CN106344554B - Application of the Resina garciniae extract in treatment pulmonary hypertension - Google Patents
Application of the Resina garciniae extract in treatment pulmonary hypertension Download PDFInfo
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- A61K31/33—Heterocyclic compounds
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- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
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Abstract
藤黄提取物在治疗肺动脉高压中的应用。本发明涉及植物提取物，具体公开了藤黄提取物及结构式(Ⅰ)所示的化合物A和结构式(Ⅱ)所示的化合物B在治疗肺动脉高压中的应用。所述藤黄提取物与所述化合物可作为唯一活性成分制备治疗肺动脉高压的药物。本发明通过试验研究发现了藤黄提取物及其中的化合物A和化合物B抑制肺动脉高压的作用，尤其适合治疗低氧血症所致的肺动脉高压。在藤黄提取物和肺动脉高压的致病的分子机理研究上做出了新的突破，为防治继发性肺动脉高压的新药筛选和临床治疗提供理论依据和靶标。
Use of Garcinia cambogia extract in the treatment of pulmonary hypertension. The invention relates to plant extracts, and specifically discloses the application of Garcinia cambogia extract, compound A represented by structural formula (I) and compound B represented by structural formula (II) in the treatment of pulmonary hypertension. The Garcinia cambogia extract and the compound can be used as the only active ingredients to prepare a medicine for treating pulmonary arterial hypertension. In the present invention, it is found through experimental research that the extract of Garcinia cambogia and its compound A and compound B have the effect of inhibiting pulmonary arterial hypertension, and are especially suitable for treating pulmonary arterial hypertension caused by hypoxemia. New breakthroughs have been made in the study of garcinia cambogia extract and the molecular mechanism of the pathogenesis of pulmonary arterial hypertension, providing theoretical basis and targets for the screening of new drugs and clinical treatment for the prevention and treatment of secondary pulmonary arterial hypertension.
Description
Technical field
The present invention relates to plant extracts, specifically, being related to application of the Resina garciniae extract in treatment pulmonary hypertension.
Background technique
Pulmonary hypertension (pulmonary arterial hypertension, PAH) cause of disease is complicated, by a variety of hearts, lung or
Pulmonary vascular disease causes.With lung parteriole vascular remodeling, the pathological characters of pulmonary arterial vascular smooth muscle proliferation.Show as pulmonary circulation
Pressure and resistance increase, and may occur in which that right cardiac load increases, right heart insufficiency, a series of lung Oligemia, so as to cause clinics
It shows, pulmonary hypertension is often in carry out sexual development in the course of disease.What enhancing pulmonary arterial vascular tension led to right heart failure seriously threatens people
The disease of class life and health.Especially idiopathic arterial PAH patient can just make a definite diagnosis for 2 years or so mostly after there is symptom, and true
Natural history after examining is in 2.5-3.4.It is " primary " and " secondary " two class that PAH, which is divided to, is recognized with to pulmonary hypertension
Gradually deeply, 2003 the World Health Organization (WHO) " pulmonary hypertension meeting " according to the cause of disease, pathologic, physiologic, therapeutic scheme
And Prognostic Characteristics classify to pulmonary hypertension, American Thoracic doctor institutes (ACCP) in 2004 and European cardiovascular disease association
(ESC) this is revised, which has directive significance to the treatment of patients with pulmonary hypertension.Traditional treatment side
Method includes oxygen uptake, heart tonifying, diuresis, calcium channel blocker and anti-coagulants auxiliary therapeutical agent etc., primarily serves the relaxation effect of symptom.
In recent years target therapeutic agent R&D and promotion use (mainly include prostacyclin drug class, phosphodiesterase 5 inhibitor,
Endothelin-receptor antagonists and the soluble guanylate cyclase agonist explored recently, serotonin transport sub- inhibitor,
Growth factor receptor inhibitors, Rho kinase inhibitor etc.) and the treatment methods such as living body lung transplantation substantially improve the prognosis of patient.
These drugs can a degree of symptom for alleviating PAH, the median survival time in the case for the treatment of patients is only 2.7 years,
Pulmonary hypertension still lacks the cure method of special efficacy at present, and therefore, finding new specific treatment drug is particularly important.
Summary of the invention
In order to solve the problems in the existing technology, it the purpose of the present invention is to provide a kind of therapeutic effect is definite, controls
Treat sitaxsentan sodium object at low cost.
In order to achieve the object of the present invention, technical scheme is as follows:
In a first aspect, the application the present invention provides Resina garciniae extract in preparation treatment pulmonary hypertension drug, with rattan
Yellow extract prepares the drug for the treatment of pulmonary hypertension as active constituent.
Further, the medicine of application preparation treatment pulmonary hypertension using Resina garciniae extract as sole active agent
Object.
Further, the Resina garciniae extract includes at least structural formula (I) compound represented A and/or structural formula
(II) compound represented B:
It should be noted that the Resina garciniae extract can be by conventional method such as alcohol extracting, chromatography of this field etc. from gamboge
It extracts and obtains in (Garcinia morella Desv) etc..
The compound A and compound B can be bought by commercial sources or utilize marketable material, by the prior art
(extracting method can be found in the Chinese patent Shen of Publication No. CN105213366A for traditional compound synthesis method synthesis
Please).It can be further purified by modes such as column chromatography, high performance liquid chromatography or crystallizations after synthesis.
The present invention still further provides structural formula (I) compound represented A and structural formula (II) compound represented B exists
Application in preparation treatment pulmonary hypertension drug.
Preferably, the drug is oral preparation.The present invention it is found through experiment that, by the Resina garciniae extract or structural formula
(I) the big of pulmonary hypertension is suffered from the oral stomach-filling of drug of compound represented A or structural formula (II) compound represented B preparation
Mouse has apparent therapeutic effect.
The present invention pass through experimental studies have found that, Resina garciniae extract of the present invention and above compound lure hypoxemia and drug
Pulmonary hypertension animal model caused by leading has apparent therapeutic effect.
But it should be recognized that pulmonary hypertension of the present invention covers pulmonary artery caused by known a variety of pathogenesis
High pressure, such as arteriosity pulmonary hypertension (PAH) (including caused by idiopathic, hereditability, drug and poisonous substance and newborn's duration), left
The disease associated pulmonary hypertension of the heart (including cardiac systolic function is not complete, Diastolic Heart failure and valvular heart disease), pulmonary disease or
Pulmonary hypertension caused by hypoxemia (including Chronic Obstructive Pulmonary Disease, Interstitial Lung Disease, sleep apnea syndrome,
Chronic plateau sickness), pulmonary hypertension caused by chronic thromboembolic pulmonary hypertension and other unknown factors, wherein for
Pulmonary hypertension application effect caused by hypoxemia is more significant.
Second aspect, the present invention provide a kind of pharmaceutical composition for treating pulmonary hypertension, the work of described pharmaceutical composition
Property ingredient be structural formula (I) compound represented A and/or structural formula (II) compound represented B.
The dosage form of described pharmaceutical composition can be any pharmaceutical dosage form, these dosage forms include: tablet, sugar-coat
Tablet, film coated tablet, enteric coated tablet, capsule, hard capsule, soft capsule, oral solution, mouth containing agent, granule, punching
Agent, powder, paste, sublimed preparation, suspension, pulvis, solution, injection, suppository, ointment, emplastrum, creme, is sprayed pill
Agent, drops, patch；It is preferred that peroral dosage form, such as: capsule, tablet, oral solution, granule, pill, powder, sublimed preparation, paste.
The peroral dosage form can contain common excipient, such as adhesive, filler, diluent, tablet agent, lubricant, disintegration
Agent, colorant, flavoring agent and wetting agent when necessary can be coated tablet.Suitable filler includes cellulose, mannose
Alcohol, lactose and other similar fillers；Suitable disintegrating agent includes starch, polyvinylpyrrolidone and starch derivatives, example
Such as sodium starch glycollate；Suitable lubricant includes, such as magnesium stearate.Suitable pharmaceutically acceptable wetting agent includes ten
Sodium dialkyl sulfate.
The treatment effective dose of pharmaceutical composition of the present invention is between 0.1~500mg/kg body weight/day.The present invention
The preferred effective dose of described pharmaceutical composition is between 0.5~300mg/kg body weight/day；More preferably l0~100mg/kg
Between body weight/day." the treatment effective dose " can be used for single drug or the drug combination treatment of related disease.
It is described treatment pulmonary hypertension pharmaceutical composition (medicament) it is preferable to use method be it is oral, preferred dosage is every
Its 10~50mg/Kg, daily regular time stomach-filling processing are primary.
The beneficial effects of the present invention are:
The present invention has found that Resina garciniae extract inhibits the effect of pulmonary hypertension by experimental study, in Resina garciniae extract and
New breakthrough is made that on the pathogenic molecular mechanism research of pulmonary hypertension, for the new drug sieve for preventing and treating condary pulmonary hypertension
Choosing and clinical treatment provide theoretical foundation and target.
The present invention further determined structural formula (I) compound represented A and structural formula (II) institute in Resina garciniae extract
Therapeutic effect of the compound B shown to pulmonary hypertension is especially suitable for pulmonary hypertension caused by treatment hypoxemia.
Technical solution provided by the invention has stronger clinical meaning, can be pulmonary hypertension precautionary measures and treatment side
Method optimization provides solid foundation.
Detailed description of the invention
Fig. 1 is the comparison of control group and experimental group rat mean pulmonary arterial pressure and right ventricular systolic pressure after hypoxemia processing.
Fig. 2 is the comparison of control group and experimental group rat right ventricular accounting after hypoxemia processing.
Fig. 3 is the comparison of control group and experimental group rat artery middle layer wall ratio after hypoxemia processing.
Fig. 4 is the comparison of control group and experimental group rat tube wall middle layer cross-sectional area ratio after hypoxemia processing.
Specific embodiment
The preferred embodiment of the present invention is described in detail below in conjunction with embodiment.It will be appreciated that following real
Providing merely to play the purpose of explanation for example is applied, is not used to limit the scope of the present invention.The skill of this field
Art personnel without departing from the spirit and purpose of the present invention, can carry out various modifications and replace to the present invention.
Experimental method used in following embodiments is conventional method unless otherwise specified.
The materials, reagents and the like used in the following examples is commercially available unless otherwise specified.
The influence test of 1 compound A of embodiment, compound B to pulmonary hypertension caused by hypoxemia
Male Sprague Dawley (SD) rat is purchased from Beijing Vital River Experimental Animals Technology Co., Ltd., weight
200 ± 20g is randomly divided into 7 groups (every groups n=10 only) (normal diet is purchased from Jun Ke institute, allows mouse to be freely eaten daily), i.e., and the
One group of normal oxygen control group, second group of anoxia model control group, second group of anoxia model corn oil control group, the 4th group of compound
A low dose group (10mg/kg/d), the 5th group of compound A high dose group (50mg/kg/d), the 6th group of Resina garciniae extract B (10mg/
Kg/ days)；7th group of feeding Resina garciniae extract B (50mg/Kg/ days).Rats in normal control group is in the normal oxygen (21%O of normal pressure2) environment feeding
It supports, remaining each group rat is placed in (oxygen concentration 11%O in full-automatic regulation normal pressure low oxygen cabin2) raising, continuous hypoxemia is carried out,
Continuing 6 weeks compound A and B treatment groups is after modeling starts 2 weeks, and daily gastric infusion 1 time is for 4 weeks.Normal group and mould
Type control group is after modeling starts 2 weeks, and stomach-filling gives considerable amount of solvent as control before each anoxic.
1, hemodynamic index measures: filled with heparin solution, (0.9% sodium chloride is molten for vena jugularis externa insertion on the right side of from rat
Liquid+heparin 10U/m1) vinyon microtubular, the other end of conduit be connected with micro pressure sensor monitoring pressure become
Change, under the guidance of pressure waveform, conduit enters right room, tricuspid orifice, right ventricle (RV) through superior vena cava, finally enters pulmonary artery
It is dry, measure mean pulmonary arterial pressure (mPAP) and right ventricular systolic end pressure (RVSP) etc..After stablizing 30 minutes, application
POWERLAB multiple tracks intelligence physiological signal collection and record system acquisition, record and analysis indices, as a result as shown in Figure 1.
2, it the measurement of the plump index of right ventricle (RV): after experiment, cuts open chest and takes out mouse heart, cut off atrial tissue.
Go out RV, left ventricle (LV) and interventricular septum (S) along interventricular septum edge separation, with the weight for weighing RV, LV and S after filter paper suck dry moisture
Amount reflects RV plumpness degree (Fig. 2) with RV/ (LV+S) ratio.
3, Pulmonary Vascular pathological examination: taking tissue block from inferior lobe of right lung same area, is placed in 10% neutral formalin (pH7.4)
Fix 2 days.Routine paraffin wax embedding, serial section, hematoxylin eosin staining and elastic fibers dye (Hart improved method Dyeing shell
Power fiber, Van Gieson are redyed), light microscopic observation lung parteriole morphological change.And it is fine with image analyzer measurement elastic force
The outer diameter (ED) for the lung parteriole (diameter is less than 100 μm) gone in dimension stained slice with respiratory bronchiole and breathing companion,
Arterial media wall thickness (MT), tube wall middle layer cross-sectional area (MA), vessel lumen cross-sectional area (VA) and blood vessel total cross-sectional area
(TAA), the percentage (MT%) (Fig. 3) that vascular wall intima-media thickness accounts for outer diameter, vascular wall middle layer cross-sectional area are then calculated separately
The percentage (MA%) (Fig. 4) of blood vessel total cross-sectional area is accounted for, reflects lung thin vessels tube wall thickening degree.Every rat lung sections are total
The These parameters for measuring 6~10 lung parterioles, calculate blood vessel index parallel statistical analysis of the mean as this rat.
The influence of each group Pulmonary Vessels in Rats pathological index and right ventricle plumpness
According to fig. 2~Fig. 4 test result can be seen that Normal group right ventricle without thickening, the right heart of anoxic control group
Room is obviously plump, and right ventricle plumpness index RV/ (LV+S) is significantly raised.Pathological examination discovery: anoxic control group right ventricle is visible
Loose cardiac muscle cell, pulmonary artery thicken, luminal stenosis.And gamboge compound two dosage groups of A and B are all to pulmonary artery
Pathology remodeling has improvement result, including reduces arterial media wall ratio, tube wall middle layer cross-sectional area ratio and reduction right ventricle fertilizer
Greatly, and there is certain dose dependent.Significant effect of the gamboge compound A than compound B under Isodose.
The compound A and compound B are by isolated in Resina garciniae extract, and verified, Resina garciniae extract also has
There are above-mentioned function and effect.
Although above the present invention is described in detail with a general description of the specific embodiments,
On the basis of the present invention, it can be made some modifications or improvements, this will be apparent to those skilled in the art.Cause
This, these modifications or improvements, fall within the scope of the claimed invention without departing from theon the basis of the spirit of the present invention.
Claims (7)
1. application of the Resina garciniae extract in preparation treatment pulmonary hypertension drug, which is characterized in that the Resina garciniae extract is extremely
Less include structural formula (I) compound represented A and/or structural formula (II) compound represented B:
2. application of structural formula (I) the compound represented A in preparation treatment pulmonary hypertension drug,
3. application of structural formula (II) the compound represented B in preparation treatment pulmonary hypertension drug,
4. described in any item applications according to claim 1~3, which is characterized in that the drug is oral preparation.
5. described in any item applications according to claim 1~3, which is characterized in that the pulmonary hypertension be low-oxygen environment and
Pulmonary hypertension caused by drug-induced.
6. application according to claim 1, which is characterized in that the drug is oral preparation.
7. application according to claim 1, which is characterized in that the pulmonary hypertension is low-oxygen environment and drug-induced draws
The pulmonary hypertension risen.
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| 中医药防治肺动脉高压的研究进展;史万祥 等;《现代中西医结合杂志》;20091231;第18卷(第34期);第4302-4306页 |
| 中药藤黄药理作用研究进展;贺百花 等;《河北北方学院学报（医学版）》;20091031;第26卷(第5期);第71-73页 |
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