CN101283996A - Application of clock wise D-methionine in preparing the medicine for preventing and curing the myelosuppression induced by radiation - Google Patents
Application of clock wise D-methionine in preparing the medicine for preventing and curing the myelosuppression induced by radiation Download PDFInfo
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- CN101283996A CN101283996A CNA2008100534658A CN200810053465A CN101283996A CN 101283996 A CN101283996 A CN 101283996A CN A2008100534658 A CNA2008100534658 A CN A2008100534658A CN 200810053465 A CN200810053465 A CN 200810053465A CN 101283996 A CN101283996 A CN 101283996A
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Abstract
The invention discloses an application of D-methionine in preparing drugs for preventing or treating bone marrow suppression induced by radiation and chemical toxicants. The modern pharmacological experiment shows that after being injected with 300-1,000 mg/Kg D-methionine, a mouse obtains obvious protective effect on bone marrow suppression induced by radiation and chemical toxicants, indicating that preventive administration can prevent and treat bone marrow damage induced by the radiation and the chemical toxicants and has inhibitory effect on tumor cell growth. The D-methionine can be mixed with conventional pharmaceutically-acceptable adjuvant and made into various dosage forms. For radiotherapy patients, the addition of a certain amount of D-methionine into nutrient solution brings effects of inhibiting tumor cell growth and protecting hematopoietic cells.
Description
Technical field
The present invention relates to the application of amino acid drug in pharmaceutical field.A kind of dextrorotation methionine (D-met) of saying so is more specifically induced the application in the bone marrow depression medicine at preparation control radiation, chemical toxicant.
Background technology
Body is exposed to the various harmful factors of extraneous physical chemistry and internal metabolism generation, as is exposed to radiation or some chemical toxicant, and the clinical patient who accepts radiotherapy, chemotherapy.Hemopoietic system is made up of the hematopoietic cell of a small amount of marrow hemopoietic stem cells and different development stage different series, very responsive to various harmful factors, inhibition in various degree can appear after sustaining damage, show as that peripheral blood leucocyte reduces, bone marrow proliferation function reduction even aplastic anemia takes place, patient's life quality is caused serious harm even threat to life.
Mostly be to adopt reinforcement nutrition or give the propagation that increases hematopoietic cells with various somatomedin bone marrow depression occurring clinically at present.Other has the chemical compound or the Chinese medicine preparation of anti-oxidative damage effect.Medicament categories is a lot, is mostly use in conjunction, and curative effect is not really definite when estimating separately, also has the generation of various side effect, as the somatomedin class, uses cost also relatively more expensive.
(D-methionine D-met) promotes growth to do years of researches as nutritional labeling to the dextrorotation methionine.Methionine content in high protein diet reaches 26mg/g, and content is higher in fermented product cheese and the yoghourt, and methionine can turn to dextrorotation from anticlockwise by transamination in the sweat.
Dextrorotation methionine (D-met) not only as nutritional labeling also as medicine.Recommend the methionine toxicity that excessive use produces as the treatment acetaminophen as WHO (1997).FDA in 2005 has ratified application before oral mucositis that oral D-met causes radiation clinical.
The animal experiment result of study shows: dextrorotation methionine (D-met) can resist the injury of acoustic nerve that platinum class tumour medicine, aminoglycosides chemical compound and noise cause, through injection or orally all can reach therapeutical effect.
Various zoology and human trial result show that it is safe that D-met uses.As removing the toxic methionine of acetaminophen, to recommend initial dose be 2.5g, gives and 2.5g every 4h subsequently, and consumption can reach 10g in the 12h.
D-met protective effect mechanism may mainly be by direct or indirect antioxidation.Nineteen ninety-five, Vogt finds that D-met can oxidation take place reversibility ground, becomes free radical scavenger.Can protect the enzyme and the protein of sulfur-bearing as the D-met of sulfur-bearing nucleophilic reagent.Cochlea superoxide dismutase, peroxidase, glutathion reductase that D-met can protect cisplatin to cause descend.Especially Intramitochondrial glutathion in the cell can also raise.
The inventor finds in experiment first: (D-methionine D-met) has the obvious treatment effect to the dextrorotation methionine in the control bone marrow depression.It is more obvious particularly to prevent and treat radiation-induced bone marrow depression, thereby has finished the present invention based on above-mentioned discovery through further testing.
Summary of the invention
The technical problem to be solved in the present invention is to seek the medicine that can protect various factors to induce the damage of medullary cell and function to be prevented and treated and treat.
Therefore, one object of the present invention is providing the dextrorotation methionine to induce the application in the bone marrow depression medicine at preparation prevention or treatment radiation, chemical toxicant.
Another object of the present invention is to provide dextrorotation methionine and other nutrient substance, promotion proliferation of bone marrow cells medicament mixed makes compositions or the dextrorotation methionine is used as support medicine and antitumor drug, reduces the toxic and side effects that chemotherapy is brought.
A further object of the present invention is to provide dextrorotation methionine and pharmaceutically acceptable pharmaceutic adjuvant to be mixed and made into various pharmaceutical compositions, or makes all kinds of health product.
For addressing the above problem, the invention provides following technical scheme:
A kind of dextrorotation methionine is induced the application in the bone marrow depression medicine at the pre-radioprotective of preparation, chemical toxicant.One preferred embodiment is: the application of dextrorotation methionine in the radiation-induced bone marrow injury medicine of preparation control.Described radiation-induced bone marrow injury comprises: accept the staff of radiocurable tumor patient, radioactive exposure, the personnel that the accidental exposure isotope exposes.
Another preferred embodiment is: the application of dextrorotation methionine in the dead medicine of the inductive BM form of preparation therapeutical chemistry poisonous substance.The inductive bone marrow depression of wherein said chemical toxicant comprises: accept chemotherapeutical tumor patient, suppress the staff of chemical toxicant contact of bone marrow and the personnel of accidental exposure.
Bone marrow depression of the present invention (bone marrow depression death) comprises that peripheral blood leucocyte descends, myelosis is bad or aplastic anemia.
The present invention further discloses the pharmaceutical composition that contains the dextrorotation methionine, it is that the dextrorotation methionine and the pharmaceutically acceptable pharmaceutic adjuvant of will treat effective dose are mixed and made into compositions.
The present invention further discloses the compositions that contains dextrorotation methionine and other nutrient substance, promotes proliferation of bone marrow cells medicine or antitumor drug, comprising medicine, prophylactic agent and health food of clinical various dosage forms or the like.It is with dextrorotation methionine and other nutrient substance, promotes the proliferation of bone marrow cells medicament mixed to make compositions or dextrorotation methionine as supporting medicine and antitumor drug such as cisplatin, carboplatin, amycin, Maryland etc. to be used the toxic and side effects that the reduction chemotherapy is brought.
Other nutrient substance of the present invention comprise: other Aminosteril KE nutritional solution, vitamin, glucose, fat milk, ion etc.
The medicine of promotion proliferation of bone marrow cells of the present invention comprises: various Chinese medicine preparation such as polysaccharide (Fructus Lycii, Tremella, ginseng polysaccharide etc.), alkaloids (berberine, Radix Sophorae Flavescentis total alkaloids etc.), Saponin class (ginsenoside, astragalin etc.) and other rise white Chinese medicine preparation as six drugs containing rehmanniae oral liquid etc.; Human granulocyte macrophage colony stimulus factor (rHuGM-CSF), rise glad in vain, inosine, levamisole, SANZHU KOUFUYE, stanozolol etc.
Dextrorotation methionine of the present invention and pharmaceutically acceptable pharmaceutic adjuvant are mixed and made into various pharmaceutical compositions, comprising: tablet, capsule, granule, pill, drop pill, pre-Emulsion, microemulsion, suspensoid, syrup, various enteric coated preparation or injection preparation or the like.Each preparation can form according to the prepared of routine.When being prepared into medicament, can add acceptable accessories, described acceptable accessories, comprise diluent, filler (as mannitol, lactose, Polyethylene Glycol) conventional in the preparation, binding agent (starch, microcrystalline Cellulose), disintegrating agent (as carboxymethyl cellulose, the low hydroxypropyl cellulose that replaces), lubricant (as Pulvis Talci, magnesium stearate), wetting agent (as propylene glycol, ethanol), stabilizing agent (EDTA-2Na, sodium thiosulfate, sodium pyrosulfite, sodium sulfite, ethanolamine, sodium bicarbonate) or the like.
When the dextrorotation methionine becomes pharmaceutical composition with pharmaceutically acceptable pharmaceutic adjuvant combined group, the amount of the active ingredient dextrorotation methionine that contains in the compositions can be according to patient's the state of an illness, specific being applied of situation of diagnosis, the amount of used dextrorotation methionine or concentration are regulated in the scope of a broad, and the weight range of dextrorotation methionine is 0.5%～90% (weight) of compositions usually.Another preferred range is 0.5%-70%.A preferred range is 3%-50% again.
Dextrorotation methionine of the present invention and other nutrient substance, promote the proliferation of bone marrow cells medicament mixed to make pharmaceutical composition or dextrorotation methionine as supporting medicine and antitumor drug to be used.General use conventional technology, combine, and make it at random to combine and be prepared into microgranule or microsphere with acceptable adjuvant and excipient on the galenic pharmacy with acceptable solid or liquid-carrier on the galenic pharmacy.Solid dosage forms comprises tablet, discrete particles, capsule, slow releasing tablet, slow-release micro-pill or the like.Solid carrier can be at least a material, and it can serve as diluent, flavouring agent, solubilizing agent, lubricant, suspending agent, binding agent, disintegrating agent and coating agent.Inert solid carrier comprises magnesium phosphate, magnesium stearate, smoothers sugar, lactose, pectin, propylene glycol, polyoxyethylene sorbitan monoleate, dextrin, starch, gelatin, cellulose substances for example methylcellulose, microcrystalline Cellulose, low melt point paraffin, Polyethylene Glycol, mannitol, cocoa butter etc.Liquid dosage form comprises solvent, suspension for example injection, injectable powder or the like.
The present invention mainly comprises the following aspects to radiation-induced myelosuppressive content of the test:
1.D-met the medullary cell damage to extracorporeal irradiation has protective effect.
2.D-met the bone marrow cells in mice function damage of accepting total irradiation is had protective effect.
3.D-met radiation is caused that bone marrow depression death has protective effect.
4.D-met to not damage of body.
Further specify the dextrorotation methionine is induced bone marrow inhibition at prevention or treatment radiation, chemical toxicant pharmacological evaluation situation below by pharmacodynamic experiment.
One, experimental technique
1, BMNC separates
The aseptic mouse femur of getting contains the Hunks liquid flushing bone marrow of 2%FCS, and Ficoll separates, preparation mononuclearcell suspension, and washing, counting is adjusted behind the required cell concentration stand-by.
2, cell viability is measured
In 96 orifice plates, set the mononuclearcell suspension that the hole adds 100ul, add by design and handle medicine 100ul, insert in 37 ℃ of carbon dioxide incubators, cultivate 6h or 18h.Take out culture plate, place room temperature, add bioluminescent reagents cell-titer 20ul, behind the vibration mixing, change the black assay plate over to, GloMax
TMThe luminous detection instrument adopts Promega to carry trace routine Cell-titerProtocol and detects.Testing result generates the Excel data automatically.
3, colony forms (clone) ability mensuration
Packing methylcellulose culture medium ,-20 ℃ of preservations.With being prepended in the 2-8 ℃ of refrigerator or thawing under the room temperature; Separate bone marrow cells in mice, the blue dyeing counting cell of Placenta Hominis is adjusted cell concentration and is added M3534, the abundant mixing of agitator, leave standstill and treat bubble collapse, connect 16# tack syringe needle, add 24 orifice plates and put into wet box with the 3ml syringe, insert 37 ℃, cultivated 14 days in the 5%CO2 incubator.
Observe under inverted microscope from cultivating beginning in the 5th day.Low power is observed colony and is formed situation, the positive colony in cell number 〉=30, and colony-forming efficiency is with per 10
5Individual plastidogenetic colony numerical table shows.
4, after total irradiation mice survival rate was measured total irradiation, routine weighing was observed the dead mouse situation every day.
Two, experimental result and discussion
1, to hematopoietic cell immunocyte cytotoxicity (contrast experiment)
Separate the mouse bone marrow cells mononuclearcell, adjust cell concentration to 2 * 10
6/ ml.Variable concentrations (10
-2M～10
-6M) L-met and D-met are prepared by RPMI-1640 culture medium or the improved culture medium that do not contain met respectively.L-met content is 10 in the conventional RP1640 culture medium
-4M.Obtained cell suspension 100ul and variable concentrations are handled medicine and are added 96 well culture plates, hatch 18 hours after, biloluminescence method carries out cell viability and measures.Found that and utilize improved culture medium to experimentize that two kinds of met all do not find the significant cytotoxicity effect.And in conventional culture medium, 10
-2, 10
-3L-met has certain toxicity to medullary cell.The results are shown in Table 1, Fig. 1.
Table 1Met is to the influence (RLU * 1000) of medullary cell vigor
2, to the tumor cell cytotoxicity
According to trial test, selected human lung cancer cell line 460, Proliferation of Human Ovarian Cell is ES-2, human leukemia cell HL60A persister and HL60S drug sensitive cell strain inoculum density.Be seeded to 96 well culture plates, add the L-met and the D-met of variable concentrations, hatch 48h after, measure cell viability.Found that add L-met and D-met to the obviously influence (Fig. 2 A) of 460 cells growth nothing, other cells ES-2, HL60A, HL60S also obtain identical result.460 cells that utilize improved culture medium to cultivate compare with D-met, and L-met has the effect (Fig. 2 B) that promotes propagation, 10
-3～10
-6M scope, the two difference have significance (P＜0.01).
3, to the protective effect of the external radiation damage of hemopoietic immunocyte
Separating bone marrow single nuclear cell adds behind the medicine of variable concentrations (10
-2M～10
-6M), hatch 30min, shine.Continue to hatch 18h after the irradiation, carry out cell viability and measure.Found that irradiation back medullary cell vigor 1,4,8Gy descend 52%, 72%, 73% respectively.Compare with the radiation matched group, D-met pair cell vigor has certain protection effect (p＜0.05～0.01).The results are shown in Table 3, Fig. 3.
Table 3Met is to the influence (RLU * 1000) of exposure medullary cell vigor
Detect the protective effect of different time dosing to the myeloid element radiation damage, select 1 lattice auspicious (Gray, Gy) exposure dose, respectively at pre-irradiation 30min, 0min, irradiation back 15min, 30min, 1h, 2h add 10
-3D-met found that so that 30min and the protection of dosing simultaneously effect are better in advance.
4. chemicals are induced the protective effect of the external damage of hemopoietic immunocyte
Separating bone marrow single nuclear cell is seeded to culture plate by finite concentration, adds the dextrorotation methionine (10 of variable concentrations
-2M～10
-6M), hatch 30min, add final concentration 5uM VP16 or 60uM camptothecine respectively, continue to hatch 18h, carry out cell viability and measure.Found that VP16 makes medullary cell cell viability decline 60.5%, camptothecine descend 35.1%.Compare with the antineoplastic agent group, do not find that the inhibition of D-met pair cell vigor has protective effect (p＞0.05).
The protective effect that the medullary cell that table 4D-met causes antitumor drug damages
Three, experiment in the body
1, D-met is to the influence of radioactive exposure bone marrow cells in mice colony-forming efficiency
Dosage is divided into 0,1,4 to mice according to penetrating, four groups of 6.5Gy, 9/group.Pre-irradiation gives normal saline, 300mg/kg, 1000mg/kg respectively, lumbar injection, 3 of every processed group.After the irradiation, extracting marrow cell, the inoculation, carry out a monosystem colony-forming test (colony-formingunit-granulocyte-macrophage, CFU-GM).Found that different exposure doses have the obvious suppression effect to mice CFU-GM, irradiation has significant protective effect (P＜0.01) and D-met is to 1Gy.
Table 5D-met is to the influence of irradiation mouse bone marrow cells CFU-GM
2, D-met is to the influence of radioactive exposure mice survival rate
30 of male C57 mices are divided into 3 groups, give normal saline, D-Met 300mg/kg, D-Met 1000mg/kg respectively, and lumbar injection was observed 30 days.Do not find after the administration that mice shows unusually.Administration group body weight and matched group zero difference.30d draws materials, and takes by weighing important organ weight such as brain, lung, thymus, liver,spleen,kidney, calculates organ index, and each group is not seen notable difference.
Table 6D-met is to the influence (g) of healthy mice body weight
45 of male C57 mices are divided into normal saline, D-Met 300mg/kg, D-Met 1000mg/kg3 group, give 7.5Gy irradiation.Pre-irradiation is injecting normal saline, D-Met 300mg/kg, D-Met1000mg/kg respectively.Irradiation back observed and recorded dead mouse situation every day, routine weighing.Calculate LD50/30.Found that D-Met 300mg/kg has the certain protection effect to shining inductive BM form death, sees Fig. 4.
Find that according to experimental result in external, the body D-met has the certain protection effect to radiation-induced Functions of Bone Marrow Cells damage, and tumor cell is not promoted proliferation function, the prompting preventive administration can be prevented and treated the damage of radiation-induced bone marrow.Therefore, according to above-mentioned experimental data, if radiotherapy patient is replaced by D-met with L-met and is helped suppressing the tumor protection hematopoietic cell in the nutritional solution of taking to tumor and medullary cell.
The good effect that the present invention is compared with prior art had is:
1, D-met is the aminoacid of using always that promotes the growth effect that has, and it is wide, safe and effective, economic and practical to originate, and commercially available widely source is arranged.
2, D-met by all means administration pharmacodynamic action is all arranged.
3, D-met can use under the 300-1000mg/kg heavy dose does not have obvious toxic and side effects.
Description of drawings:
Fig. 1 Met is to the influence (%) of medullary cell vigor;
Fig. 2 Met is to the influence of lung cancer cell line 460 propagation;
Fig. 3 Met is to the influence (%) of exposure medullary cell vigor;
The protective effect of Fig. 4 Met radiation murine.
The specific embodiment
The present invention will be further described below in conjunction with embodiment.These embodiment describe typical case of the present invention, but the present invention is not limited to this.
The specific embodiment
In order to explain enforcement of the present invention more fully, provide following example of formulations.These embodiment explain rather than limit the scope of the invention.
Embodiment 1
D-met100mg, lactose 50mg, microcrystalline Cellulose 80mg, starch 50mg, hydroxyl methylcellulose 40mg, magnesium stearate 5mg.With active component, lactose, starch, microcrystalline Cellulose are crossed 100 mesh sieves, and abundant mixing, 2% hydroxyl methylcellulose aqueous solution joined in the above-mentioned mixed-powder mix, cross 20 mesh sieve system soft materials, make wet granular in 45-55 ℃ of drying, carboxymethylstach sodium, magnesium stearate are joined tabletting in the above-mentioned dried particles.
Embodiment 2
D-met 100mg, cleislanthin-B 500mg adds 4g (lactose-microcrystalline cellulose 5: 1), magnesium stearate 1%, with 70% alcohol granulation, tabletting promptly.
Embodiment 3
D-met 10g, mannitol 60g adds the dissolving of 1000ml water for injection, supplies water for injection to 2000ml, adds proper amount of active carbon and removes thermal source, and the 0.2um microporous filter membrane filters, fill, lyophilization makes 2000 freeze-dried powders.Specification: 70mg/ props up, and injection for intravenous is used.
Embodiment 4
D-met 10g adds dextrin 10g, lactose 30g with 60% alcohol granulation, drying, encapsulated, makes 1000 seed lac wafers.Specification: 50mg/ grain.
Embodiment 5
D-met 20g, Radix Codonopsis 5g, Radix Astragali 5g add starch 10g, micropowder silica gel 5g, magnesium stearate 1.5g incapsulates behind the mixing, makes 1000 capsules.
Embodiment 6
D-met 0.3g, inosine 0.2g, mannitol 9.4g, the sweet 0.2g of A Siba, sodium pyrosulfite 0.003g, essence 0.1g crosses 100 mesh sieves respectively with principal agent and adjuvant.Earlier adjuvant is fully mixed, take by weighing the recipe quantity adjuvant then and fully mix with principal agent.Add binding agent system soft material again, 20 mesh sieves are granulated, 55 ℃ of dryings, and 20 mesh sieve granulate sift out fine powder, make granule, packing.
Embodiment 7
D-met 10g, alkaloids berberine 15g adds sodium benzoate 3g, adds water to 1000ml, leaves standstill, filter, embedding, sterilization promptly gets oral liquid.
Embodiment 8
D-met 10g, SANZHU KOUFUYE 1000ml, potassium sorbate 3g adds water to 1000ml, leaves standstill, filter, embedding, sterilization promptly gets healthcare dietetic liquid.
In sum, among the embodiment that content of the present invention is not confined to, the knowledgeable people in the same area can propose other embodiment easily within technological guidance's thought of the present invention, but this embodiment comprises within the scope of the present invention.
Claims (10)
1, the dextrorotation methionine is induced the application in the bone marrow depression medicine at preparation control radiation, chemical toxicant.
2, the described application of claim 1 is characterized in that the application of dextrorotation methionine in the radiation-induced bone marrow injury medicine of preparation prevention.
3, the described application of claim 1 is characterized in that the application of dextrorotation methionine in the dead medicine of the inductive bone marrow depression of preparation therapeutical chemistry poisonous substance.
4, the described application of claim 1, wherein said radiation-induced bone marrow depression comprises the staff who accepts radiocurable tumor patient, radioactive exposure, the personnel that the accidental exposure isotope exposes.
5, the described application of claim 1, the inductive bone marrow depression of wherein said chemical toxicant comprises the staff of the chemical toxicant contact of accepting chemotherapeutical tumor patient, suppressing bone marrow and the personnel of accidental exposure.
6, each described application of claim 1-3 is characterized in that described bone marrow depression, comprises that peripheral blood leucocyte descends, myelosis is bad or aplastic anemia.
7, each described application of claim 1-3 is characterized in that the dextrorotation methionine and the pharmaceutically acceptable pharmaceutic adjuvant of treatment effective dose are mixed and made into compositions.
8, each described application of claim 1-3, it is characterized in that with it be with dextrorotation methionine and other nutrient substance, promote the proliferation of bone marrow cells medicament mixed make compositions or with the dextrorotation methionine as supporting medicine and antitumor drug to be used.
9, each described application of claim 7-8 is characterized in that described compositions is tablet, capsule, granule, pill, drop pill, pre-Emulsion, suspensoid, syrup, various enteric coated preparation or injection.
10, each described application of claim 1-3 is characterized in that the dextrorotation methionine and the pharmaceutically acceptable pharmaceutic adjuvant of effective dose are mixed and made into health product.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107174587A (en) * | 2016-03-10 | 2017-09-19 | 中国医学科学院放射医学研究所 | Application of the fourth disulfonic acid Ademetionine in terms of anti-radiation effect |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107174587A (en) * | 2016-03-10 | 2017-09-19 | 中国医学科学院放射医学研究所 | Application of the fourth disulfonic acid Ademetionine in terms of anti-radiation effect |
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