the follow-up promotion and application of this medical material are restricted.Modern study shows, Herba Elephantopi Mollis contains Fols Picridis fuscipilosae glycosides (picriside) A, B, C, lactucin (lactucin), 11 β-13-dihydro lactucins (11 β-13-dihydrolactucin), false Radix Crepidis elongatae glycoside (caepidiaside) A and Herba Ixeritis Denticulatae lactone (ixerin) F etc., also containing polysaccharide and flavone compound, other chemical compositions are not quite clear; Pharmacological research shows, Herba Elephantopi Mollis water extraction, and cross D101 macroporous resin, water elution part has blood sugar lowering, regulating blood lipid action.
Altay Heteropappus hispidus (Thunb.) Less.-Aster hispidus Thunb． is the dry capitulum of feverfew Altay Heteropappus hispidus (Thunb.) Less.-Aster hispidus Thunb． (Heteropappus altaicus (Willd) Novopokr.).Summer, autumn two gather when season, the flowers are in blossom, dry in the shade.Record in 1998 " Drug Standard of Ministry of Public Health of the Peoples Republic of China mongolian medicine fascicle ", its sweet in the mouth, hardship, cool in nature, light, gently puckery, function for killing " gluing ", heat clearing away, removing toxic substances, for pestilence, measles, scarlet fever, heat in blood, scorchingly hot, " precious day " heat.
Flos et Folium Eritrichii Rupestris is raw Flos et Folium Eritrichii Rupestris (Eritrichium rupestre(Pall.) Bunge of comfrey stone) dry aerial parts.Gather when summer, the flowers are in blossom, removing root and impurity, dry in the shade.Record in 1998 " Drug Standard of Ministry of Public Health of the Peoples Republic of China mongolian medicine fascicle ", it is cool in nature, bitter in the mouth, sweet.Have and kill " gluing ", heat clearing away, removing toxic substances.For warm influenza, " association's day " human connection disease, " association's day " heat.
Salon's is the dry body of Scincidae animal salon (Scinncus officinalis Linnaeus).The whole year all can catch, and removing internal organs, put into salt in body, dry.Record in 1998 " Drug Standard of Ministry of Public Health of the Peoples Republic of China Uigurs medicine fascicle ".There is tonifying YANG keep fit, strong muscle diuresis, pain relieving of dispeling cold.For Inhibited sexual desire, impotence, oligospermia is weak, and hemiplegia limb quivers, joint osteodynia, dysuria.
Lazurite is silicates mineral cordierites, main containing Na
6ca [AlSiO
4]
6(SO
4, Cl, S)
2.After excavating, removing silt and assorted stone.Record in 1998 " Drug Standard of Ministry of Public Health of the Peoples Republic of China Uigurs medicine fascicle ".Have removing abnormal humour, the burning of control body fluid, control abnormal savda produces, treating blood disorders of nourishing heart, logical stagnant effect of stimulating the menstrual flow.Vexed for melancholy, restlessness, the weak blood resistance of the heart, amenorrhea cough with asthma.
Namely existing document and patent etc., there is not yet pharmaceutical composition of the present invention: the compositions of Herba Elephantopi Mollis, Altay Heteropappus hispidus (Thunb.) Less.-Aster hispidus Thunb．, Flos et Folium Eritrichii Rupestris, salon's, lazurite composition is for the preparation of the report for the treatment of leukemia medicament.
Summary of the invention
One is the object of the present invention is to provide to treat leukemic pharmaceutical composition and preparation method thereof.
The present invention is achieved through the following technical solutions:
The present invention is raw materials used
Herba Elephantopi Mollis is the dry aerial parts of feverfew Herba Elephantopi Mollis (Picris japonica T hunb.); Altay Heteropappus hispidus (Thunb.) Less.-Aster hispidus Thunb． is the dry capitulum of feverfew Altay Heteropappus hispidus (Thunb.) Less.-Aster hispidus Thunb． (Heteropappus altaicus (Willd) Novopokr.); Flos et Folium Eritrichii Rupestris is raw Flos et Folium Eritrichii Rupestris (Eritrichium rupestre(Pall.) Bunge of comfrey stone) dry aerial parts; Salon's is the dry body of Scincidae animal salon (Scinncus officinalis Linnaeus); Lazurite is silicates mineral cordierites, main containing Na
6ca [AlSiO
4]
6(SO
4, Cl, S)
2.
One of the present invention treats leukemic pharmaceutical composition, it is characterized in that: be made up of following crude drug by weight: Herba Elephantopi Mollis 1-3 part, Altay Heteropappus hispidus (Thunb.) Less.-Aster hispidus Thunb． 3-5 part, Flos et Folium Eritrichii Rupestris 2-4 part, the sub-1-2 part of salon, lazurite 4-6 part.
One of the present invention treats leukemic pharmaceutical composition, it is characterized in that: be made up of following crude drug by weight: Herba Elephantopi Mollis 2 parts, Altay Heteropappus hispidus (Thunb.) Less.-Aster hispidus Thunb． 4 parts, Flos et Folium Eritrichii Rupestris 3 parts, salon's 1.5 parts, lazurite 5 parts.
One of the present invention treats leukemic pharmaceutical composition, it is characterized in that: be make as follows: each crude drug was pulverized 80 order-200 mesh sieves, makes powder or tablet or pill.
One of the present invention treats leukemic pharmaceutical composition, it is characterized in that: be make as follows: Herba Elephantopi Mollis, Altay Heteropappus hispidus (Thunb.) Less.-Aster hispidus Thunb．, Flos et Folium Eritrichii Rupestris, three taste medical materials use water as Extraction solvent, 70 DEG C-95 DEG C extractions, extraction time is 2-5 time, each extraction time is 2-6 hour, and each solvent load is 8-15 times of Herba Elephantopi Mollis weight; Filter, merge extractive liquid, concentrated, dry, obtain extract A; Salon's, lazurite are ground into fine powder, mix, to obtain final product with extract A.
The leukemic pharmaceutical composition for the treatment of of the present invention, in preparation by improving the application in NCK, IL-2, IL-6, IFN-gamma activity treatment leukemia medicament.
Gained pharmaceutical composition of the present invention, by regulatory T-cell subset proportions and promote that the secretion of these cytokines plays its immunoregulation effect, recover self suppressed immunologic function and kill and wound residual leukaemia, thus confirm that it has and induce IL-2, the effect of IL-6 and IFN-γ, has certain effect to leukemic therapy apparatus immunity function restructuring.Our experimental result also shows, gained pharmaceutical composition of the present invention has enhancing IL-2 and NCK active function, illustrates that pharmaceutical composition of the present invention has certain protective effect to the immunosuppressant of P388 leukemia mouse after chemotherapy.Infer its mechanism of action may with enhancing Exploration of Red Cell Immuno-adhesive Function, impel erythrocyte to discharge NCK activity factor, regulate NCK-IFN-IL-2 immunological network relevant.
The treatment leukemia medicament that pharmaceutical composition of the present invention and chemical drugs or Chinese medicine or natural drug form.
The leukemic pharmaceutical composition for the treatment of of the present invention and chemical drugs or Chinese medicine or natural drug form treats leukemia medicament by improving NCK, IL-2, IL-6, IFN-gamma activity.
Detailed description of the invention
Treat leukemia medicament composition and method of making the same below by specific experiment example and embodiment to one of the present invention to be described further, but be not limited to the present invention.
Embodiment 1: pharmaceutical composition and preparation method thereof
Pharmaceutical composition is made up of following crude drug by weight: Herba Elephantopi Mollis 2 parts of Altay Heteropappus hispidus (Thunb.) Less.-Aster hispidus Thunb． 4 parts of Flos et Folium Eritrichii Rupestris 3 parts of salon's 1.5 parts of lazurite 5 parts;
Pharmaceutical composition preparation method: each crude drug was pulverized 150 mesh sieves, mixing, adds appropriate water pill, dry, to obtain final product.
Embodiment 2: pharmaceutical composition and preparation method thereof
Pharmaceutical composition is made up of following crude drug by weight: Herba Elephantopi Mollis 1 part of Altay Heteropappus hispidus (Thunb.) Less.-Aster hispidus Thunb． 5 parts of Flos et Folium Eritrichii Rupestris 2 parts of salon's 1 part of lazurite 6 parts;
Pharmaceutical composition preparation method: each crude drug was pulverized 80 mesh sieves, mixing, to obtain final product.
Embodiment 3: pharmaceutical composition and preparation method thereof
Pharmaceutical composition is made up of following crude drug by weight: Herba Elephantopi Mollis 3 parts of Altay Heteropappus hispidus (Thunb.) Less.-Aster hispidus Thunb． 3 parts, Flos et Folium Eritrichii Rupestris 4 parts, salon's 2 parts, lazurite 4 parts;
Pharmaceutical composition preparation method: each crude drug was pulverized 200 mesh sieves, mixing, makes granule with Diluted Alcohol, dry, adds starch, magnesium stearate, tabletting, to obtain final product.
Embodiment 4: pharmaceutical composition and preparation method thereof
Pharmaceutical composition is made up of following crude drug by weight: Herba Elephantopi Mollis 3.5kg Altay Heteropappus hispidus (Thunb.) Less.-Aster hispidus Thunb． 3.5kg Flos et Folium Eritrichii Rupestris 4.5kg salon sub-2.5kg lazurite 4.8kg;
Pharmaceutical composition preparation method: Herba Elephantopi Mollis, Altay Heteropappus hispidus (Thunb.) Less.-Aster hispidus Thunb．, Flos et Folium Eritrichii Rupestris, three taste medical materials use water as Extraction solvent, and 70 DEG C of extractions, extraction time is 5 times, and each extraction time is 2 hours, and each solvent load is 8 times of three taste medical material weight; Filter, merge extractive liquid, concentrated, dry, to obtain final product;
Customary adjuvant can be added and make various dosage form on pharmaceutics.
Embodiment 5: pharmaceutical composition and preparation method thereof
Pharmaceutical composition is made up of following crude drug by weight: Herba Elephantopi Mollis 2.5kg Altay Heteropappus hispidus (Thunb.) Less.-Aster hispidus Thunb． 3.3kg Flos et Folium Eritrichii Rupestris 3.8kg salon son 2 kg lazurite 3.5kg;
Pharmaceutical composition preparation method: Herba Elephantopi Mollis, Altay Heteropappus hispidus (Thunb.) Less.-Aster hispidus Thunb．, Flos et Folium Eritrichii Rupestris, three taste medical materials use water as Extraction solvent, and 95 DEG C of extractions, extraction time is 2 times, and each extraction time is 6 hours, and each solvent load is 15 times of three taste medical material weight; Filter, merge extractive liquid, concentrated, dry, obtain extract A; Salon's, lazurite are ground into fine powder, mix, to obtain final product with extract A;
Add customary adjuvant and make various dosage form on pharmaceutics.
Experimental example 1: pharmaceutical composition is to L
615the test of pesticide effectiveness of leukemia mouse
1. modeling method: aseptically get L
615leukemia mouse spleen makes 25% normal saline cell suspension, gives the L that grows up
615mouse hypodermic inoculation, all there is leukemia in result, transplants continuously, set up stable L with morbidity mice spleen oncocyte at Syngenic mice
615leukemia Model.
L
615the foundation of leukemia cell line, removes L
615the spleen of leukemia mouse, shreds spleen in Hanks liquid, makes leukaemia free out, by collected by centrifugation free cell, then uses RPMI1640 culture fluid (containing 10% calf serum) to be diluted to 8*10
6the Cell sap of/ml, cultivates at 37 DEG C.Cultivate 20d and find there is adherent fusiform cells in culture, around it, have the round cell island of propagation.When separately being cultivated by cells different for two kinds of forms, spindle cell can normal adherent growth, and suspension cell growth is slow; Again by two kinds of cells Mixed culture again, two kinds of Growth of Cells are vigorous, after 45d, by the round cell of suspension growth single culture again, pass to for 12 generations always, and Growth of Cells is good, thus sets up this cell strain.
2. the medicine composite for curing leukemia test of pesticide effectiveness.
Material: Kunming mouse (Shandong Province's Experimental Animal Center).Embodiment 1, embodiment 2, embodiment 4 obtain pharmaceutical composition, cyclophosphamide (Hengrui Medicine Co., Ltd., Jiangsu Prov.), standard RhIL-2 (Beijing Shuanglu Pharmaceutical Co., Ltd.), school of life and health sciences cellular resources center, Yackl and IL-2 dependent cells strain CTLL(Chinese Academy of Sciences Shanghai), RPMII640 cell culture fluid and hyclone (Huamei Bio-Engrg Co.); Tetramethyl azo azoles salt (MTT), dodecyl sodium sulfate and canavaline, dimethyl formamide is (Sigma Products); Sample injector, CO
2incubator, ELX-800 microplate reader (Bio-Tek company of the U.S.); The 96 flat Tissue Culture Plates in hole, Epics flow cytometer (Beckman company of the U.S.).
Method: modeling as stated above.Experiment grouping first group is Normal group, and 20 615 is mice, after conventional raising 1w, and intraperitoneal injection of saline 0.2ml/d, normal saline enema 0.3ml, each 1 time of upper and lower noon.2nd group is model group, after conventional raising 1w, and inoculation L
615leukaemia, the same Normal group of inoculation post processing.3rd group is Western medicine group, and 20 conventional raisings, after one week, inoculate L
615leukaemia, after inoculation the 3rd day starts ip cyclophosphamide, 200mg/kg, 1 time/d.4th group of-6 groups is respectively pharmaceutical composition group (embodiment 1), pharmaceutical composition group (embodiment 2), pharmaceutical composition group (embodiment 4), get respectively 20 conventional raise 1d after, inoculation L
615leukaemia, gives pharmaceutical composition group (embodiment 1), pharmaceutical composition group (embodiment 2), pharmaceutical composition group (embodiment 4) gavage on the 3rd day, 0.3ml, each 1 time of upper and lower noon after inoculation respectively.Above each treated animal often group get 10 in the 5th day put to death, get spleen and carry out related immune Indexs measure, remaining each animal carries out observation life cycle.
Observation index: 1. observe life cycle.2. T cell Subsets.3. IL-2, IL-6, IFN-gamma activity measures.
Statistical method: data represent with ± s, adopts Mi-crosoft Excel to carry out t inspection.
Result:
Life cycle: pharmaceutical composition group of the present invention life cycle, comparatively model group and Western medicine group obviously extended, statistics there were significant differences P<0.01, in table 1.
Table 1 each experimental group compares life cycle
Note: compared with model group
*p<0.01, compared with Western medicine group
△p<0.01.
IL-2, IL-6, IFN-gamma activity: after Western medicine group leukemia mouse chemotherapy, it secretes IL-2, IL-6, the level of IFN-γ significantly declines, and the secretion level of pharmaceutical composition group IL-2 of the present invention, IL-6, IFN-γ obviously increases, both have significant difference (P<0.01), in table 2 at contrast.
Table 2 respectively organizes IL-2, and IL-6, IFN-gamma activity changes
Note: compared with Normal group
*p<0.01, compared with model group
△p<0.01, compared with Western medicine group
▲p<0.01.
The whether normal of immunologic function is one of key factor of tumor development, and immunologic function is by performed by the cytokine secreted by immunocyte, T cell subset proportions imbalance after leukemia mouse chemotherapy, IL-2, IL-6, the levels of cytokine secretion such as IFN-γ decline, and point out the immunologic function of now body to be in inhibitory state.And after the application of the invention medicine composite for curing, IL-2, IL-6, the levels of cytokine secretion such as IFN-γ go up, illustrate that pharmaceutical composition of the present invention is by promoting that the secretion of these cytokines plays its immunoregulation effect, recovers self suppressed immunologic function to kill and wound residual leukaemia, thus proved invention pharmaceutical composition has and induces IL-2, the effect of IL-6 and IFN-γ, has certain effect to leukemic therapy apparatus immunity function restructuring.
Experimental example 2: pharmaceutical composition is to the pharmacodynamics test of P388 leukemia mouse.
1. modeling method: get ascitic type P
388leukemia mouse, de-cervical vertebra is put to death, and abdominal part is sterilized, suction ascites, and add normal saline mixing, it is (1-1.5) * 10 that microscope lowers intact cells concentration
7individual/ml, the inoculum density of every Mus 0.2ml(Kunming mouse and dosage) carry out lumbar injection.
2. pharmaceutical composition is to P
388the impact of natural killer cell (NCK), interleukin-2 (IL-2) activity after leukemia mouse chemotherapy.
Material: Kunming kind one-level mice (Shandong Province's Experimental Animal Center), 50, male and female half and half, body weight 18-22g.Pharmaceutical composition prepared by embodiment 4, cyclophosphamide (Hengrui Medicine Co., Ltd., Jiangsu Prov.), standard RhIL-2 (Beijing Shuanglu Pharmaceutical Co., Ltd.), school of life and health sciences cellular resources center, Yackl and IL-2 dependent cells strain CTLL(Chinese Academy of Sciences Shanghai), RPMII640 cell culture fluid and hyclone (Huamei Bio-Engrg Co.); Tetramethyl azo azoles salt (MTT), dodecyl sodium sulfate and canavaline, dimethyl formamide is (Sigma Products); Sample injector, CO
2incubator, ELX-800 microplate reader (Bio-Tek company of the U.S.); The 96 flat Tissue Culture Plates in hole, Epics flow cytometer (Beckman company of the U.S.).
Modeling and group technology: get 40 mices, inoculation P
388the strain of Lymphocytic leukemia tumor (inoculation method: get ascitic type P388 leukemia mouse, de-cervical vertebra is put to death, and abdominal part is sterilized, suction ascites, adds normal saline mixing, and it is 1.5*107/ml that microscope lowers intact cells concentration, every mice right oxter injection 0.2ml), be divided into 4 groups at random.Another 10 is normal blank group.
Processing method: 1. normal blank group: with 0.4ml/20g normal saline ig; 2. P
388leukemia Model group: with 0.4ml/20g normal saline ig; 3. chemotherapy group: with 0.4ml/20g normal saline ig; 4. chemotherapy adds pharmaceutical composition low dose group: respectively with 50mg extract in 0.4ml normal saline ig; 5. chemotherapy adds pharmaceutical composition high dose group: be dissolved in 0.4ml normal saline ig with 100mg extract.3. the continuous ig14d of each group above, give simultaneously, 4., 5. organize ip cyclophosphamide 35mg/kg/d, be used in conjunction 6d.In the 15th day, de-cervical vertebra was put to death, and aseptically got spleen NCK, IL-2 active.
Detection method: NCK Activity determination is with reference to Jiang Zhonghua method, and IL-2 activity test method is with reference to Qian Yukun method.
Statistical method: adopt many group means to compare, namely first do variance analysis, remake q inspection.
Result: result shows, it is active that pharmaceutical composition of the present invention can improve NCK and IL-2.In table 3
Table 3 is group NCK and IL-2 expression activitiy respectively
Note: compare with normal group,
*p<0.05,
*p<0.01; Compare with model group,
△p<0.05,
△ △p<0.01; Compare with chemotherapy group,
#p<0.05,
##p<0.01.
NCK is one of three major types lymphocyte, be the important composition composition of the early stage antineoplastic immune supervisory role of body, be a group broad-spectrum anti-tumor cell, its killing activity does not need the prior sensitization of antigen, do not rely on antibody and thymus, not by the restriction of major histocompatibility antigen (MHC) yet.NCK does not need specific antigen to stimulate for virus infected cell and tumor cell in vivo, immune complex and target cell surface structure all directly can bring out the immunoreation of NCK, the a large amount of cytokine of rapid secretion, as interferon-γ (IFN-γ), tumor necrosis factor-alpha (TNF-α), GM-CSF (GM CSF), IL-2 etc., regulates phagocyte and T, B cell function.IL-2, IFN can increase again the activity of NCK simultaneously, therefore body exists NCK-IFN-IL-2 immunological network to have scholar to think.The glycoprotein of the 15KD that IL-2 is mainly produced by T cell, and act on T cell, impel T cell to breed.IL-2 is main, the most strong SCIFs in body.IL-2 can induce or promote the activity of various kinds of cell toxic cell, as NCK, cytotoxic T lymphocyte (CTL), Lymphatic circulation (LAK) and tumor infiltrating lymphocyte (TIL) etc., these cells are most important in the immune surveillance and antineoplastic immune of body.Our experimental result shows, P388 leukemia mouse self and immunity function after chemotherapy are suppressed, NCK and IL-2 activity all has reduction in various degree, and after chemotherapy, P388 leukemia mouse is starkly lower than normal group and model group.This is because chemotherapeutic is on immune impact, also kills and wounds or inhibit caused by LAK cell while killing tumor cell.Recent study finds, the NCK of tumor mice activity reduces, may with body lotus tumor time, the cytokine network antitumor action of its immunocyte is not normal relevant, and as immunosuppressive factor in serum exists and increased activity, immunological enhancement factor active declines.Can by suppressing the generation of IFN thus making NCK activity be suppressed further after giving chemotherapeutic on this basis.In normal body, IL-2 has self forward immunoregulation effect, but at most of tumor mice, IL-2 system exists obviously suppression or disorderly.Most researcher is thought, the ability and all having IL-2 reactivity that tumor patient produces IL-2 reduces in various degree, may SMXO and Ts function strengthen relevant in or host hyperfunction with IL-2 catabolism.After giving chemotherapeutic, inducing of IL-2 is suppressed further, thus increases the weight of the decline of tumor mice immunity.After giving medicine composite for curing of the present invention, high dose group NCK and IL-2 is all increased significantly.Our experimental result shows, Herba Elephantopi Mollis extract has enhancing IL-2 and NCK active function, illustrates that pharmaceutical composition of the present invention has certain protective effect to the immunosuppressant of P388 leukemia mouse after chemotherapy.Infer its mechanism of action may with enhancing Exploration of Red Cell Immuno-adhesive Function, impel erythrocyte to discharge NCK activity factor, regulate NCK-IFN-IL-2 immunological network relevant.
Claims (7)
1. the leukemic pharmaceutical composition for the treatment of, it is characterized in that being made up of following crude drug by weight: Herba Elephantopi Mollis 2 parts of Altay Heteropappus hispidus (Thunb.) Less.-Aster hispidus Thunb． 4 parts of Flos et Folium Eritrichii Rupestris 3 parts of salon's 1.5 parts of lazurite 5 parts, prepare as follows: each crude drug was pulverized 150 mesh sieves, mixing, add appropriate water pill, drying, to obtain final product.
2. the leukemic pharmaceutical composition for the treatment of, it is characterized in that being made up of following crude drug by weight: Herba Elephantopi Mollis 1 part of Altay Heteropappus hispidus (Thunb.) Less.-Aster hispidus Thunb． 5 parts of Flos et Folium Eritrichii Rupestris 2 parts of salon's 1 part of lazurite 6 parts, prepare as follows: each crude drug was pulverized 80 mesh sieves, mixing, to obtain final product.
3. the leukemic pharmaceutical composition for the treatment of, it is characterized in that being made up of following crude drug by weight: Herba Elephantopi Mollis 3 parts of Altay Heteropappus hispidus (Thunb.) Less.-Aster hispidus Thunb． 3 parts of Flos et Folium Eritrichii Rupestris 4 parts of salon's 2 parts of lazurite 4 parts, prepare as follows: each crude drug was pulverized 200 mesh sieves, mixing, granule is made with Diluted Alcohol, dry, add starch, magnesium stearate, tabletting, to obtain final product.
4. the leukemic pharmaceutical composition for the treatment of, it is characterized in that being made up of following crude drug: Herba Elephantopi Mollis 3.5kg Altay Heteropappus hispidus (Thunb.) Less.-Aster hispidus Thunb． 3.5kg Flos et Folium Eritrichii Rupestris 4.5kg salon sub-2.5kg lazurite 4.8kg, prepare as follows: Herba Elephantopi Mollis, Altay Heteropappus hispidus (Thunb.) Less.-Aster hispidus Thunb．, Flos et Folium Eritrichii Rupestris, three taste medical materials use water as Extraction solvent, 70 DEG C of extractions, extraction time is 5 times, and each extraction time is 2 hours, and each solvent load is 8 times of three taste medical material weight; Filter, merge extractive liquid, concentrated, dry, to obtain final product.
5. the leukemic pharmaceutical composition for the treatment of, it is characterized in that being made up of following crude drug: Herba Elephantopi Mollis 2.5kg Altay Heteropappus hispidus (Thunb.) Less.-Aster hispidus Thunb． 3.3kg Flos et Folium Eritrichii Rupestris 3.8kg salon son 2 kg lazurite 3.5kg, prepare as follows: Herba Elephantopi Mollis, Altay Heteropappus hispidus (Thunb.) Less.-Aster hispidus Thunb．, Flos et Folium Eritrichii Rupestris, three taste medical materials use water as Extraction solvent, 95 DEG C of extractions, extraction time is 2 times, and each extraction time is 6 hours, and each solvent load is 15 times of three taste medical material weight; Filter, merge extractive liquid, concentrated, dry, obtain extract A; Salon's, lazurite are ground into fine powder, mix, to obtain final product with extract A.
6., according to pharmaceutical composition according to claim 1 or claim 2, it is characterized in that by improving IL-2, IL-6, IFN-gamma activity treatment leukemia.
7. pharmaceutical composition according to claim 4, is characterized in that by improving NCK, IL-2 active treatment leukemia.
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| 治肝活髓-再障治疗的藏医学思路;达日德杰;《家庭医药》;20071231;31 * |
| 治肝活髓-治疗血液病的藏医学思路;达日德杰;《求医问药》;20071231;14 * |
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