CN103006667A - Application of tanshinone IIA or pharmaceutically acceptable salt in preparation of medicament for treating or inhibiting mucus in wind pipe - Google Patents
Application of tanshinone IIA or pharmaceutically acceptable salt in preparation of medicament for treating or inhibiting mucus in wind pipe Download PDFInfo
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- CN103006667A CN103006667A CN2012105119018A CN201210511901A CN103006667A CN 103006667 A CN103006667 A CN 103006667A CN 2012105119018 A CN2012105119018 A CN 2012105119018A CN 201210511901 A CN201210511901 A CN 201210511901A CN 103006667 A CN103006667 A CN 103006667A
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Abstract
The invention discloses an application of tanshinone IIA or pharmaceutically acceptable salt in preparation of medicament for treating or inhibiting mucus in a wind pipe. The tanshinone IIA or pharmaceutically acceptable salt can obviously inhibit the hypersecretion of mucoprotein in the wind pipe of the lung tissue. Compared with the commonly used mucolytic agents, the tanshinone IIA or pharmaceutically acceptable salt can obviously inhibit the expression and the secretion of mucoprotein, and the obvious side and toxic effects can not be found.
Description
Technical field
The present invention relates to the new purposes of tanshinone IIA, especially relate to the application of acceptable salt in the medicine of preparation treatment or inhibition air flue mucus hypersecretion on tanshinone IIA (T II A) or its materia medica.
Background technology
Air flue mucus is by a kind of complex that is distributed in air flue and alveolar inner surface of human airway epithelial cells, type Ⅱ penumonocyte and gland cell secretion, comprises water, electrolyte and various organic compound.Mucin is a kind of high molecular glycoprotein, is most important composition in the mucus, has determined that physics characteristic and the biology (protection) of gathering, stickiness, viscoelasticity and the lubricity of mucus learned characteristic.Up to now, find to have altogether 21 kinds of mucin, with different digital name behind the MUC, wherein 12 kinds have expression at air flue, comprise MUC1,2 respectively, 4,5AC, 5B, 7,8,11,13,16,19, and 20, and wherein MUC1 and MUC5AC are the mucinous main components of air flue.Divide by construction features, mucin mainly is divided into film conjunction type and gel formation type two large classes, and main difference is whether have the cross-film district, and the main effect of the latter is that mucin is anchored on the cell membrane.MUC1 belongs to film conjunction type mucin, mainly is distributed in epithelial top, and a small amount of expression is also arranged on some hemocytees.MUC1 is comprised of fragment three parts in extracellular segment, transmembrane segment and the born of the same parents, and molecular weight is about 200KD, and concrete size depends on the glycosylation quantity of its extracellular segment.MUC5AC belongs to gel formation type mucin, in the mucin of normal lung, MUC5AC has accounted for about 90%, remaining 10% almost all is comprised of MUC1, MUC4 and three kinds of film conjunction type of MUC16 mucin, wherein MUC1 has occupied again rear three's major part, although all the other 8 kinds of mucin also can detect expression in lung, content is atomic.
Under normal circumstances, mucin other composition in mucus forms effectively barrier together, can separate various pathogenic microorganism, harmful substance, and gets rid of foreign body by the regular swing of cilium.In the diseases take mucus hypersecretion as feature such as chronic obstructive pulmonary disease (COPD), pulmonary cystic fibrosis (CF), bronchial asthma, the airway mucus excessive secretion that continues and the change of rheological properties can cause impaired, the forfeiture of mucociliary clearance function, make bacteria planting become possibility, Polyblennia also can cause SAO, flow limitation, gas exchange dysfunction etc. in addition, the decline of carrying out property of pulmonary function finally causes mortality obviously to increase.
At present, if the drug main N-acetylcystein of clinical inhibition air flue mucus hypersecretion commonly used, ambroxol etc., this type of medicine is as mucolytic drugs, can reduce the viscosity of expectorant and make it liquefaction, thereby promote sputum to discharge, but this class medicine has more untoward reaction, as feel sick, vomiting, dyspepsia, scorching hot even choke coughed, bronchospasm etc., some patient is forced to stop the use of such medicine because of serious adverse effect.Tanshinone IIA is the monomeric substance of extracting from motherland's conventional medicament Radix Salviae Miltiorrhizae, and at present main effect is the auxiliary treatment for cardiovascular disease such as coronary heart diseases and angina pectoris, myocardial infarctions.
Summary of the invention
The object of the present invention is to provide the new purposes of acceptable salt on tanshinone IIA or its materia medica, i.e. tanshinone IIA and derivant thereof the new application in pharmacy.
Particularly, the object of the invention is to provide acceptable salt on tanshinone IIA or its materia medica as the preparation treatment or suppresses application in the medicine of air flue mucus hypersecretion.
Acceptable salt can use separately or use with the form of pharmaceutical composition on tanshinone IIA of the present invention or its materia medica, and described pharmaceutical composition comprises acceptable salt and pharmaceutical carrier on tanshinone IIA or its materia medica.
The treatment effective dose of acceptable salt is the dosage that suppresses the effect of air flue mucus hypersecretion isoreactivity for producing after the individual administration on described tanshinone IIA or its materia medica.And when giving individual single dose or multiple dose, dosage comprises the effect of pharmacokinetic property, route of administration, what characteristic (sex, age, body weight, health condition, build) of patient's situation, symptom degree and the treatment of depositing, therapeutic frequency and the expectation of acceptable salt on tanshinone IIA or its materia medica according to many factors and difference.
Generally, the independent medication of acceptable salt can reach the effect for the treatment of on described tanshinone IIA or its materia medica.It is 30mg/ time that described tanshinone IIA or derivatives thereof acts on individual each dosage as active component, one day twice, just can reach the effect of remarkable inhibition air flue mucus hypersecretion.
Acceptable salt can carry out individual administration by number of ways on described tanshinone IIA and the materia medica thereof, and that route of administration comprises is oral, intravenous injection etc.Correspondingly, described tanshinone IIA or derivatives thereof can be prepared into oral formulations and injection with pharmaceutically suitable carrier.Wherein, oral formulations comprises tablet, capsule, microcapsule, soft capsule, granule, drop pill, oral liquid and powder.Injection comprises intravenous injection and injectable powder.Can also different pharmaceutically suitable carrier can be equipped with according to the dosage form needs, antioxidant, emulsifying agent, stabilizing agent and antifungus agent can be added simultaneously.
Beneficial effect of the present invention is as follows:
Acceptable salt can obviously suppress the mucinous hypersecretion of air flue in the lung tissue on tanshinone IIA and the materia medica thereof, compare with mucolytic drugs commonly used at present, the obvious expression and secretion of inhibition of mucin of acceptable salt on tanshinone IIA and the materia medica thereof, and do not find not have obvious toxic and side effects.
Description of drawings
The depression effect of Fig. 1 A549 cell MUC1 expression that to be sodium tanshinon IIA silate injection induce lipopolysaccharide (LPS);
Compare with the LPS group, tanshinone IIA can obviously suppress the MUC1 expression that LPS induces, * P＜0.05.
The impact of Fig. 2 mucus hypersecretion mouse model lung tissue MUC1 expression that to be sodium tanshinon IIA silate injection induce LPS;
Compare with the LPS group, sodium tanshinon IIA silate injection can obviously suppress the MUC1 expression that LPS induces, * P＜0.05.
The impact of MUC1 extracellular segment expression in Fig. 3 mucus hypersecretion mouse model bronchoalveolar lavage fluid (BALF) that to be sodium tanshinon IIA silate injection induce LPS;
Compare with the LPS group, tanshinone IIA can obviously suppress the expression of MUC1 extracellular segment among the mucus hypersecretion mice BALF, * P＜0.05.
The impact of MUC5AC expression in Fig. 4 mucus hypersecretion mouse model bronchoalveolar lavage fluid (BALF) that to be sodium tanshinon IIA silate injection induce LPS;
Compare with the LPS group, tanshinone IIA can obviously suppress the expression of MUC5AC among the mucus hypersecretion mice BALF, * P＜0.01.
The specific embodiment
Below in conjunction with the new purposes of acceptable salt in field of medicaments on example and accompanying drawing the present invention is further elaborated tanshinone IIA or its materia medica; but following embodiment only purpose of the present invention does not limit protection scope of the present invention for illustrating.
Embodiment one: the impact of the epithelial cell MUC1 expression that acceptable salt pair LPS induces on sodium tanshinon IIA silate injection or its materia medica
One,
Main experiment material
1, people's type Ⅱ penumonocyte is the A549 cell: available from the biological product collecting center (ATCC) of Unite States Standard
2, DMEM culture medium, hyclone: U.S. Gibico company
3, the anti-MUC1 monoclonal antibody of rabbit: U.S. Abcam company
4, goat anti-rabbit igg: U.S. Sigma company
5, goat anti-mouse igg: U.S. KPL company
6, lipopolysaccharide (LPS): available from U.S. Sigma company
7, tanshinone IIA (sulfonate, purity＞99%): available from Nat'l Pharmaceutical ﹠ Biological Products Control Institute (NICPBP)
8, cell pyrolysis liquid:
Two, key instrument
1, CO2 gas incubator: Denmark Thermo company
2, inverted phase contrast microscope: German Leica company
3, the long multi-functional microplate reader of all-wave: Denmark Thermo company
4, table-type high-speed refrigerated centrifuge: Shanghai Lishen Scientific Equipment Co., Ltd.
5, vortice: German IKA company
6, electronic scale: Beijing Sai Duolisi instrument company
7, all size micropipettor: Gilson company
8, electrophresis apparatus: U.S. Bio-Rad company
Three,
Experimental technique
1, sodium tanshinon IIA silate injection is intervened LPS stimulates the A549 cell
Be divided into four groups with cultivating the good A549 cell of growth conditions that obtains, Normal group, T II A group, LPS group and T II A+LPS group are established three multiple holes for every group.T II A+LPS group is the medicine-feeding group.The medicine-feeding group is carried out pretreatment with sodium tanshinon IIA silate injection first, and final concentration is 25ug/ml, adds LPS after two hours, and final concentration is 10ug/ml, and matched group adds normal saline.
2, the detection of A549 cell Mucin1 expression
, add the cell pyrolysis liquid collection and respectively organize cell protein, and measure protein concentration after 24 hours until the LPS effect, row Western blot detects the expression of respectively organizing cell MUC1.
Experimental result: as shown in Figure 1, can obviously the raise expression of A549 cell MUC1 of LPS, sodium tanshinon IIA silate injection obviously suppress the rising of the MUC1 level that this LPS induces, separately to sodium tanshinon IIA silate injection on the expression of MUC1 without impact.
Conclusion: tanshinone IIA can suppress the rising of the A549 cell MUC1 level that LPS induces.
Embodiment two: the impact that the mucus hypersecretion mouse model lung tissue MUC1 that acceptable salt pair LPS induces on tanshinone IIA or its materia medica expresses
One, main experiment material:
1, SPF level C57 mice, body weight 20-25g, Guangdong Province's Experimental Animal Center
All the other experiment materials are with embodiment one
Two, key instrument
1, ultrasonic disruption instrument: U.S. SONICS company
2, Potter-Elvehjem Tissue Grinders: German IKA company
All the other experimental apparatus are with embodiment one
Three,
Experimental technique
1, the foundation of the LPS mucus hypersecretion mouse model of inducing
The C57 mice is divided into four groups at random: Normal group, T II A group, LPS group and T II A+LPS group, every group comprises 6-8 mice.The sodium tashinone II A sulfonate injection dosage is the 25mg/kg body weight, lumbar injection; The LPS dosage is the 1mg/kg body weight, and per nasal splashes into.The Normal group per nasal splashes into the normal saline of equal volume.
2, the detection of lung tissue MUC1 expression
After 24 hours, mice is respectively organized in pentobarbital sodium anesthesia, and eyeball is got blood, and the wound tracheal intubation is arranged, and with normal saline lavation lungs, 0.6ml/ time, totally 6 times, leaves and takes bronchoalveolar lavage fluid (BALF).Take out part mouse lung tissue, electric homogenizer homogenate adds and organizes lysate, ultrasonic disruption, and low-temperature centrifugation is left and taken the albumin suspension, and measures each histone concentration.Western blot detection is respectively organized mouse lung and is organized the MUC1 protein level.
Experimental result: as shown in Figure 2, the mucus hypersecretion mouse lung that LPS induces organizes MUC1 expression compared with normal matched group obviously to raise, tanshinone IIA can obviously suppress the expression that the mucus hypersecretion mouse lung is organized MUC1, and organizing the MUC1 expression to compare with Normal group to tanshinone IIA group mouse lung does not separately have difference.
Conclusion: tanshinone IIA can obviously reduce the expression that mucus hypersecretion mouse lung that LPS induces is organized MUC1.
3, the detection of MUC1 extracellular segment in the bronchoalveolar lavage fluid
Owing to digested the coming off of the outside branch of the born of the same parents of MUC1 enters in the mucus, therefore be necessary to detect the expression of the extracellular segment of MUC1.Respectively organize mice bronchoalveolar lavage fluid low-temperature centrifugation with what leave and take, albumin suspension in the collection detects the level of MUC1 extracellular segment in the bronchoalveolar lavage fluid with enzyme linked immunosorbent assay (ELISA).
Experimental result: as shown in Figure 3, the horizontal compared with normal matched group of mucus hypersecretion mice bronchoalveolar lavage fluid MUC1 that LPS induces obviously raises, tanshinone IIA can obviously suppress the level of mucus hypersecretion mice bronchoalveolar lavage fluid MUC1, and comparing with Normal group to tanshinone IIA group mice bronchoalveolar lavage fluid MUC1 level does not separately have difference.
Conclusion: sodium tanshinon IIA silate injection can obviously reduce the expression of MUC1 extracellular segment in the mucus hypersecretion mice bronchoalveolar lavage fluid that LPS induces.
Embodiment three: the impact that MUC5AC expresses in the mucus hypersecretion mice bronchoalveolar lavage fluid that acceptable salt pair LPS induces on tanshinone IIA or its materia medica
One. main experiment material:
1, MUC5AC antibody: U.S. RD company
All the other experiment materials and instrument are with embodiment two
Two,
Experimental technique
1, the foundation of the LPS acute lung injury model of inducing
With embodiment two
2, the detection of MUC5AC in the bronchoalveolar lavage fluid
Respectively organize mice bronchoalveolar lavage fluid low-temperature centrifugation with what leave and take, albumin suspension in the collection detects the level of MUC1 extracellular segment in the bronchoalveolar lavage fluid with enzyme linked immunosorbent assay (ELISA).
Experimental result: as shown in Figure 4, the horizontal compared with normal matched group of mucus hypersecretion mice bronchoalveolar lavage fluid MUC5AC that LPS induces obviously raises, tanshinone IIA can obviously suppress the level of MUC5AC in the mucus hypersecretion mice bronchoalveolar lavage fluid, and comparing with Normal group to tanshinone IIA group mice bronchoalveolar lavage fluid MUC5AC level does not separately have difference.
Conclusion: sodium tanshinon IIA silate injection can obviously reduce the expression of MUC5AC in the mucus hypersecretion mice bronchoalveolar lavage fluid that LPS induces.
Claims (5)
- On tanshinone IIA or its materia medica acceptable salt as preparation treatment or suppress application in the medicine of air flue mucus hypersecretion.
- 2. application according to claim 1 is characterized in that, acceptable salt uses separately on described tanshinone IIA or its materia medica.
- 3. application according to claim 1, it is characterized in that, acceptable salt uses with the form of pharmaceutical composition on described tanshinone IIA or its materia medica, and described pharmaceutical composition comprises acceptable salt and pharmaceutical carrier on tanshinone IIA or its materia medica.
- 4. according to claim 1 and 2 or 3 described application, it is characterized in that acceptable salt and pharmaceutically suitable carrier are prepared into oral formulations or injection on described tanshinone IIA or its materia medica.
- 5. application according to claim 4 is characterized in that, described oral formulations comprises tablet, capsule, microcapsule, soft capsule, granule, drop pill, oral liquid and powder; Described injection comprises intravenous injection and injectable powder.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103235901A (en) * | 2013-05-07 | 2013-08-07 | 黑龙江中医药大学 | Method for determining phase transition boundary of microemulsion drug carrier of tanshinone IIA |
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2012
- 2012-12-04 CN CN2012105119018A patent/CN103006667A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| 刘明东: "JNK通路在急性胰腺炎相关性肺损伤中的作用机制及丹参酮IIA的干预作用研究", 《南京中医院大学博士学位论文》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103235901A (en) * | 2013-05-07 | 2013-08-07 | 黑龙江中医药大学 | Method for determining phase transition boundary of microemulsion drug carrier of tanshinone IIA |
| CN103235901B (en) * | 2013-05-07 | 2014-12-10 | 黑龙江中医药大学 | Method for determining phase transition boundary of microemulsion drug carrier of tanshinone IIA |
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Application publication date: 20130403 |