CN102274236B - Drug for prevention and treatment of cardiotoxicity induced by anthracycline antibiotics, and application thereof - Google Patents
Drug for prevention and treatment of cardiotoxicity induced by anthracycline antibiotics, and application thereof Download PDFInfo
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- CN102274236B CN102274236B CN 201010201577 CN201010201577A CN102274236B CN 102274236 B CN102274236 B CN 102274236B CN 201010201577 CN201010201577 CN 201010201577 CN 201010201577 A CN201010201577 A CN 201010201577A CN 102274236 B CN102274236 B CN 102274236B
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Abstract
The invention relates to a drug for prevention and treatment of cardiotoxicity induced by anthracycline antibiotics, and an application thereof. Flavone can be adopted for preparing the drug for prevention and treatment of the cardiotoxicity induced by the anthracycline drugs after modifying a plurality of sites such as 3, 5, 6, 7, 3', 4' and the like on the chemical structural formula of the flavone. The experimental results show that: with the flavone compounds, the cardiotoxicity induced by adriamycin can be reduced, myocardial contraction function can be improved, and oxygen radicals can be removed; cardiac tissue overoxidation damage induced by the adriamycin can be reduced, and cardiac function can be improved; the cardiotoxicity to the human body induced by the anthracycline drugs during chemotherapy can be effectively reduced, the pain of the patient undergoing the chemotherapy can be reduced, and the death rate caused by the anthracycline drugs can be reduced.
Description
Technical field
The present invention relates to a kind of medicine and application thereof that prevents and treats cardiac toxicity, relate in particular to substituted flavonoids and application thereof for the preparation of anthracycline antibiotics cardiac toxicity medicine.
Background technology
Amycin claims again doxorubicin (DOX), it is the anthracycline antibiotics that extracts from the light grey mutant of loose Streptothrix, it can intercalation of DNA base pair between, and be closely adhered on DNA, stop the effect of DNA dependent rna polymerase, disturb transcription, suppress the generation of RNA, also can stop copying of DNA, belong to cell cycle nonspecific agent (CCNSA).Since 1860s was found, it was because antitumaous effect is strong, and chemotherapeutic index is higher, and amycin is one of effective antitumour medicine always, is widely used in clinically the treatment of the various malignant tumor such as leukemia, lymphoma, solid cancer, and is evident in efficacy.With the anthracene nucleus medicament of amycin structural similarity, also include daunorubicin, aklavine, epirubicin, pirarubicin, idarubicin and mitoxantrone etc., all obtaining good curative effect aspect the treatment malignant tumor.
But identical with most of antitumor drug, the anthracycline antibiotics untoward reaction such as amycin are more, and as heart failure, myocardial ischemia, hypertension and arrhythmia etc., wherein heart failure is the most serious and modal cardiac toxicity.Accumulated dose is the most significant risk factor, can cause left chamber function abnormal; Accumulated dose surpasses 600mg/m
2The time, the incidence rate of congestive heart failure is up to 40% left and right; For studies show that of child's cancer survivor, treatment finished after 30 years in addition, and 73% patient can suffer from least one chronic disease, and 42% patient suffers from serious life-threatening disease, paralysis occurred or died from chronic disease.Serious cardiac toxicity has not only affected patient's life quality, and has limited the clinical application of anthracene nucleus medicament, so the cardiac toxicity that anthracene nucleus medicament causes has become cardiologist and the common problems of concern of tumor expert; And along with the increase of aged tendency of population and tumor incidence, the cardiac toxicity of understanding and correct processing antitumor drug is most important for the treatment of tumor patient.
At present, for anthracene ring antitumor medicinal cardiac toxicity mechanism, seeking heart protective agent is one of approach of control cardiotoxicity induced by anthracyclines, adopt biphenyl compound to be used for preventing and treating cardiac toxicity in propargyl amine and derivant and W02009048760A2 as adopting in patent US2008182804A1 to adopt in cyano group oxime compound, US2008090915A1, but above-mentioned patent drug or itself be with toxic, or preparation difficulty, high cost; And at present that is that all right is ripe to the research of cardiotoxicity induced by anthracyclines reaction, also finds no the Therapeutic Method of effect, and it is very few especially that existing approval is used for clinical heart protective agent.
The iron chelator dexrazoxane is unique protective agent for the clinical prevention doxorubicin cardiotoxicity of FDA approval, iron chelator has high-affinity to iron ion in addition, can reduce amycin and be combined with iron ion, and then reduce oxygen-derived free radicals generation, determined curative effect; Patent CN101352438A also discloses a kind of deferiprone medicine.But research finds that such medicine may cause serious bone marrow depression, and may affect amycin to the activity of some malignant tumor, and therefore, U.S.'s clinical tumor, chemotherapy and radiation expert association has been used as corresponding restriction to clinical the making of dexrazoxane; Secondly, the drug prices such as dexrazoxane are expensive, and can only be with slow quiet pushing away after the lactic acid solution dissolving, and its use is very limited.Therefore, the protective agent of exploitation determined curative effect, economical and practical new control anthracycline antibiotics cardiac toxicity has Great significance.
Summary of the invention
The invention provides a kind of medicine and application thereof of new control anthracycline antibiotics cardiac toxicity, this effective ingredient is substituted flavonoids.Flavone compound claims again bioflavonoids, finger has the chromone ring and phenyl ring is the general name of a compounds of basic structure, the derivant of chromone or chromanane, take flavone (2-phenyl chromone) as the derivative class xanthein of parent nucleus, it extensively is present in each position of plant.Replacing flavone can extract from Chinese medicine or be obtained through chemical modification by extract; because it has antioxidation, antiinflammatory isoreactivity; the heart and injury that the anthracycline antibiotics such as amycin are induced has significant protection effect, can be used for preventing and alleviating the cardiac toxicity of anthracene ring antitumor medicinal.
The medicine of control anthracycline antibiotics cardiac toxicity provided by the invention, its effective ingredient are 3,5,6,7,3 ', 4 '-replacement flavone, and described replacement flavone structural formula is as follows:
Wherein, in described replacement flavone structural formula, R3, R4 and R6 are hydroxyl; R5 is
Further, in described replacement flavone structural formula, R
1For hydrogen base, hydroxyl or
Further, in described replacement flavone structural formula, R
2Be hydrogen base or hydroxyl.
The application of described medicine provided by the invention in control anthracycline antibiotics cardiac toxicity.
Wherein, described anthracycline antibiotics is a kind of in amycin, daunorubicin, aklavine, epirubicin, pirarubicin, idarubicin or mitoxantrone.
Flavone compound distributes very wide in plant kingdom, extensively be present in each position of plant, mainly is present in Rutaceae, Labiatae, pulse family, Umbelliferae, Ginkgoaceae and Compositae.According to the study, approximately have in 20% Chinese herbal medicine and contain flavone compound, as seen its resource is abundant.Flavone compound can directly obtain from food, also can extract from the plant of being rich in flavone compound, so the present invention's raw material wide material sources used, cost also reduces greatly, and uses safety.
External, in vivo test studies have shown that; the heart and injury that the replacement flavone is induced amycin has significant protection effect; can be used for prevention and alleviate the anthracene ring antitumor medicinal cardiac toxicity; thereby enlarge the clinical practice of amycin, and alleviated toxic and side effects that anthracene ring antitumor medicinal brings to the patient and the misery of patients undergoing chemotherapy.
Description of drawings
Fig. 1 is that scutellarin is to the influence curve figure of amycin myocardial cell activity;
Fig. 2 is that scutellarin is on the comparison diagram that affects of amycin administration rat blood serum serum cardiac troponin T;
Fig. 3 is that scutellarin is on the comparison diagram that affects of amycin administration rat left ventricular ejection fraction;
Fig. 4 is that scutellarin is on the comparison diagram that affects of amycin administration rat left-ventricular short-axis Fractional shortening;
Fig. 5 is that scutellarin is on the histopathologic impact contrast of amycin administration rat heart photo.
The specific embodiment
Scutellarin (scutellarein-7-O-β-D-Glucose glycosides, abbreviation SCU) claim again scutellarin, be extract from the dry herb of feverfew Erigeron breviscapus (Vant.) Hand.-Mazz., in conjunction with the flavone compound of a glucuronic acid, the main active of widely used Herba Erigerontis injection clinically, clinical general use intravenous drip administration; Be mainly used in apoplexy sequela, coronary heart disease, the treatment of the diseases such as angina pectoris.The scutellarin chemical constitution is as follows:
That is: replace R in the flavone structural formula
1And R
2Be the hydrogen base; R3, R4 and R6 are hydroxyl; R5 is
The below illustrates 3,5,6,7 take scutellarin as example by specific embodiment, the application of 3 ', 4 '-replacement flavone in control anthracycline antibiotics cardiac toxicity.
The index of estimating doxorubicin cardiotoxicity comprises: malonaldehyde (MDA) level and heart tissue pathological examination in the cTnT in serum, the lactic dehydrogenase enzyme level in serum, echocardiography, heart tissue.
Embodiment (one): the in vitro study of scutellarin to the protective effect of amycin myocardial cell toxicity.
At first add FBS to prepare culture medium in DMEM, in culture medium, FBS concentration is 10%; It is 2 * 10 that rat H9c2 myocardial cell is diluted to concentration with culture medium
5The cell suspension of individual/mL, and be inoculated in 96 well culture plates, cultivate after 24 hours, carry out drug treating.Establish respectively the scutellarin solution group of blank group, medication group (containing 2 μ M doxorubicin hydrochlorides) and variable concentrations (10,25,50,100 μ M).Cultivate after 48 hours, measure with mtt assay, use microplate reader to measure the absorbance at 570nm place, calculating myocardium cytoactive.
With reference to Fig. 1, with respect to blank group cytoactive 100%, during 2 μ M doxorubicin hydrochloride, myocardial cell activity is 41.18%, and after merging the scutellarin that uses 10 μ M, 25 μ M, 50 μ M and 100 μ M, cytoactive is increased to respectively 49.80%, 60.13%, 68.98% and 81.98%.
Experiment in vitro explanation scutellarin can prevent and alleviate the myocardial cell injury that amycin causes in experiment in vitro.
Embodiment (two): study in the body of scutellarin to caused by doxorubicin rat heart toxicity.
1: medicine and reagent:
Adriamycin vial is available from Wanle Pharmaceutical Co Ltd, Shenzhen, and specification: 10mg/ props up, lot number: 0804E1.
Scutellarin (yellow powder, purity＞98%) is available from upper Haikang nine chemical industry company limiteies, lot number: 080516.
Mda test kit lot number: 20080813
Determination of lactate dehydrogenase test kit lot number: 20080813
Coomassie brilliant blue protein determination kit lot number: 20080813
Above test kit all builds up Science and Technology Ltd. available from Nanjing.
2: animal: cleaning level male and healthy SD rat (credit number: SCXX (Shanghai) 2008-0016, west, Shanghai pul-Bi Kai laboratory animal company limited), body weight 200～250g, raise in constant-temperature purification ventilation Animal House, ad lib and drinking-water, natural lighting is raised a week to conform before experiment.
3: experimental technique:
The healthy male SD rat of 32 220～250g is weighed and is divided at random 4 groups afterwards, and 8 every group, administration by the following method:
Blank group: abdominal cavity single injection equal-volume normal saline, continuous three days injecting normal salines of tail vein;
Amycin group (DOX): abdominal cavity single injection doxorubicin hydrochloride 20mg/kg body weight, continuous three days injecting normal salines of tail vein;
Scutellarin treatment group (DOX+SCU): abdominal cavity single injection doxorubicin hydrochloride 20mg/kg body weight, tail vein injection scutellarin 5mg/kg body weight once a day, continues three days;
Scutellarin matched group (DOX): abdominal cavity single injection normal saline, tail vein injection scutellarin 5mg/kg body weight once a day, continues three days.
Give for the last time scutellarin after 24 hours, do echocardiography after rat anesthesia.Then the abdominal cavity aorta is got blood, separation of serum.Put to death animal and take out fast heart, after normal saline flushing, the up and down crosscut is divided into two parts, and wherein a part is fixing in 10% formalin, HE dyeing, and microscopically tissues observed pathology change; Another part is preserved in liquid nitrogen, measures MDA content in tissue.
3.1: serum Myocardial TnT level
The content of serum cardiac troponin T adopts the immunochemiluminescence method to detect, and checkout equipment is RocheElecsys 2010 type immunoluminescence instrument.
With reference to Fig. 2, in figure, " * * " expression is compared with amycin and is had significant difference, P＜0.01.
The content of the serum Myocardial TnT of blank group and scutellarin matched group is below detectability (0.01ng/mL) all, and the level that the amycin group is the serum cardiac troponin T of model group significantly raises, compare with the blank group, P＜0.01, the cTnT of scutellarin treatment group is compared P＜0.01 close to matched group with the amycin group.
3.2: echocardiography
The anesthesia of rats by intraperitoneal injection amobarbital injection cuts off chest hair after stupor.It is lain on the back lie low on flat board, extremity are fixed.Siemens Sequoir 512 colorful ultrasonic instrument, frequency probe are that 8～12MHz detects rat heart physiology variation.
With reference to Fig. 3 and Fig. 4, in figure, " * * " expression is compared with amycin, has significant difference, P＜0.01; " * " expression is compared with amycin, has significant difference, P＜0.05.
After administration 72h, the amycin group is compared with the blank group, and rat left chamber's ejection fraction (LVEF%) significantly reduces, and two groups exist significant difference ((47.5 ± 15.59) vs (78.72 ± 7.25), P＜0.01); Left chamber minor axis Fractional shortening (LVFS%) significantly reduces, and two groups exist significant difference ((20.66 ± 8.06) vs (43.7 ± 6.76), P＜0.01).
After merging the use scutellarin, the scutellarin treatment group is compared with the amycin group, LVEF% significantly raises, two groups exist significant difference ((76.7 ± 7.83) vs (47.5 ± 15.59), P＜0.05), there is not significant difference ((76.7 ± 7.83) vs (78.72 ± 7.25)) with the blank group; The scutellarin treatment group is compared with the amycin group, LVFS% also significantly raises, there is significant difference ((40.28 ± 7.36) vs (20.66 ± 8.06) with the amycin group, P＜0.01), there is not significant difference ((40.28 ± 7.36) vs (43.7 ± 6.76)) with the blank group.
3.3 the content of malonaldehyde in heart (MDA)
Core dirty tissue and normal saline on the rocks are made 10% tissue homogenate, then operate according to Mda test kit description.Use the protein content of Coomassie brilliant blue kit measurement tissue homogenate, the MDA content in computation organization.
With reference to table 1, the amycin group causes that the content of lipid peroxidation product malonaldehyde in heart tissue significantly raises, and compares P＜0.01 with the blank group.In scutellarin treatment group rat heart tissue, the content of malonaldehyde close to the blank group, is compared with the amycin group and is had significant difference, P＜0.01.
3.4 lactic acid dehydrogenase in serum (LDH) content
Get rat blood serum, according to the operation of determination of lactate dehydrogenase test kit description, and the protein content in use Coomassie brilliant blue kit measurement serum, calculate the LDH content in serum.
With reference to table 1, the amycin group causes that in serum, the content of lactic acid dehydrogenase significantly raises, and compares P＜0.01 with the blank group; In scutellarin treatment group rat blood serum, the content of lactic acid dehydrogenase close to the blank group, is compared with the amycin group and is had significant difference, P＜0.01.
Table 1 scutellarin causes the impact of rat heart oxidative damage on doxorubicin hydrochloride
*: compare with amycin, have significant difference, P＜0.01.
3.5. heart tissue pathological examination
Heart tissue after 10% formalin solution is fixing, paraffin embedding, the section of being cut into 3～5 μ m, HE dyeing, optical microphotograph Microscopic observation heart tissue pathology change.
With reference to Fig. 5, picture A is blank group (amplifying 100 times), B is amycin group (amplifying 100 times), C, D are amycin group (amplifying 200 times), E is amycin group (amplifying 400 times), F is scutellarin treatment group (amplifying 100 times), and G is scutellarin treatment group (amplifying 200 times), and H is scutellarin matched group (amplifying 100 times).
Blank group and scutellarin matched group are normal heart tissue anatomical structure (picture A and H).After lumbar injection 20mg/kg amycin, the amycin group presents serious heart tissue pathology damage, visible myocardial fibrosis, muscular degeneration of heart and necrosis under light microscopic, and there is cell infiltration the part, accidental vacuolation (photo B, C, D and E).And after merging the use scutellarin, the tissue pathology checking of scutellarin treatment group presents slight heart and injury, visible indivedual myocardial cell degeneration and necrosis, and there is cell infiltration the part, and without fibrosis and vacuolation (photo F and G).
Above-mentioned experimental result demonstration, the substituted flavonoids such as scutellarin can improve myocardium shrinkage function to improve cardiac function; And removing oxygen-derived free radicals, heart tissue peroxide injury due to the anthracene nucleus medicaments such as reduction amycin, thereby the cardiac toxicity due to the reduction anthracene nucleus medicament, to alleviate the anthracene nucleus medicament chemotherapeutic period to the cardiac toxicity that human body produces, alleviate the painful of patients undergoing chemotherapy and reduce the mortality rate that anthracene nucleus medicament causes.
Above specific embodiments of the invention are described in detail, but it is just as example, the present invention is not restricted to specific embodiment described above.To those skilled in the art, any equivalent modifications that the present invention is carried out and substituting also all among category of the present invention.Therefore, not breaking away from impartial conversion and the modification of doing under the spirit and scope of the present invention, all should contain within the scope of the invention.
Claims (1)
1. the application of scutellarin in preparation control anthracycline antibiotics cardiac toxicity medicine, it is characterized in that, described anthracycline antibiotics is a kind of in amycin, daunorubicin, aklavine, epirubicin, pirarubicin, idarubicin or mitoxantrone.
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| CN107115372B (en) * | 2016-02-25 | 2020-07-07 | 任立群 | An antitumor pharmaceutical composition containing folium Apocyni Veneti total flavonoids |
| CN109200045A (en) * | 2017-06-30 | 2019-01-15 | 中国科学院西北高原生物研究所 | Application and pharmaceutical composition of the Anthocyanin-rich Extract in the pharmaceutical composition of preparation prevention and treatment anthracene nucleus medicament myocardiocyte toxicity |
| CN110946856B (en) * | 2019-12-09 | 2022-03-04 | 中国药科大学 | Pharmaceutical composition for preventing and treating anthracycline antibiotic cardiotoxicity and application thereof |
| CN112353810B (en) * | 2020-11-23 | 2023-08-25 | 湖州师范学院求真学院 | Use of compound F-B in preparation of products for preventing and/or treating heart injury |
| CN112353944A (en) * | 2020-11-23 | 2021-02-12 | 湖州师范学院求真学院 | Anticancer combined medicine composition containing compound F-B |
| CN112386704B (en) * | 2020-11-23 | 2023-07-04 | 中国科学院西北高原生物研究所 | Anticancer combination composition comprising compound F-C |
| CN112237587B (en) * | 2020-11-23 | 2023-04-25 | 湖州师范学院 | Anticancer combination composition comprising compound F-A |
| CN112972468B (en) * | 2021-03-29 | 2022-03-22 | 湖州师范学院 | Application of alkaloid compound Hip in preparation of products for preventing and/or treating heart injury |
| CN113244255A (en) * | 2021-05-08 | 2021-08-13 | 清华大学 | Application of breviscapine as medicine for preventing and treating cardiotoxicity of chemotherapeutic medicine |
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| CN1565465A (en) * | 2003-06-26 | 2005-01-19 | 天津药物研究院 | Injection preparation containing breviscapine active component and its preparation method |
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|---|---|---|---|---|
| CN1565465A (en) * | 2003-06-26 | 2005-01-19 | 天津药物研究院 | Injection preparation containing breviscapine active component and its preparation method |
| CN1596905A (en) * | 2003-09-20 | 2005-03-23 | 谢亚苏 | Erigeron breviscapus dispersion tablet |
Non-Patent Citations (2)
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| 张春霞等.灯盏细辛中黄酮类成分药理活性的研究进展.《中国新药杂志》.2008,第17卷(第2期), |
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