CN109044997A - The new application of cinnaldehydrum - Google Patents
The new application of cinnaldehydrum Download PDFInfo
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- CN109044997A CN109044997A CN201810973728.0A CN201810973728A CN109044997A CN 109044997 A CN109044997 A CN 109044997A CN 201810973728 A CN201810973728 A CN 201810973728A CN 109044997 A CN109044997 A CN 109044997A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/11—Aldehydes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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Abstract
The present invention provides a kind of new application of cinnaldehydrum, specifically purposes of the cinnaldehydrum in preparation prevention and treatment anticancer drug cardiotoxicity caused drug or health care product.For the cardiac toxic that anticancer drug causes, cinnaldehydrum is used to prevent and treat cardiac toxic caused by anticancer drug for the first time by the present invention.The result shows that: cinnaldehydrum improves the decrease of the cardiac short axis shortening rate as caused by anticancer drug, cinnaldehydrum can weaken damage of the anticancer drug to cardiac ejection fraction, heart weight ratio caused by anticancer drug increases extremely can be by cinnaldehydrum Effective Regulation, while heart area area caused by anticancer drug expands and left ventricular posterior wall is thinning can be also effectively improved by cinnaldehydrum.This illustrates that the cardiac toxic of anticancer drug can be effectively reduced in cinnaldehydrum, can be used for preventing and treating damage of the anticancer drug to body cardiac function, provides new thinking for the prevention and treatment of anticancer drug cardiac toxic.
Description
Technical field
The invention belongs to pharmaceutical technology fields, are related to a kind of new application of cinnaldehydrum.
Background technique
Adriamycin (Doxorubicin, DOX) is the clinically used anti-evil for having the characteristics that antitumor spectra is wide, anti-tumor activity is strong
Property tumour medicine, is widely applied in the treatment of Several Kinds of Malignancy.And adriamycin is while playing its antitumor action, meeting
Cardiotoxity is generated, is mainly shown as dilated cardiomyopathy and severe heart failure (Ewer MS, Ewer
SM.Cardiotoxicity of anticancer treatments:what the cardiologist needs to
know.Nat Rev Cardiol.2010；7(10)).And development is the patient of congestive heart failure after adriamycin chronic treatment
The death rate may be up to 50% (Chatterjee K, Zhang J, Honbo N, Karliner JS.Doxorubicin
cardiomyopathy.Cardiology 2010；115 (2): 155-162), in clinical studies, doxorubicin dosages accumulation is arrived
The illness rate of left ventricular systolic dysfunction reaches 50~60% in the patient of 430~600mg/ml, and cardiomyopathy hair can be observed
Very significant (Filipa S.C, Ana B, Rita G, the et al.Doxorubicin-Induced of sick rate
Cardiotoxicity:From Bioenergetic Failure and Cell Death to Cardiomyopathy.Med
Res Rev 2014；34(1):1-30).Existing numerous studies are by the research such as HSP20, PI3K, Honokiol to adriamycin
Induced cardiotoxicity (Bartlett JJ, Trivedi PC, Pulinilkunnil T.Autophagic
dysregulation in doxorubicin cardiomyopathy.J.Mol.Cell.Cardiol.2017；104:1-8),
But there is not the method for effectively treating doxorubicin cardiotoxicity really yet clinically.
Cinnaldehydrum (trans-cinnamaldehyde, TCA) is a kind of effective component for being present in natural plants cortex cinnamomi, one
The organic compound of kind alkene aldehydes, is in pale yellowish oil liquid, there is strong cinnamic odor, since molecule has olefine aldehydr knot
Structure, it is bad to light and oxygen stability, it is slightly soluble in water, is dissolved in chloroform, ether, ethyl alcohol.Chemical molecular formula C9H8O, average molecular matter
Amount is 132.16.Cinnaldehydrum has anti-inflammatory (Youn H S, Lee J K, Choi Y J, et al.Cinnamaldehyde
suppresses toll-like receptor 4activation mediated through the inhibition of
Receptor oligomerization.Biochem Pharmacol, 2008,75 (2): 494), antitumor (Zhang J H,
Liu L Q, He Y L, et al.Cytotoxic effect of trans-cinnamaldehyde on human
Leukemia K562cells.Acta Pharmacol Sin, 2010,31 (7): 861), antibacterial (NaveedR, Hussain I,
Tawab A, et al.Antimicrobial activity of the bioactive components of essential
oils from Pakistani spices against Salmonella and other multi-drug resistant
Bacteria.BMC Complement Alternat Med, 2013,13:265.), anti-diabetic, anti-obesity (Saifudin
A, Kadota S, Tezuka Y.Protein tyrosine phosphatase 1B inhibitory activity of
indonesian herbal medicines and constituents of Cinnamomum burmannii and
Zingiber aromaticum.J Nat Med.2013；67 (2): 264), neuroprotection (Pyo J H, Jeong Y K, Yeo
S, et al.Neuroprotective effect of trans-cinnamaldehyde on the 6-
Hydroxydopamine-induced dopaminergic injury.Biol Pharm Bull, 2013,36 (12):
1928.) multiple pharmacological effects such as.At present numerous studies have demonstrated that it is with extensive pharmacological action, to the nervous system disease,
A variety of diseases such as genital system diseases, cardiovascular disease, tumor disease, diabetes and obesity embody certain prevention and control
Treatment effect.
But it in terms of up to the present cinnaldehydrum has cardiac toxic caused by prevention and treatment anticancer drug, but has not been reported.
Summary of the invention
Based on this, the main object of the present invention is to provide a kind of new application of cinnaldehydrum, and specifically a kind of cinnaldehydrum is being made
Purposes in standby prevention and treatment anticancer drug cardiotoxicity caused drug or health care product.
The purpose of the present invention is what is be achieved through the following technical solutions:
Purposes of the cinnaldehydrum in preparation prevention and treatment anticancer drug cardiotoxicity caused drug or health care product.
In wherein some embodiments, the anticancer drug is chemotherapeutics.
In wherein some embodiments, the chemotherapeutics is adriamycin.
In wherein some embodiments, the cardiac toxic is cardiomegaly, myocardial area increases, left ventricular posterior wall becomes
It is thin.
In wherein some embodiments, the cardiac toxic is cardiac systolic function damage.
In wherein some embodiments, the cardiac systolic function damage is that cardiac short axis shortening rate weakens.
In wherein some embodiments, the cardiac toxic is cardiac ejection function damage.
In wherein some embodiments, the cardiac ejection function damage is cardiac ejection fraction reduction.
In wherein some embodiments, the drug is oral preparation or ejection preparation.
In wherein some embodiments, the oral preparation is selected from tablet, capsule, soft capsule, granule, suspension
One of agent, dripping pill, pill, oral liquid；The ejection preparation is injection or powder-injection.
In wherein some embodiments, the tablet is conventional tablet, dispersible tablet, oral disnitegration tablet or sustained release tablets.
Compared with prior art, the present invention have it is following the utility model has the advantages that
For the cardiac toxic that anticancer drug (adriamycin especially in chemotherapeutics) causes, the present invention is for the first time by cassia bark
Aldehyde is for preventing and treating cardiac toxic caused by anticancer drug.The result shows that: it is short that cinnaldehydrum improves the heart as caused by anticancer drug
Axis shortening rate (FS) reduces, and cinnaldehydrum can weaken damage of the anticancer drug to cardiac ejection fraction (EF), at the same time anticarcinogen
Myocardial area caused by object increases, left ventricular posterior wall is thinning and heart weight ratio also can be effectively improved extremely by cinnaldehydrum.This
Illustrate that cinnaldehydrum can effectively reduce cardiac toxic caused by anticancer drug, can be used for preventing and treating anticancer drug to body heart
The damage of function provides new thinking for the prevention and treatment of cardiac toxic caused by anticancer drug.
Detailed description of the invention
Fig. 1 modeling administration time axis figure；
Fig. 2 ultrasonic cardiography, which detects cinnaldehydrum intervention (50mg/kg), improves heart contraction and Ejection function caused by adriamycin
It is abnormal；
Fig. 3 hematoxylin-eosin (HE) dyeing detection cinnaldehydrum intervention (50mg/kg) improves cardiac shape caused by adriamycin
It learns abnormal；
Fig. 4 cinnaldehydrum intervention (50mg/kg) is effectively improved the exception of heart weight ratio caused by adriamycin.
Specific embodiment
It to facilitate the understanding of the present invention, below will be to invention is more fully described.But the present invention can be to be permitted
Mostly different form is realized, however it is not limited to embodiment described herein.On the contrary, purpose of providing these embodiments is makes
It is more thorough and comprehensive to the understanding of the disclosure.
Unless otherwise defined, all technical and scientific terms used herein and belong to technical field of the invention
The normally understood meaning of technical staff is identical.Term as used herein in the specification of the present invention is intended merely to description tool
The purpose of the embodiment of body, it is not intended that in the limitation present invention.Term as used herein "and/or" includes one or more phases
Any and all combinations of the listed item of pass.
With reference to the accompanying drawings and detailed description, the invention will be further described, and method therefor is unless otherwise instructed
It is conventional method.
Embodiment 1
The present embodiment provides a kind of new applications of cinnaldehydrum.Mainly caused by detecting cinnaldehydrum intervention to by adriamycin
Heart and the improvement result of motor function exception test the purposes of cinnaldehydrum.
1, experimental animal feeding
SPF grades of C57BL/6 mouse: male the age 8 weeks, is pleased experimental animal breeding Co., Ltd by Jinan friend and is provided.SPF
Grade animal center raising, raises area's temperature generally between 25~28 DEG C, humid control is between 40~70%, micro computer control
Fluorescent lamp illuminating system, 12h light and shade replace automatically.The regular cleaning of animal center, replacement animal litter, addition feed, can
Freely absorb SFP grades of breeding grade feeds and drinking-water.
2, drug and main agents
Cinnaldehydrum is purchased from Sigma company；Adriamycin is purchased from Ruibio company of Germany.
3, efficacy testing
(1) animal packet: control group (Control), adriamycin model group (Dox), model add basic, normal, high dose of cinnaldehydrum
It measures intervention group (Dox+TCA, 25mg/kg, 50mg/kg and 100mg/kg), totally five groups, every group of 6 animals.
(2) modeling method: adriamycin is continuously injected intraperitoneally 5 days in 8 week old mouse, dosage 3mg/kg/day.
(3) preparation of cinnaldehydrum (TCA):
1) 0.5% (m/v) carboxymethyl cellulose sodium (CMC-Na) is configured: with 0.9% (m/v) physiological saline, in magnetic agitation
Revolving speed 600rpm, 60 DEG C of heating, dissolve CMC-Na powder, 30~60min, until being completely dissolved, until no milky white precipitate on device.
2) TCA configure: with 4 DEG C refrigerate 0.5% (m/v) CMC-Na dissolution configuration final concentrations be respectively 25mg/kg, 50mg/kg,
The TCA injection of 100mg/kg, mixes, and 4 DEG C of refrigerations are spare.
(4) medication: starting to be administered on the same day with modeling, and various concentration cinnaldehydrum is injected in cassia bark aldehyde treatment abdominal cavity respectively
Injection 25,50 and 100mg/kg/day, control group be injected intraperitoneally 0.5% (m/v) CMC-Na, continuous 14 days.Specific modeling is given
Medicine time shaft is shown in Fig. 1.
(5) measurement of pharmacodynamic results:
By mouse ultrasonic technique aroused in interest, using toy photoacoustic ultrasound imaging system (Vevo 2100,
VisualSonics, Canada) M-Mode to mouse parasternal cardiac short axis be imaged (Fig. 2A), using its carry LV Trace survey
Software measurement is measured, is obtained and the maximally related parameter of mouse heart function, including cardiac short axis shortening rate, ejection fraction.Pass through the heart
Dynamic ultrasound observation and data statistics discovery, cinnaldehydrum improve the cardiac short axis shortening rate as caused by adriamycin in concentration dependent
(FS) weaken and cardiac ejection fraction is substantially reduced (table 1).Illustrate that cinnaldehydrum can effectively reverse heart caused by adriamycin to receive
Contracting function and Ejection function damage.
Table 1
In order to further affirm improvement of the cinnaldehydrum to cardiac function, pass through mouse transfer rod motor behavior observation device
Accelerating persistent movement time and movement on rotating rod in (JLBehv-RRTG-5, Shanghai Ji amount, China) monitoring mouse 5min
Total distance.Transfer rod movement statistics the result shows that adriamycin causes mouse movement total distance and persistent movement time to be decreased obviously,
Illustrate that mouse movement ability is remarkably decreased.After tri- concentration cinnaldehydrum of 25mg/kg, 50mg/kg, 100mg/kg are intervened, mouse fortune
Kinetic force is all improved in varying degrees, wherein only the cinnaldehydrum administration concentration improvement mouse movement ability effect of 50mg/kg is most strong
(table 2).Therefore comprehensive Echocardiography detection and transfer rod motion result, after most effective dosage (50mg/kg) will be selected to carry out
Continuous research.
Table 2
Embodiment 2
The present embodiment provides a kind of new applications of cinnaldehydrum.Mainly caused by detecting cinnaldehydrum intervention to by adriamycin
The protective effect of the function of heart, weight and morphological abnormalities test the purposes of cinnaldehydrum.
1, experimental animal feeding
SPF grades of C57BL/6 mouse: male the age 8 weeks, is pleased experimental animal breeding Co., Ltd by Jinan friend and is provided.SPF
Grade animal center raising, raises area's temperature generally between 25~28 DEG C, humid control is between 40~70%, micro computer control
Fluorescent lamp illuminating system, 12h light and shade replace automatically.The regular cleaning of animal center, replacement animal litter, addition feed, can
Freely absorb SFP grades of breeding grade feeds and drinking-water.
2, drug and main agents
Cinnaldehydrum is purchased from Sigma company；Adriamycin is purchased from Ruibio company of Germany.
3, efficacy testing
(1) animal packet: control group (Control), control add cinnaldehydrum group (Control+TCA), adriamycin model group
(Dox), model adds cinnaldehydrum intervention group (Dox+TCA, 50mg/kg), and totally four groups, every group of 10-12 animal.
(2) modeling method (with embodiment 1).
(3) preparation of cinnaldehydrum (TCA, 50mg/kg) and medication (with embodiment 1).
(4) cardiac short axis shortening rate, ejection fraction test method (with embodiment 1).
(5) heart weight ratio (HB/WB): 1) weighing each group mouse weight, records weight data (unit g).2) it draws materials
Method: using 0.1% (m/v) chloral hydrate anesthesia mouse, and mouse web portion upwards and after fixing limbs, is opened thoracic infusion to liver
Dirty no color, completely removes mouse heart.3) cardiac weight records: removing heart and weighs cardiac weight immediately, records heart weight
It measures data (unit mg).4) data statistics: (single divided by the mouse weight numerical value with every mouse heart weight amount (unit mg)
Position g), obtains heart weight ratio (HB/WB).Software is analyzed using GraphPad Prism 7, analyzes each group mouse HB/WB ratio
Value difference is different.
(6) hematoxylin-eosin (HE) dyes: 1) drawing materials: after completely removing mouse heart, heart being pressed ultrasonic short axis view
Direction, average 3 equal parts are cut into 3 pieces, middle section are taken to be put into 4% paraformaldehyde got ready in advance.2) dehydration embedding: heart group
It knits after block fixes 8 hours in 4% paraformaldehyde, is put into dewaterer and is dehydrated by the program that table 3 is shown, dehydration is completed laggard
Row paraffin embedding, it is spare that embedded wax stone is put into 4 DEG C of refrigerators.3) paraffin section: with histotome (HM340E, Microm,
Germany embedded tissue is sliced by 5 μ m thicks), it is spare that wax melting is toasted after slice.4) HE is dyed: aobvious according to table 4
The program shown carries out hematoxylin eosin staining, after slide is dried in ventilation, with resinene mounting.It is used after mounting is dry
Just setting microscope film making.5) data statistics: using Image J software, is sliced heart left chamber short axis view heart area face to each group
Long-pending and rear wall thickness is for statistical analysis.
Table 3
Table 4
4, pharmacodynamic results:
(1) cardiac short axis shortening rate, ejection fraction test
Using Vevo2100 toy photoacoustic ultrasound imaged cardiac ultrasonic device M-Mode to mouse parasternal cardiac short axis
It is imaged (Fig. 2A), is obtained and mouse heart shortening fraction and ejection fraction using LV Trace Survey Software.Detection statistics knot
Fruit shows: compared with the control group, cardiac short axis shortening rate caused by adriamycin weakens, lowers cardiac ejection fraction；Cinnaldehydrum
(50mg/kg) although intervening does not influence the heart function parameter of Normal group mouse, its significantly improve by and Ah mould
Cardiac short axis shortening rate caused by element weakens (Fig. 2 B), lowers cardiac ejection fraction exception (Fig. 2 C).These results illustrate cassia bark
Aldehyde can effectively reverse cardiac systolic function caused by adriamycin and Ejection function to damage.
(2) HB/WB ratio interpretation of result
According to HB/WB statistical result (Fig. 3), adriamycin administration increases mouse HB/WB ratio significantly relative to control group,
Show that adriamycin may cause mouse heart aberrant mast.The HB/WB ratio and control group of the mouse of independent cinnaldehydrum administration are small
Mouse compares no notable difference；And compared with adriamycin model group, model adds the HB/WB ratio of cinnaldehydrum intervention group mouse significant
It reduces (Fig. 3).These results illustrate that cinnaldehydrum can effectively prevent heart abnormality caused by adriamycin loose.
(3) HE coloration result is analyzed
Dyeing (Fig. 4 A) according to HE can be clearly seen that the size and left ventricular wall thickness of heart.HE dyes statistical result
It will lead to heart after showing adriamycin administration and become larger, and left ventricular posterior wall thickness is obviously thinning；By cinnaldehydrum (50mg/kg)
After treatment, the pathologic variation of the myocardial area as caused by adriamycin (Fig. 4 B) and left ventricular posterior wall thickness has obvious recovery (figure
4C)。
In conclusion for the cardiac toxic that anticancer drug (adriamycin especially in chemotherapeutics) causes, the present invention
Cinnaldehydrum is used to prevent and treat cardiac toxic caused by anticancer drug for the first time.The result shows that: improve to cinnaldehydrum concentration dependent
The damage of cardiac short axis shortening rate, cardiac ejection fraction as caused by anticancer drug；Cinnaldehydrum can be reduced to be caused by anticancer drug
Heart weight ratio increase extremely, to improve the cardiomorphology as caused by anticancer drug abnormal.This illustrates that cinnaldehydrum can induce and subtracts
The cardiac toxic of few anticancer drug, can be used for preventing and treating damage of the anticancer drug to body cardiac shape and function, is anti-
The prevention and treatment of cancer drug cardiac toxic provide new thinking.
Each technical characteristic of embodiment described above can be combined arbitrarily, for simplicity of description, not to above-mentioned reality
It applies all possible combination of each technical characteristic in example to be all described, as long as however, the combination of these technical characteristics is not deposited
In contradiction, all should be considered as described in this specification.
The embodiments described above only express several embodiments of the present invention, and the description thereof is more specific and detailed, but simultaneously
It cannot therefore be construed as limiting the scope of the patent.It should be pointed out that coming for those of ordinary skill in the art
It says, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to protection of the invention
Range.Therefore, the scope of protection of the patent of the invention shall be subject to the appended claims.
Claims (10)
1. purposes of the cinnaldehydrum in preparation prevention and treatment anticancer drug cardiotoxicity caused drug or health care product.
2. purposes according to claim 1, which is characterized in that the anticancer drug is chemotherapeutics.
3. purposes according to claim 2, which is characterized in that the chemotherapeutics is adriamycin.
4. purposes according to any one of claims 1 to 3, which is characterized in that the cardiac toxic is cardiomegaly.
5. purposes according to claim 4, which is characterized in that the cardiomegaly is that heart weight ratio increases, is myocardium
Area increases, left ventricular posterior wall is thinning.
6. purposes according to any one of claims 1 to 3, which is characterized in that the cardiac toxic is heart contraction function
It can damage.
7. purposes according to claim 6, which is characterized in that the cardiac systolic function damage is that cardiac short axis shortens
Rate reduces.
8. purposes according to any one of claims 1 to 3, which is characterized in that the cardiac toxic is cardiac ejection function
It can weaken.
9. purposes according to claim 8, which is characterized in that the cardiac ejection function damage is cardiac ejection fraction
It reduces.
10. purposes as described in any one of claims 1 to 3, which is characterized in that the drug is oral preparation or injection system
Agent.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110302397A (en) * | 2019-08-09 | 2019-10-08 | 西北工业大学 | The coating mesoporous silica drug of pH responsiveness stannic oxide/graphene nano piece is double to carry composite nanoparticle and preparation method |
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| CN104161798A (en) * | 2013-05-17 | 2014-11-26 | 天津天士力现代中药资源有限公司 | Compound red sage root extract and application thereof |
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Inventor after: Chen Yongjun Inventor after: Wu Xiaoli Inventor after: Xu Nenggui Inventor after: Yao Lin Inventor after: Zhou Sisi Inventor after: Wang Jingya Inventor after: Lu Tian Inventor after: Wang Yicong Inventor after: Chen Hao Inventor before: Chen Yongjun Inventor before: Wu Xiaoli Inventor before: Xu Nenggui Inventor before: Yao Lin Inventor before: Zhou Sisi Inventor before: Wang Jingya Inventor before: Lu Tian Inventor before: Wang Yicong Inventor before: Chen Hao |
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Application publication date: 20181221 |