CN103202877A - Application of total salvianolic acids in drugs for preventing cardiotoxicity induced by arsenic trioxide and tumor inhibition synergic drugs - Google Patents
Application of total salvianolic acids in drugs for preventing cardiotoxicity induced by arsenic trioxide and tumor inhibition synergic drugs Download PDFInfo
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- CN103202877A CN103202877A CN2013100907796A CN201310090779A CN103202877A CN 103202877 A CN103202877 A CN 103202877A CN 2013100907796 A CN2013100907796 A CN 2013100907796A CN 201310090779 A CN201310090779 A CN 201310090779A CN 103202877 A CN103202877 A CN 103202877A
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- radix salviae
- salviae miltiorrhizae
- arsenic trioxide
- phenolic acids
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Abstract
The invention provides application of total salvianolic acids in drugs for preventing cardiotoxicity induced by arsenic trioxide and tumor inhibition synergic drugs. Drug compositions comprise total salvianolic acids, arsenic trioxide and one or more carriers or excipient medically acceptable.
Description
Technical field
The present invention relates to the application of a kind of medicinal active ingredient in the preparation medicine, relate in particular to the application of Radix Salviae Miltiorrhizae total phenolic acids in the preparation medicine, belong to medical technical field.
Background technology
Arsenic trioxide (As
2O
3) be to treat one of the most effective medicine of acute promyelocytic leukemia (APL) at present, be defined as the first-selected medication of APL recurrence by U.S. NCCN.Arsenic trioxide is also being obtained some achievements aspect the treatment research of malignant tumor such as lymphoma, myeloma in recent years.Though the arsenical of conventional therapy dosage is comparatively safe, some untoward reaction still often appear in clinical practice, and particularly cardiac toxicity reaction has limited As
2O
3Clinical being extensive use of.Arsenic trioxide causes the research of cardiac toxicity at present, though bibliographical information is all arranged both at home and abroad, mostly is the small sample data, rare large clinical research.External report uses arsenic agent treatment leukemia cardiac toxicity incidence rate up to 92.9%, even 100%.The cardiac toxicity that arsenic trioxide causes is mainly ECG change, and 50% above patient can cause that the Q-T interval prolongs, and other performance has sinus tachycardia, nonspecific ST-T to change and tachycardia.Modal acute complication also has fluid retention (pericardium, hydrothorax).In addition, weight person torsade de pointes can occur in treatment, dissociation or sudden death etc.At present for AS
2O
3The cardiac toxicity that occurs in the chemotherapy process does not still have specific therapy, and conventional vein uses large doses of vitamin C to alleviate.
Radix Salviae Miltiorrhizae is to be widely used in treating cardiovascular disease such as angina pectoris, heart infarction, apoplexy etc. all the time.Radix Salviae Miltiorrhizae total phenolic acids is the salvianolic acid of the abundantest and biologically active in the Radix Salviae Miltiorrhizae, has been proved to be to have important cardiovascular protection effect.Studies have shown that Radix Salviae Miltiorrhizae total phenolic acids has the effect of the tumor propagation of inhibition, prompting Radix Salviae Miltiorrhizae total phenolic acids and the cancer therapy drug coupling effect of performance efficacy enhancing and toxicity reducing in treatment of cancer probably.By protective effect and the molecular mechanism of systematic study Radix Salviae Miltiorrhizae total phenolic acids to myocardial cell injury and the cardiac toxicity of Arsenic Trioxide Induced, find Radix Salviae Miltiorrhizae total phenolic acids and As
2O
3(ATO) drug combination can be given full play to the efficacy enhancing and toxicity reducing effect of the two, and improve the clinical efficacy of arsenic trioxide and reduce its cardiac toxicity,
Summary of the invention
According to a first aspect of the present invention, provide Radix Salviae Miltiorrhizae total phenolic acids for the preparation of the application in the medicine of cardiac toxicity of protection Arsenic Trioxide Induced.
According to another aspect of the present invention, provide the application of the compositions that contains Radix Salviae Miltiorrhizae total phenolic acids and arsenic trioxide in the preparation antitumor drug.
Radix Salviae Miltiorrhizae total phenolic acids of the present invention obtains by adopting extracting method well known in the art to extract in the salviamiltiorrhizabung.
Medicine of the present invention is made pharmaceutical composition by active component and one or more pharmaceutically acceptable carriers or excipient.
Medicine of the present invention can also contain one or more other have similar effect active component.
The amount of the contained Radix Salviae Miltiorrhizae total phenolic acids in minimum dose unit of pharmaceutical composition of the present invention is 2-200mg.
Pharmaceutical composition of the present invention is any acceptable forms form clinically.The various dosage forms that comprise oral and parenteral form.Being used for when oral, can be tablet, capsule, soft capsule, oral liquid, syrup, granule, drop pill, oral cavity disintegration tablet, slow releasing tablet, slow releasing capsule, controlled release tablet, controlled release capsule; When being used for the parenteral approach, can be liquid drugs injection, freeze-dried powder, aseptic powder injection, transfusion.Pharmaceutical composition preferred tablet of the present invention and liquid drugs injection dosage form.
Described pharmaceutically acceptable carrier or the optional self application of excipient comprise filler, binding agent, lubricant, disintegrating agent, cosolvent, surfactant, absorption carrier etc. in the pharmaceutical excipient of oral formulations.
Described pharmaceutically acceptable carrier or the optional self application of excipient comprise solvent, antioxidant, cosolvent, adsorbent, osmotic pressure regulator, pH regulator agent in the pharmaceutical excipient of injection.
The minimum dose unit of pharmaceutical composition refers to a slice, a capsule, one bag of granule or an injection etc.
Dosage form of the present invention can be used usual any method production of using in pharmaceutical preparation technology, is not particularly limited.
For example, tablet of the present invention can use suitable method granulation well known in the art, drying and screening main active and excipient, binding agent etc., adds lubricant etc. in the gained mixture, mixes then and forms tablet.Pelletize can be undertaken by any suitable method well known in the art, for example wet granulation, non-slurry pelletizing or heating pelletize.Suitable limiting examples comprises uses high-speed stirred comminutor, fluidized granulation drying machine, Squeezinggranulator or cylinder compactor to carry out pelletize.In addition, for example method dry and screening can be carried out according to the needs of pelletize.The mixture of main active, excipient, binding agent, lubricant etc. also can be formed directly in tablet.
Film coating can use any film coating device known in the art if desired, and as film coating substrate, suitable example comprises sugar-coat base, hydrophilic film coating base, enteric film coating base and sustained release film coat base.
Description of drawings
Fig. 1: Radix Salviae Miltiorrhizae total phenolic acids and arsenic trioxide coupling are to the influence of myocardial damage
Fig. 2: Radix Salviae Miltiorrhizae total phenolic acids strengthens arsenic trioxide to the antitumor action of A549 tumor cell
Fig. 3: Radix Salviae Miltiorrhizae total phenolic acids strengthens arsenic trioxide to the antitumor action of S180 mice with tumor
The specific embodiment
The present invention is described in further detail below in conjunction with specific embodiment.
Embodiment one: Radix Salviae Miltiorrhizae total phenolic acids and arsenic trioxide coupling are to myocardial protective effect in the body
As in the body
2O
3The mouse cardiac muscle disease model of inducing is set up
The ICR mice (Beijing dimension tonneau China, Beijing, China) in Mus age in 6-8 week.Animal adapt to 1 week and during freely obtain food and water.60 mices are divided into 4 groups at random: the blank group; ATO organizes (1.5mg/kgAs
2O
3); ATO+ Radix Salviae Miltiorrhizae total phenolic acids 5mg/kg group; ATO+ Radix Salviae Miltiorrhizae total phenolic acids 10mg/kg group; ATO+ Radix Salviae Miltiorrhizae total phenolic acids 20mg/kg group; Tail vein injection is all adopted in all processing, and inject once every day, two weeks.Blank group mice is injected the 10ml/kg normal saline; ATO group injection 1.5mg/kgAs
2O
3; ATO+ Radix Salviae Miltiorrhizae total phenolic acids group injects earlier 5,10 respectively, the 20mg/kg Radix Salviae Miltiorrhizae total phenolic acids, injects 1.5mg/kgAs after 1 hour
2O
3
Morphological examination
After administration finished for two weeks, aroused in interest ultrasonic, with heavy dose of pentobarbital sodium mice is all caused death then, the dirty tissue of coring is with 4% formaldehyde fixed.The tissue slice of 5mm dyes with hematoxylin and eosin.Under optical microscope, carry out morphological examination, the results are shown in Figure 1.
As shown in Figure 1, blank group: organizational structure is normal substantially.The ATO group: large tracts of land cardiac muscle fiber dissolving fracture, volume is hemorrhage.ATO+ Radix Salviae Miltiorrhizae total phenolic acids 5mg/kg group: small size cardiac muscle fiber dissolving fracture, hemorrhage on a small quantity.ATO+ Radix Salviae Miltiorrhizae total phenolic acids 10mg/kg group: a small amount of cardiac muscle fiber dissolving fracture.ATO+ Radix Salviae Miltiorrhizae total phenolic acids 20mg/kg group: organizational structure is normal substantially, rarely seen a small amount of petechia.
Plasma collection and biochemistry detection
Under chloral hydrate anesthesia, use capillary tube to collect the blood sample of mice endocanthion.Blood sample in back one hour of collection at the centrifugal 10min of 3000rpm, LDH in the blood plasma subsequently, GSH-PX, AST, SOD, the activity of CK is according to manufacturers instruction, by from Jiancheng Bio-engineering Institute (Nanjing, China) the commercial detection test kit of buying is measured, and the results are shown in Table 1.
Table 1 Radix Salviae Miltiorrhizae total phenolic acids and arsenic trioxide coupling are to the influence of myocardium enzyme activity in the blood plasma
As shown in table 1, to compare with arsenic trioxide (ATO) group, the middle and high dosage of Radix Salviae Miltiorrhizae total phenolic acids and arsenic trioxide coupling group can reduce LDH, CK, the activity of AST improves protective enzyme SOD, the activity of GSH-PX.
Embodiment two: Radix Salviae Miltiorrhizae total phenolic acids and arsenic trioxide coupling are to the influence of antitumor action
Radix Salviae Miltiorrhizae total phenolic acids associating arsenic trioxide is to the influence of A549 tumor cell
The A549 cell is inoculated in 96 orifice plates with 5 * 104 density, normal group is blank, the ATO group adds the arsenic trioxide of 10 μ M, other the three groups arsenic trioxide+Radix Salviae Miltiorrhizae total phenolic acids coupling groups that are respectively 10 μ M, and the Radix Salviae Miltiorrhizae total phenolic acids consumption of coupling group is respectively 25,50,100 μ g/ml behind the processing cell 48h, detect cell viability with MTT, and the calculating inhibitory rate of cell growth, the results are shown in Figure 2.
As shown in Figure 2, Radix Salviae Miltiorrhizae total phenolic acids can significantly strengthen the suppression ratio that arsenic trioxide suppresses external A549 cell growth.
Radix Salviae Miltiorrhizae total phenolic acids associating arsenic trioxide is to the influence of S180 in-vivo tumour mice
ICR mouse hypodermic inoculation 5 * 10
6The S180 cell of density.After 24 hours, mice is divided into 4 groups at random, 15 every group.(a) mice is injected 10ml/kg saline (b) ATO group injection 1.5mg/kgAs in the normal group
2O
3; (c) ATO+ Radix Salviae Miltiorrhizae total phenolic acids group is injected 5,10,20mg/kg Radix Salviae Miltiorrhizae total phenolic acids respectively earlier, injects 1.5mg/kgAs after 1 hour
2O
3; Be tail vein injection, inject once every day, two weeks.After administration finished for two weeks, put to death mice and take out tumor, the weighing tumor weight the results are shown in Figure 3.
As shown in Figure 3, Radix Salviae Miltiorrhizae total phenolic acids and arsenic trioxide coupling can improve the suppression ratio of S180 tumor in the mice body of ATO.
Claims (10)
1. Radix Salviae Miltiorrhizae total phenolic acids is for the preparation of the application in the medicine of cardiac toxicity of protection Arsenic Trioxide Induced.
2. contain the application of compositions in the preparation antitumor drug of Radix Salviae Miltiorrhizae total phenolic acids and arsenic trioxide, wherein the cardiac toxicity of Radix Salviae Miltiorrhizae total phenolic acids protection Arsenic Trioxide Induced.
3. pharmaceutical composition for the protection of the cardiac toxicity of Arsenic Trioxide Induced; be made up of active component and one or more pharmaceutically acceptable carriers or excipient, active component is Radix Salviae Miltiorrhizae total phenolic acids or contains Radix Salviae Miltiorrhizae total phenolic acids and the compositions of arsenic trioxide.
4. pharmaceutical composition according to claim 3 wherein also contains one or more other antitumor drug in the active component.
5. pharmaceutical composition according to claim 3, the amount that it is characterized in that the contained Radix Salviae Miltiorrhizae total phenolic acids in minimum dose unit is 2-200mg.
6. according to each described pharmaceutical composition of claim 3-5, it is prepared to any acceptable forms clinically.
7. pharmaceutical composition according to claim 6 is characterized in that described dosage form comprises the various dosage forms of oral and parenteral form.
8. pharmaceutical composition according to claim 7 is characterized in that described pharmaceutically acceptable carrier or excipient are used for being selected from when oral filler, binding agent, lubricant, disintegrating agent, cosolvent, surfactant, absorption carrier; Be selected from solvent, antioxidant, cosolvent, adsorbent, osmotic pressure regulator, pH regulator agent when being used for the parenteral approach.
9. pharmaceutical composition according to claim 8 is characterized in that described dosage form is used for being selected from when oral tablet, capsule, soft capsule, oral liquid, syrup, granule, drop pill, oral cavity disintegration tablet, slow releasing tablet, slow releasing capsule, controlled release tablet, controlled release capsule; Be selected from liquid drugs injection, freeze-dried powder, aseptic powder injection, transfusion when being used for the parenteral approach.
10. pharmaceutical composition according to claim 9 is characterized in that described dosage form is tablet or liquid drugs injection dosage form.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109498610A (en) * | 2018-12-07 | 2019-03-22 | 哈尔滨医科大学 | A kind of medical composition and its use for alleviating the cardiac toxic syndrome that arsenic trioxide induces |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101411746A (en) * | 2007-10-19 | 2009-04-22 | 中国科学院上海药物研究所 | Novel use of salvia root extract |
-
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101411746A (en) * | 2007-10-19 | 2009-04-22 | 中国科学院上海药物研究所 | Novel use of salvia root extract |
Non-Patent Citations (2)
| Title |
|---|
| MIN WANG等: "Cardioprotective effect of salvianolic acid B against arsenic trioxide-induced injury in cardiac H9c2 cells via the PI3K/Akt signal pathway", 《TOXICOLOGY LETTERS》 * |
| 郝良纯等: "亚砷酸治疗急性早幼粒细胞性白血病心脏毒性的发生机制及防治进展", 《中国中西医结合儿科学》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109498610A (en) * | 2018-12-07 | 2019-03-22 | 哈尔滨医科大学 | A kind of medical composition and its use for alleviating the cardiac toxic syndrome that arsenic trioxide induces |
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Application publication date: 20130717 |