CN107041884A - A kind of new application of Radix Codonopsis alkaloid monomer - Google Patents
A kind of new application of Radix Codonopsis alkaloid monomer Download PDFInfo
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- CN107041884A CN107041884A CN201610081593.8A CN201610081593A CN107041884A CN 107041884 A CN107041884 A CN 107041884A CN 201610081593 A CN201610081593 A CN 201610081593A CN 107041884 A CN107041884 A CN 107041884A
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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Abstract
The invention belongs to pharmaceutical technology field, and in particular to a kind of Radix Codonopsis alkaloid monomer or its salt are preparing the application in being used to treat the medicine of pulmonary hypertension.Experimental study proves, mean pulmonary arterial pressure (MPAP), the RVSP of Radix Codonopsis alkaloid monomer or its salt to pulmonary arterial pressure high pressure（RVSP）, the plump index (RVHI) of right ventricle there is obvious mitigation to act on.The medicine is available for the pulmonary hypertension caused by preventing and treating idiopathic pulmonary hypertension, heredity pulmonary hypertension, medicine and poisonous substance correlation pulmonary hypertension, hazards or disease associated pulmonary hypertension, pulmonary veno occlusive disease and (or) pulmonary capillaries knurl sample disease, any one or a few illness in persistent pulmonary hypertension of the new-born.
Description
Technical field
The present invention relates to the new application of Radix Codonopsis alkaloid, more particularly to a kind of Radix Codonopsis alkaloid monomer is preparing the application in being used to treat the medicine of pulmonary hypertension, belongs to field of medicaments category.
Background technology
Pulmonary hypertension (pulmonary arterial hypertension, PAH) be by pulmonary vascular resistance and pulmonary artery pressure progressive rise with the characteristics of a kind of pathological and physiological condition, it is mainly characterized by causing pulmonary vascular resistance progressive to raise with reconstructing by the contraction of lung parteriole, blood vessel hyperplasia, and then cause Pulse Doppler, cause right ventricle plump, can finally cause patient to die from right heart failure.Its haemodynamics diagnostic criteria is：Under the quiescent condition of sea level, right heart catheter detection mean pulmonary arterial pressure >=25mmHg.
PAH harm is big, case fatality rate is high.Current PAH target therapeutic agent mainly has 3 classes, including prostacyclin analogs, endothelin-receptor antagonists (endothelin
Receptor antagonists, ERA) and PDE5（Phosphodiesterase, PDE-5）Inhibitor, its application can obviously improve the life span and survival state of patient.Three class targeted drugs need not be queried in PAH treatment status, but on the whole, and PAH medication effect fails satisfactory, still has many PAH patients dead because of right heart failure；Or receive still have serious symptom after regular treatment, it is difficult to improve the quality of living, and PAH target therapeutic agents are generally import medicine, it is expensive, basic medical insurance Drug catalogue is not included in, and hepatotoxicity effect is obvious, and it is the problem of PAH patient must face to combine medication for a long time.Therefore, Advantages of TCM is played, searching safety, economic treatment PAH Chinese medicine, the prognosis and its quality of life of raising to improvement PAH patient are significant.
Publication No. CN1789244 patent application, and Publication No. CN102659656 the patent applications report preparation method of Radix Codonopsis alkaloid monomer.Inventor has found that Radix Codonopsis alkaloid monomer has obvious therapeutic effect in terms of pulmonary hypertension is treated after further experimental study.
The content of the invention
The invention discloses the purposes of Radix Codonopsis alkaloid monomer as shown in Figure 1 or its salt in preventing and treating pulmonary hypertension medicine is prepared.
Radix Codonopsis alkaloid monomer salt used refers to Radix Codonopsis alkaloid monomer and the pharmaceutically acceptable bronsted lowry acids and bases bronsted lowry addition salts of many kinds of organic or inorganic acid formation, and the physiologically acceptable salt including being commonly used in pharmaceuticals industry in the present invention.This kind of pharmaceutically acceptable salt includes acetate, benzoate, hydrochloride, cinnamate, citrate, formates, fumarate, hydroxyl acetate, lactate, malate, citrate, maleate, hydroxymaleic acid salt, malonate, mandelate, nitrate, oxalates, phthalate, phosphate, hydrophosphate, dihydric phosphate, pyrophosphate, propionate, phenylpropionic acid salt, salicylate, sulfate, disulfate, pyrosulfate, sulphite, bisulfites, sulfate, tartrate etc..It is preferred that salt be acetate, hydrochloride, benzoate, citrate in any one.Most preferably citrate.
The compounds of this invention can be prepared into pharmaceutical preparation by methods known in the art.The compounds of this invention is preferably made injecting medicine-feeding form.Can, with ampule form, suitable pharmaceutic adjuvant can also be added and be prepared into infusion solutions.Said preparation can be solution, suspension or the emulsion form in aqueous or oiliness carrier, can also add suitable suspending agent, stabilizer, dispersant or adjust reagent of osmotic pressure etc..In addition, solid sterile powder can be made in the compounds of this invention, be prepared dissolve with suitable carrier before the use.
According to the present invention, for treating the specific dosage needed for pulmonary hypertension, it will be determined according to factors such as the order of severity, the methods of administration of the state of an illness, general acceptable and effective dosage is 30 to 300mg/ days.It is preferred that intravenous injection administration, dosage is 60 to 150mg/ days.
The pulmonary hypertension treated of the present invention is idiopathic pulmonary hypertension, heredity pulmonary hypertension, medicine and poisonous substance correlation pulmonary hypertension, hazards or disease associated pulmonary hypertension, pulmonary veno occlusive disease and (or) the pulmonary hypertension caused by pulmonary capillaries knurl sample disease, any one or a few illness in persistent pulmonary hypertension of the new-born.
The heredity pulmonary hypertension that the present invention is treated is pulmonary hypertension caused by one in BMPR2, ALKl, ENG, SMAD9, CAV1, KCNK3 or excessively individual gene mutation.
Hazards or disease associated pulmonary hypertension that the present invention is treated, it is one or more factors such as hazards or disease CTD, HIV, portal hypertension, heredity heart disease, snail fever, chronic hemolytic anemia.
Brief description of the drawings
Fig. 1 is the chemical structural formula of Radix Codonopsis alkaloid monomer of the present invention.
Embodiment
The invention is further described below by specific embodiment.Below for Radix Codonopsis alkaloid monomer of the present invention preventing and treating pulmonary hypertension in body animal hydraulic test.
Embodiment 1 ：Radix Codonopsis alkaloid monomer combines the influence that monocrotaline causes SD pulmonary arterial pressure in rats high pressures to lobectomy of lungs
2.1. experimental animal：SD rats, 3 monthly ages, male, 200 ± 20g, 48
2.2 Experimental agents and equipment：Radix Codonopsis alkaloid monomer (hereinafter referred to as DSA), monocrotaline（Purchased from Sigma companies）, chloraldurate, urethane, pressure transducer and PowerLab physiology information detectings and processing system
2.3 monocrotaline is combined using lobectomy of lungs（MCT）Severe PAH models are set up in injection：Rat is weighed, and 12% urethane is through intraperitoneal injection（8ml/kg）After anesthesia, 16G iv cannule promoting the circulation of qi cannulas, connection Harvard lung ventilators (tidal volume 2ml；Frequency, 80 beats/min；PEEP1.0cmH20.The intercostal of left side the 4th enters chest, ligatures and cuts off the left side lobe of the lung, the rat lobe of the lung is the leaf of left side 1, the leaf of right side 4 closes chest.Operation departs from lung ventilator, warming, lasting oxygen uptake 4 hours after terminating.Continue after raising 1 week, by 60mg/kg single intraperitoneal injections MCT, MCT starts administration after injecting 1 week, is administered 4 weeks.
Blank control group：Sham-operation+physiological saline（Isometric i.p.）1 time+give physiological saline（i.v）
Model group：Lobectomy of lungs（After 1 week）+MCT（60 mg/kg, i.p.）1 time+give isometric physiological saline（i.g）
DSA low dose groups：Lobectomy of lungs（After 1 week）+MCT（60 mg/kg, i.p.）1+DSA（15mg/kg/d, i.v）
DSA middle dose groups：Lobectomy of lungs（After 1 week）+MCT（60 mg/kg, i.p.）1+DSA（30mg/kg/d, i.v）
DSA high dose groups：Lobectomy of lungs（After 1 week）+MCT（60 mg/kg, i.p.）1+DSA（60mg/kg/d, i.v）
Positive drug group：Lobectomy of lungs（After 1 week）+MCT（60 mg/kg, i.p.）1 time+give silaenafil（7.5 mg/kg/d）
2.4 haemodynamics are measured and right ventricle plumpness detection：The 4th week after MCT injections, rat mean pulmonary arterial pressure is measured.After rat is anaesthetized with 10% chloraldurate (3mL/kg) intraperitoneal injection, it is intubated from right vena jugularis externa to pulmonary trunk, pressure transducer and PowerLab physiology information detectings and processing system (ADInstruments) are connect, its RVSP is recorded when inserting after conduit enters right ventricle stabilization（RVSP）, when there is pulmonary artery waveform in patient monitor, the record mean pulmonary arterial pressure (MPAP) after it is stable.Survey after RVSP, completely cut rat heart, left atrium and big blood vessel are cut off at along atrioventricular junction, separate right ventricle (RV) and left ventricle+interventricular septum (LV+S), with quality is claimed after filter paper suck dry moisture, it is the plump index (RVHI) of right ventricle to calculate RV/ (LV+S) value.
2.5 statistical analysis：Statistical analysis is carried out using the statistical softwares of SPSS 17.0, data are represented with Mean ± S.E, are compared between group and are used one-way analysis of variance.P
<0.05 is that difference has significant.
2.6 experimental result
2.6.1 experimental animal death condition：This experiment shares SD rats 48, and dead 1, dead 1 of MCT groups show as expiratory dyspnea, mouth and nose cyanosis before rats death.
2.6.2 DSA is shown to PAH rats RVSP result, is compared with blank control group, and model group has significant difference (p with each administration group<0.001)；Compared with model group, DSA low dosages (p<0.01), DSA middle dosages (p<0.01) with high dose (p<0.001), silaenafil group (p<0.01) RVSP can be significantly reduced；Compared with positive drug, DSA middle dosages and high dose group are more notable to PAH rats RVSP reducing effect.
2.6.3 DSA is shown to PAH rats mPAP result, is compared with blank control group, and model group has significant difference (p with each administration group<0.001)；Compared with model group, DSA middle dosages (p<0.001) with high dose (p<0.01), silaenafil (p<0.01) group can significantly reduce mPAP；Compared with positive drug, DSA each groups do not have significant difference to PAH rats mPAP reducing effect.
2.6.4 DSA is shown to PAH rats RVHI result, is compared with blank control group, and model group has significant difference (p with each administration group<0.001)；Compared with model group, DSA low dosages (p<0.05), middle dosage (p<0.01) with high dose (p<0.01) RVHI can be significantly reduced；Compared with positive drug, DSA middle dosages and high dose group are more preferable to PAH rats RVHI reducing effect（It is shown in Table 1）.
Influences of the table 1.DSA to PAH rats RVSP, mPAP, RVHI
| Group | N | RVSP(mmHg) | mPAP(mmHg) | RVHI(%) |
| Blank control group | 8 | 22.57±0.46 | 11.94±0.25 | 24.38±0.36 |
| Model group | 7 | 45.29±0.88### | 35.73±0.94### | 55.26±1.22### |
| DSA low dose groups | 8 | 36.34±0.85**### | 30.68±0.93### | 46.81±1.11*### |
| DSA middle dose groups | 8 | 33.96±1.31**### | 25.77±1.34***### | 40.05±1.53**### |
| DSA high dose groups | 8 | 31.28±1.27***## | 27.33±0.98**### | 38.43±1.81**### |
| Silaenafil group | 8 | 37.77±1.42**### | 26.84±1.14**### | 45.33±1.65*### |
Note：Compared with normal group##P ﹤ 0.01,###P ﹤ 0.001；Compared with model group*P ﹤ 0.05,**P ﹤ 0.01,***P ﹤ 0.001
It these results suggest that, Radix Codonopsis alkaloid monomer DSA combines mean pulmonary arterial pressure (MPAP), RVSP that monocrotaline causes SD pulmonary arterial pressure in rats high pressures to lobectomy of lungs（RVSP）, the plump index (RVHI) of right ventricle there is obvious mitigation to act on, and in certain dose dependent；With the increase of Radix Codonopsis alkaloid monomer DSA concentration, its mitigation effect is more obvious.Silaenafil group and Radix Codonopsis alkaloid monomer DSA can effectively treat PAH, but therapeutic actions of the Radix Codonopsis alkaloid monomer DSA to PAH is more preferable.
Claims (6)
1. the purposes of Radix Codonopsis alkaloid monomer or its salt in preventing and treating pulmonary hypertension medicine is prepared shown in a kind of following schema of chemical constitution.
2. purposes according to claim 1, it is characterised in that：Wherein the salt of Radix Codonopsis alkaloid monomer is any one in acetate, hydrochloride, benzoate, citrate.
3. purposes according to claim 1, it is characterised in that the medicine is injecting medicine-feeding form.
4. purposes according to claim 1, it is characterised in that：The pulmonary hypertension is idiopathic pulmonary hypertension, heredity pulmonary hypertension, medicine and poisonous substance correlation pulmonary hypertension, hazards or disease associated pulmonary hypertension, pulmonary veno occlusive disease and (or) the pulmonary hypertension caused by pulmonary capillaries knurl sample disease, any one or a few illness in persistent pulmonary hypertension of the new-born.
5. heredity pulmonary hypertension according to claim 4, it is characterised in that：The pulmonary hypertension one or more gene mutations in BMPR2, ALKl, ENG, SMAD9, CAV1, KCNK3 cause.
6. hazards according to claim 4 or disease associated pulmonary hypertension, it is characterised in that：The pulmonary hypertension hazards or disease are the one or more such as CTD, HIV, portal hypertension, heredity heart disease, snail fever, chronic hemolytic anemia.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201610081593.8A CN107041884A (en) | 2016-02-05 | 2016-02-05 | A kind of new application of Radix Codonopsis alkaloid monomer |
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| CN201610081593.8A CN107041884A (en) | 2016-02-05 | 2016-02-05 | A kind of new application of Radix Codonopsis alkaloid monomer |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1789244A (en) * | 2004-12-13 | 2006-06-21 | 南京宇道科技开发有限公司 | Pyrrolidine derivative, preparation method thereof and pharmaceutical composition containing the compound |
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- 2016-02-05 CN CN201610081593.8A patent/CN107041884A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1789244A (en) * | 2004-12-13 | 2006-06-21 | 南京宇道科技开发有限公司 | Pyrrolidine derivative, preparation method thereof and pharmaceutical composition containing the compound |
Non-Patent Citations (3)
| Title |
|---|
| JING-YU HE等: "The genus Codonopsis (Campanulaceae): a review of phytochemistry, bioactivity and quality control", 《J NAT MED》 * |
| 李刚: "ACE2激活对大鼠重度肺动脉高压的影响及机制研究", 《中国博士学位论文全文数据库 医药卫生科技辑》 * |
| 马秀萍、祝家庆主编: "《内科学临床进展》", 31 August 1999, 军事医学科学出版社 * |
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Application publication date: 20170815 |