CN104398503A - Use of fargesin and its derivative in preparation of drugs for treating or preventing pulmonary hypertension - Google Patents
Use of fargesin and its derivative in preparation of drugs for treating or preventing pulmonary hypertension Download PDFInfo
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
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Abstract
The invention relates to a novel medical use of fargesin and its derivative and especially relates to a use of fargesin and its derivative in preparation of drugs for treating or preventing pulmonary hypertension. Fargesin, fargesin derivative, fargesin salt or fargesin solvate as a single active component or one of active components is compounded to one or more excipients, the composition is processed to form tablets, capsules, particulates, an oral liquid and an injection by conventional methods, is suitable for whole body administration and is used for preventing or treating idiopathic pulmonary hypertension, left-side cardiac disease-related pulmonary hypertension, pulmonary hypertension caused by lung disease and/or low oxygen, chronic thromboembolic pulmonary hypertension or pulmonary hypertension caused by unknown reasons.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, relate to the novelty teabag of fargesin, particularly relate to fargesin and derivant thereof the new opplication at preparation treatment/prophylaxis of pulmonary hypertension.
Background technology
Pulmonary hypertension (Pulmonary Arterial Hypertension, PAH) be the clinical common high malignancy disease of involving systemic pulmonary circulation, its principal character is that pulmonary artery pressure and pulmonary vascular resistance Progressive symmetric erythrokeratodermia raise, and finally can cause patient's right heart failure and dead.American Thoracic doctor learns, in the evidence-based medicine EBM clinical practice updated Guidelines of relevant Diagnosis of Pulmonary Hypertension and the treatment of issuing, PAH to be defined as mean pulmonary arterial pressure >=25mmHg, CP or PLA left atrial pressure≤15mmHg.Research finds: this sick average age of onset is 36 years old, and the PAH patient of 75% dies from 5 years after diagnosis, and after symptom occurs, mean survival time (MST) is 2.8 years; Have right heart failure shower, the mean survival time is less than 1 year.Visible, PAH is chronic syndrome more common in recent years, and its treatment difficulty is large, and poor prognosis, has become the focus of global medical research, difficult point.
The pathogenic factor of PAH is comparatively complicated, environmental factors, inherited genetic factors and other factors all likely form PAH, and these factors cause cardiovascular 26S Proteasome Structure and Function to change, and mainly involve pulmonary artery and the right heart, be embodied in right ventricle plumpness, right atrium is expanded; Main pulmonary artery is expanded, and around lung small artery is sparse; Lung small artery endotheliocyte, smooth muscle cell proliferation are loose, and tunica intima fibrosis thickens, middle pachyhymenia, luminal stenosis, and inaccessible, torsional deformation, changes in plexi.ESC in 2009 and European pneumatology can upgrade Diagnosis of Pulmonary Hypertension classification, the large class of PAH five caused by the many factors that new classification comprises PAH, chronic thromboembolic PAH and not bright reason caused by arterialness PAH, the disease associated PAH of the left heart, pulmonary disease and (or) hypoxia: 1. arterialness PAH, comprises PAH, dependency PAH (congenital heart disease, portal hypertension, connective tissue disease, chronic hemolytic anemia etc.), neonate persistence PAH caused by idiopathic PAH, hereditability PAH, medicine and poisonous substance; 2. the disease associated PAH of the left heart, comprises systolic dysfunction, Diastolic Heart failure, valvular heart disease; 3. PAH caused by pulmonary disease or hypoxemia, comprises chronic obstructive pulmonary disease, Interstitial Lung Disease, other pulmonary disease, sleep apnea syndrome, chronic plateau sickness, abnormal development etc. with restricted, obstructive or mixed ventilatory disorder; 4. chronic thromboembolic PAH; 5. fail to understand PAH caused by mechanism and (or) number of mechanisms, comprise disease in the blood system, metabolic disease etc.Wherein PAH caused by pulmonary disease and (or) hypoxia is modal type in patient, accounts for 36.12% of the total number of cases of PAH.
The treatment of PAH is a difficult problem for medical circle always, is also that Medical studies one of most active field.The medical treatment of conventional P AH, often for the improvement of the symptoms such as right heart insufficiency and the formation of pulmonary artery primary thrombus, mainly comprises oxygen uptake, diuresis, heart tonifying and anticoagulant etc.In recent years, some medicines improving patients ' life quality and clinical prognosis are applied to clinical gradually, comprise 1. calcium ion antagonist, find only effective to the patient of 10% at present; 2. prostacyclin class medicine, comprising: epoprostenol, UT-15, shellfish prostacyclin, Ilomedin ring element; 3. endothelin-receptor antagonists, comprising: bosentan, BSF208075, Sai Tashengtan; 4. phosphodiesterase-5 (PDE-5) inhibitor, the medicine gone on the market has: sldenafil, tadanafil; 5. Rho inhibitors of kinases, as fasudil; 6. statins: as simvastatin [Gao Hanhua, Chen Can, Huangshi peace .PAH progress. the practical medicine of China, 2009,4 (14): 229-232].There are the following problems over the course for the treatment of for said medicine: mainly for be arterialness PAH, therapy target is single; Exist pulmonary artery selectivity not strong, produce the hypotensive serious side reaction of patient body circulation; In addition untoward reaction is many, side effect large, and life in patients decline is also the FAQs in treatment clinical course.Therefore, to find and development of new PAH medicine remains one of challenge that medical research personnel face.
The traditional Chinese medical science thinks that PAH is similar to clinical symptoms such as the syndrome of dyspnea, phlegm retention, pulmonary distension, aqueous vapors, research finds, some Chinese medicines and effective ingredient thereof also have the effect of control PAH, such as: the lung heart is peaceful, Compound macrostem onion capsule, Ramulus Cinnamomi Poria pill, SHUXUENING, SONGLING XUEMAIKANG JIAONANG, Herba Erigerontis, veratryl alcohol, ligustrazine, tanshinone IIA, tetrandrine etc. [Shi Wanxiang. the progress of Chinese medicine prevention PAH. clinical practice, 2013,127 (2): 60-64]; But there is no the Chinese medicine preparation that specificity is treated for PAH at present.
Flos Magnoliae is the dry flower of Magnoliacea plant Flos Magnoliae (Magnolia biondii Pamp.), Magnolia denudata (Magnolia denudate Desr.) or Flos Magnoliae (Magnolia sprengeri Pamp.), main product in Henan, Anhui, Sichuan, the ground such as Shaanxi, begin to be loaded in " Tang's draft ", there is dispersing wind and cold, the effect of clearing the nasal passage.Recent study finds, fargesin (Fargesin) is one of effective ingredient in Flos Magnoliae, and belong to bisepoxy lignans's compound, its molecular formula is: C
21h
22o
6, structural formula is shown in Fig. 1, and molecular weight is 370.396, and chemistry is by name: 5-[(1S, 3aR, 4R, 6aR)-4-(3,4-Dimethoxyphenyl) tetrahydro-1H, 3H-furo [3,4-c] furan-1-yl]-1,3-benzodioxole.Fargesin can respectively from the alabastrum of Magnoliaceae Y biondii(Pamp)D.L.Fu. (Magnolia biondii Pamp.), the leaf of the smooth Flos Magnoliae (Magnolia kobusDC.var.borealis Sarg.) of Magnoliaceae shrimp, the root of Rutaceae Oleum Linderae Pericarpium Zanthoxyli (Zanthoxylum utileHuang), the peel of stem of Rutaceae thorniness Pericarpium Zanthoxyli (Zanthaxylum myriacanthum Wall.exHook), the aerial parts of Piperaceae P. austrosinense (Piper austrosinense C.DC.), the fruit of Semen Myristicae section chief Fructus Amomi Rotundus (Virola elongata Wurb), the alabastrum of Compositae Tanacetum vulgare L platymiscium chryanthemum parthenium (Chryanthemum Parthenium), the root of Aristolochiaceae boat leaf Fructus Aristolochiae (Aristolochia cymbifera), the leaf of Rutaceae Fructus Zanthoxyli Dissiti (Zanthoxylumdissitum Hemsl), the alabastrum of Magnoliaceae line calyx Flos Magnoliae (Magnolia fargesii Cheng), the extraction and isolation such as the alabastrum of Fa Shi Flos Magnoliae (Magnolia fargesii Cheng) obtain.Fargesin has platelet activating factor receptor antagonistic activity, and this acts on the bisepoxy lignans's compound being better than other.In addition, also there is antiinflammatory, antiallergic, protect the liver and stimulate report [the Sun-Sil Choi of Sugar intake effect, et al.Fargesin, a component of FlosMagnoliae, stimulates glucose uptake in L6myotubes.J Nat Med, 2013,67:320 – 326].
But do not find any report that can be used for PAH treatment about fargesin so far.
Summary of the invention
The first object of the present invention is to provide fargesin to prepare the application for the treatment of or in prophylaxis of pulmonary hypertension medicine.
The second object of the present invention is to provide fargesin derivant and salt or solvate thereof to prepare the application for the treatment of or in prophylaxis of pulmonary hypertension medicine.
Wherein, described fargesin derivant is fargesin halo, sulfonation, nitrated, hydroxylation, alkoxide, esterification products.
Fargesin derivant can salify or solvate, and wherein said salt comprises sodium salt, potassium salt etc., and described solvate refers to hydrate, alcoholate etc.Those skilled in the art will envision that to possess the core texture identical with fargesin based on fargesin derivant, therefore, its salt or solvate possess desirable effect equally in preparation treatment or prophylaxis of pulmonary hypertension medicine.
Pulmonary hypertension of the present invention covers the pulmonary hypertension that known multiple pathogenesis causes, as arterialness pulmonary hypertension (comprises idiopathic, hereditability, caused and the neonate persistence of medicine and poisonous substance), the disease associated pulmonary hypertension of the left heart (comprises cardiac systolic function incomplete, Diastolic Heart failure and valvular heart disease), caused by pulmonary disease or hypoxemia, pulmonary hypertension (comprises chronic obstructive pulmonary disease, Interstitial Lung Disease, sleep apnea syndrome, chronic plateau sickness), chronic thromboembolic pulmonary hypertension, and pulmonary hypertension caused by other not clear factors, wherein, more remarkable for the pulmonary hypertension effect caused by pulmonary disease or hypoxemia.
Medicine of the present invention, using fargesin, fargesin derivant and salt thereof or solvate for single-activity composition or as one of active component, when its as active component for the moment, optionally be effective to the active component of pulmonary hypertension with other, as epoprostenol, sldenafil, fasudil etc. form the active component of medicine, jointly to obtaining desirable cooperative effect.
In addition to the active ingredient (s, medicine of the present invention also comprises pharmaceutically acceptable at least one excipient (pharmaceutical carrier).Described excipient is understood by those skilled in the art, and include but are not limited to: disintegrating agent, lubricant, dispersant etc., those skilled in the art can be selected according to the actual demand of preparation, and the present invention is not particularly limited this.
Medicine of the present invention, can be prepared into pharmaceutically various common dosage forms via conventional method, as tablet, capsule, pill, powder, granule, suspensoid, oral administration solution, powder pin or injection etc.Optional oral, the Sublingual of administering mode, vein, subcutaneous, transdermal or topical etc., give animal or human with unit dosage fonn.
The unit dosage fonn that medicine of the present invention is suitable comprises peroral dosage form (such as tablet, capsule, pill, powder, granule, oral administration solution or suspension), Sublingual or buccal administration dosage form, vein, subcutaneous, transdermal or intramuscular dosage form (such as injection, powder pin etc.).In addition, described medicine can be ordinary preparation, slow releasing preparation, quick releasing formulation and controlled release preparation.
The present invention is simultaneously for the pharmaceutical preparation containing fargesin, fargesin derivant and salt or solvate provides desirable embodiment, specifically, when preparing the solid composite medicament of tablet or capsule form, the excipient that can add in active component, comprise diluent, as lactose, dextrin, starch, pregelatinized Starch, sucrose, mannitol, microcrystalline Cellulose etc.; Adhesive, as polyvinylpyrrolidone, methylcellulose, hypromellose etc.; Disintegrating agent, as carboxymethyl starch sodium, crosslinked carboxy methylcellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, crospolyvinylpyrrolidone etc.; Lubricant, as silicon dioxide, magnesium stearate, stearate, corn starch, Pulvis Talci etc., correctives, as mannitol, aspartame, saccharin sodium and stevioside etc., in addition, also surfactant can be added, as dodecyl sodium sulfate, sodium dioctyl sulfosuccinate, sucrose ester and poloxamer etc.
When preparing the pharmaceutical composition of pill, the excipient that can add in active component, comprises diluent and absorbent, as lactose, glucose, dextrin, starch, sucrose, cocoa butter etc.; Adhesive, as arabic gum, tragacanth, gelatin, Mel etc.; Disintegrating agent, as methylcellulose, ethyl cellulose, dry starch, agar powder, alginate etc.
The figuration that oral administration solution or suspension can add, comprises sweeting agent, as saccharin sodium, sucrose, cyclamate, aspartame and stevioside etc.; Suspending agent, as polyvinylpyrrolidone, microcrystalline Cellulose, sucrose, hydroxypropyl emthylcellulose etc.; Antiseptic, as parabens, sodium benzoate, methyl parahydroxybenzoate, propyl p-hydroxybenzoate etc.
The excipient that granule can add, comprises filler, adhesive, coloring agent and correctives etc.
Injection preparation, as injection, Emulsion, lyophilized injectable powder etc., can use the various diluent that this area is conventional, as water, ethanol, Polyethylene Glycol, propylene glycol, oxidation isooctadecanol etc., and cosolvent, buffer agent or pH adjusting agent etc.In addition, in order to prepare isotonic injection, sodium chloride, glucose or glycerol etc. can be added.
Tablet of the present invention can be pure tablet, also tablet can be made coated tablet further, such as film-coat, sugar-coat etc.By preparing polymeric matrix or use specific polymer in film coating, tablet can be made rapid release, slow release or controlled release form.Capsule can be soft capsule or hard capsule, is not with film or band film, to have rapid release, slow release or controlled release properties.
In pharmaceutical composition of the present invention, fargesin is prepared with dosage unit usually.Every dosage unit contains 5 to 500 milligrams of fargesins, gives every day 1 time or repeatedly.Also can adopt higher or comparatively low dosage under particular case, the suitable dose of each patient is by doctor according to mode of administration, and age of this patient, body weight and reaction finally determine.
The present invention surprisingly finds that fargesin and derivant thereof have particularly significant application of active for PAH caused by pulmonary disease or hypoxemia first, and the treatment for the pulmonary hypertension caused by other many reasons has broad application prospects equally.
Accompanying drawing explanation
Fig. 1 is the structural formula of fargesin;
Fig. 2 is that fargesin affects schematic diagram to TNF-alpha content in hypoxia model rat peripheral serum;
Fig. 3 is that fargesin affects schematic diagram to TNF-alpha content in hypoxia model lung tissue of rats;
Fig. 4 is that fargesin dose-dependently reduces the model group pulmonary artery that KCl causes and shrinks schematic diagram.
Detailed description of the invention
Enumerate exemplary embodiments below, the present invention is further described, but be not construed as limiting the invention in any form.
Embodiment 1
Fargesin slow releasing tablet (content used is weight percentage) is obtained by following formula
Preparation method is as follows:
(1) by fargesin, lactose, hydroxypropyl emthylcellulose, microcrystalline Cellulose, polyvinylpyrrolidone mix homogeneously, granulate with dehydrated alcohol;
(2) be placed in by wet granular in about 50 DEG C of drying baker, controlling moisture is about 2%;
(3) dried particles is after 20 mesh sieve granulate, adds magnesium stearate, mix homogeneously, by specification tabletting, to obtain final product.
Embodiment 2
Fargesin tablet (content used is weight percentage) is obtained by following formula
Preparation method is as follows:
(1) fargesin, lactose are pulverized respectively, cross 100 mesh sieves, starch direct mistake 100 mesh sieve is for subsequent use;
(2) get appropriate amount of starch to add solution and become gelatinized corn starch, standbyly make adhesive;
(3) starch of fargesin, lactose and surplus is mixed, add adhesive soft material, cross 20 mesh sieves and granulate;
(4) be placed in by wet granular in about 50 DEG C of drying baker, controlling moisture is about 2%;
(5) dried particles is after 20 mesh sieve granulate, adds magnesium stearate, mix homogeneously, by specification tabletting, to obtain final product.
Embodiment 3
Fargesin dispersible tablet (content used is weight percentage) is obtained by following formula
Preparation method is as follows:
(1) by fargesin, microcrystalline Cellulose, carboxymethyl starch sodium, aspartame, 80 mesh sieves are crossed, for subsequent use;
(2) get the PVP K30 of full dose, make the aqueous solution that concentration is 5%, be stirred to and dissolve completely, for making adhesive;
(3) by fargesin, microcrystalline Cellulose, carboxymethyl starch sodium, aspartame mix homogeneously, with adhesive soft material, cross 20 mesh sieves and granulate;
(4) wet granular is placed in about 60 DEG C of dryings, controlling moisture is about 2%
(5) dried particles is after 20 mesh sieve granulate, adds Pulvis Talci, magnesium stearate, mix homogeneously, by specification tabletting, to obtain final product.
Embodiment 4
Fargesin capsule (content used is weight percentage) is obtained by following formula
Fargesin 50%
Starch 50%
Preparation method is as follows:
(1) fargesin, lactose are pulverized respectively, cross 100 mesh sieves, fully mix, for subsequent use;
(2) medicated powder of mixing is filled into No. 2 capsulae vacuuses by specification, obtains final product.
Embodiment 5
Fargesin granule (content used is weight percentage) is obtained by following formula
Preparation method is as follows:
(1) fargesin, starch, Icing Sugar are pulverized respectively, cross 100 mesh sieves, for subsequent use;
(2) get the dextrin of full dose, the ethanol-water solution with 40% makes the aqueous solution that concentration is 2%, is stirred to and dissolves completely, for making adhesive;
(3) by fargesin, starch, Icing Sugar mix homogeneously, with adhesive soft material, cross 20 mesh sieves and granulate;
(4) be placed in by wet granular in about 50 DEG C of drying baker, controlling moisture is about 2%;
(5) dried particles is after 20 mesh sieve granulate, by specification splitting, to obtain final product.
Embodiment 6
Fargesin injection is obtained by following formula
Preparation method is as follows:
(1) added by fargesin in ethanol and propylene glycol solution, the ultrasonic fargesin that makes dissolves;
(2) pH to 6-7.5 is adjusted with 1% hydrochloric acid;
(3) 0.22 μm of microporous filter membrane is crossed;
(4) embedding is in 1000 ampoule bottles, to obtain final product.
Embodiment 7
Fargesin injection is obtained by following formula
Preparation method is as follows:
(1) added by fargesin in ethanol and propylene glycol solution, the ultrasonic fargesin that makes dissolves;
(2) adjust pH to 6-7.5 with 1% hydrochloric acid, inject water to 50000mL;
(3) 0.22 μm of microporous filter membrane is crossed;
(4) embedding is in 1000 bottles, to obtain final product.
The therapeutic effect of fargesin of the present invention to PAH is illustrated further below by way of test example.
Test example 1: fargesin is to the preventive and therapeutic effect of PAH caused by hypoxia
Laboratory animal: SD rat, male, body weight 200 ± 20g, purchased from The Fourth Military Medical University's Experimental Animal Center.
Experiment grouping: animal is divided into 6 groups at random, i.e. dosage group (50mg/kg/d), fargesin high dose group (100mg/kg/d), positive controls (fasudil 50mg/kg/d in Normal group, model group, fargesin low dose group (25mg/kg/d), fargesin, the known ideal medicament that can be used for PAH), often organize 10.
Experimental procedure: rats in normal control group is raised in atmospheric pressure environment, all the other are respectively organized rat and are placed in (atmospheric pressure is about 50kPa, oxygen concentration 10%) raising in full-automatic regulation hypobaric hypoxia cabin, and carry out intermittent Hypoxia, every day carries out 8 hours, continues 6 weeks.Fargesin treatment group is after modeling starts 2 weeks, gastric infusion before each anoxia.Normal group and model group are after modeling starts 2 weeks, and before each anoxia, gavage gives the solvent of a great deal of in contrast.
Hemodynamic index measures: on the right side of rat, external jugular vein inserts the vinyon microtubular being filled with heparin solution (0.9% sodium chloride solution+heparin 10U/m1), the other end of the conduit monitoring pressure that is connected with micro pressure sensor changes, under the guiding of pressure waveform, conduit enters right room, tricuspid orifice, right ventricle (RV) through superior vena cava, finally enter pulmonary trunk, measure mean pulmonary arterial pressure (mPAP) etc.The microtubular of another full heparin solution inserts left common carotid and measures average common carotid artery pressure (mCAP) by micro pressure sensor.After stablizing 30min, application POWERLAB multiple tracks intelligence physiological signal collection and recording system collection, record and analysis indices.
The mensuration of right ventricle (RV) plump index: after experiment terminates, cuts open breast and takes out mouse heart, cut off atrial tissue.Go out RV along interventricular septum edge separation, left ventricle (LV) and interventricular septum (S), weigh RV with after filter paper suck dry moisture, the weight of LV and S, reflects the plump degree of RV with RV/ (LV+S) ratio.
Pulmonary Vascular pathology detection: get piece of tissue from inferior lobe of right lung same area, is placed in 10% neutral formalin (pH7.4) and fixes 2 days.Routine paraffin wax embeds, serial section, hematoxylin-eosin staining and elastic fibers dye (Har ' t improved method dyed elastic fiber, Van Gieson redyes), light Microscopic observation lung small artery morphological change.And with image analyzer measure accompany capable lung small artery (diameter is less than 100 μm) in elastic fibers stained with respiratory bronchioles and alveolar duct external diameter (ED), arterial media wall thickness (MT), tube wall middle level cross-sectional area (MA), vessel lumen cross-sectional area (VA) and the total cross-sectional area of blood vessel (TAA), then the percentage ratio (MT%) that blood vessel wall intima-media thickness accounts for external diameter is calculated respectively, blood vessel wall middle level cross-sectional area accounts for the percentage ratio (MA%) of the total cross-sectional area of blood vessel, reflection lung thin vessels tube wall thickening degree.6 ~ 10 arteriolar These parameters of lung are measured in the section of every induced lung altogether, calculate mean and to walk abreast statistical analysis as the blood vessel index of this rat.
The impact of human peripheral blood and lung tissue inflammatory factor: gather each group of rat plasma and lung tissue, prepare lung homogenate, centrifuging and taking supernatant.Adopt rat tumor necrosis factor-alpha (TNF-α) test kit, experimental procedure to specifications, respectively standard substance, plasma sample and lung tissue sample are added (100 μ l/ hole) in respective aperture, reacting hole is sealed with shrouding gummed paper, 37 DEG C of incubation 90min, wash plate 5 times; Except blank well, add biotinylated antibody working solution (100 μ l/ hole), seal reacting hole with shrouding gummed paper, 37 DEG C of incubation 60min, wash plate 5 times; Except blank well, add enzyme conjugates working solution (100 μ l/ hole), seal reacting hole with shrouding gummed paper, 37 DEG C of lucifuges hatch 30min, wash plate 5 times; Add chromogenic substrate 100 μ l/ hole, 37 DEG C of lucifuges hatch 15min; Add stop buffer 100 μ l/ hole, after mixing, at once measure OD
450value (in 10min).
Statistical procedures: experimental data represents with mean ± standard error (Mean ± SEM), compares between group and adopts t inspection or variance analysis to add up.P<0.05 represents that two groups of difference have significant.
Result: the mPAP of hypoxia model group is significantly higher than normal pressure matched group (P<0.05), illustrate that hypoxia process is induction of obvious PAH, the mPAP of fargesin basic, normal, high administration group is all remarkable in hypoxia model group (P<0.05), show that fargesin has the effect significantly reducing the PAH that hypoxia brings out, in table 1.Result of study is also pointed out, and fargesin also has certain reducing effect to systemic blood pressure-mCAP while reduction pulmonary artery pressure.Normal group right ventricle is without thickening, and model group right ventricle is obviously plump, and plump index RV/ (LV+S) of right ventricle obviously raises, in table 2.Pathology detection finds: the visible loose myocardial cell of right ventricle, pulmonary artery thickens, luminal stenosis.Fargesin, compared with model group, dose-dependently can alleviate myocardial hypertrophy, lung small artery tube wall thickening and luminal stenosis, and high dose group is better than positive control fasudil.In addition, the impact of fargesin on hypoxic rats peripheral blood and lung tissue inflammatory factor the results are shown in Figure 2 and 3.Compared with Normal group, hypoxia model group rat peripheral blood and lung tissue proinflammatory cytokines TNF-α all obviously raise (P < 0.05), and fargesin can obviously suppress the TNF-alpha levels caused by hypoxia to increase (P < 0.05).
Above result shows, fargesin not only has the activity for the treatment of conditions associated with hypoxia PAH, and has antiinflammatory potentiality, all shows significant difference in basic, normal, high dosage group.
Table 1 fargesin is on the impact of hemodynamics index
* compared with normal oxygen matched group,
#compared with anoxia group, P<0.05
Table 2 fargesin is on the impact of the plump index of rat right ventricular
* compared with normal oxygen matched group,
#compared with anoxia group, P<0.05
Test example 2: fargesin is to the preventive and therapeutic effect of P of Rats AH caused by monocrotaline
Laboratory animal: SD rat, male, body weight 200 ± 20g, purchased from The Fourth Military Medical University's Experimental Animal Center.
Experiment grouping: animal is divided into 6 groups at random, i.e. Normal group, monocrotaline (MCT) group, MCT+ fargesin (25mg/kg) group, MCT+ fargesin (50mg/kg) group, MCT+ fargesin (100mg/kg) group, MCT+ sldenafil group (150mg/kg), often organizes 10 animals.
Experimental procedure: MCT ethanol and normal saline (2 ︰ 8) mixed liquor are made into 2% solution, except normal group, other group presses the disposable injection of 60mg/kg body weight intraperitoneal.The solution that Normal group disposable celiac injection ethanol and normal saline are prepared according to volume ratio 2 ︰ 8.Modelling treatment group on the same day gives fargesin gavage, and positive drug group sldenafil gastric infusion, Normal group and model control group give normal saline gastric infusion.Administration every day 1 time, successive administration 28d, until 12h drug withdrawal before checking.
The mensuration of hemodynamic index: with test example 1.
The mensuration of the plump index of RV: with test example 1.
Pulmonary Vascular pathology detection: with test example 1.
The impact of human peripheral blood and lung tissue inflammatory factor: gather each group of rat blood serum and lung tissue sample, adopt rat TNF-α and Interleukin-1β (IL-1 β) test kit, experimental procedure to specifications measures the content of inflammatory factor in peripheral blood and lung tissue.
Statistical procedures: with test example 1.
Result: at the end of experiment, model group rats weight obviously alleviates, the withered rough tarnish of chaeta, and part surface sticks rust sample particulate matter, and there is blood sample symptom at nostril place, and administration group and the above-mentioned situation of positive drug group rat have clear improvement.The change of each group of rat mPAP and mCAP is in table 3.Model group rats mPAP 35.2 ± 5.1mmHg compares with normal rats mean pulmonary arterial pressure 18.3 ± 2.9mmHg, significantly raises (P<0.05), illustrates that MCT process is induction of obvious PAH.Gavage gives sldenafil can suppress the rising of pulmonary arterial pressure in rats by significance; The mPAP of the basic, normal, high administration group of fargesin, all lower than model group, shows that fargesin has the effect significantly reducing the PAH that MCT brings out, and this effect is in obvious dose-dependence.Model group mCAP, compared with normal group, slightly declines, but without significant difference (P>0.05).Compare with Normal group, model group right ventricle is obviously plump, plump index RV/ (LV+S) of right ventricle obviously raises (P<0.05), and fargesin can obviously raise by the RV/ (LV+S) that induces of the reduction MCT of dose dependent.Pathological examination shows, the apparition of model group rats lung arteriolopathy, endotheliocytic swelling, degeneration, downright bad and come off, the obvious hypertrophy of middle film smooth muscle, and blood vessel wall be irregular thickening, luminal stenosis, and with tube wall and surrounding inflammatory cell infiltration.Sldenafil group is compared with model group, and the apparition of lung arteriolopathy alleviates, pulmonary artery lower thickness, and tube chamber becomes large, and tube wall and around cell infiltration alleviate to some extent.Fargesin group is compared with model group, and lung small artery pathological changes significantly alleviates, pulmonary artery lower thickness, and tube chamber becomes large, and tube wall and around inflammatory cell infiltration alleviate.In addition, the impact of the rat peripheral blood that brings out MCT of fargesin and lung tissue inflammatory factor the results are shown in Table 4.Compared with Normal group, MCT model group rats peripheral blood and lung tissue proinflammatory cytokines TNF-α and IL-1 β all obviously raise (P < 0.05), and the TNF-α that fargesin can obviously and dose-dependently suppress MCT to bring out and IL-1 β level increase (P < 0.05).
Table 3 fargesin is on the impact of the plump index of MCT rat model hemodynamic index and right ventricle
* compared with matched group,
#compared with MCT group, P<0.05
Table 4 fargesin is on the impact of TNF-α in MCT rat model Peripheral Blood and lung tissue and IL-1 β content
* compared with matched group,
#compared with MCT group, P<0.05
Test example 3: fargesin causes the vasoconstrictive impact of rat pulmonary artery to hypoxia
Laboratory animal: BALB/c mouse, male, body weight 20 ± 3g, purchased from The Fourth Military Medical University's Experimental Animal Center.
Experimental procedure: Normal group is raised in atmospheric pressure environment by mice, all the other two groups of mice administrations are placed on (O in hypoxia cabin
2: 10%) raise, every day carries out 8 hours, continues 6 weeks.Mice is dissected, in being separated pulmonary artery on ice, being cut into the thin vessels ring of about 1mm, being placed in containing 37 DEG C of 2mM Ca
2+the physiology bath of PSS 20ml, passes into gaseous mixture (5%CO
2-95%O
2) oxygenate, vascular ring connects polygraph record tension variation through tension pick-up.Regulate initial tension, balance 60min, changes 60mM KCl preshrinking blood vessel, wait rise to plateau stable after, add the fargesin (Fargesin) of series concentration by ascending cumulative concentration, the change of record vascular ring tension force.
Statistical procedures: experimental data represents with mean ± standard error (Mean ± SEM), compares between group and adopts t inspection or variance analysis to add up.P<0.05 represents that two groups of difference have significant.
Result: the results are shown in Figure 4.After anoxia, fargesin can the model group pulmonary artery tension force that causes of the reduction KCl of dose dependent.
In addition, test shows after deliberation, because fargesin internal metabolism is comparatively rapid, half-life is less than 2h, therefore carried out the lipophilic moieties such as alkoxide, esterification and modify or make slow releasing tablet (see embodiment 1, effect is particularly remarkable), can action time of prolong drug further, improve the accumulative drug level of fargesin in blood, thus improve medicine to the prevention effect of pulmonary hypertension.
Although above with general explanation, detailed description of the invention and test, the present invention is described in detail, and on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, all belong to the scope of protection of present invention.
Claims (10)
1. the application of fargesin in preparation treatment or prophylaxis of pulmonary hypertension medicine.
2. fargesin derivant and salt thereof or the application of solvate in preparation treatment or prophylaxis of pulmonary hypertension medicine.
3. application according to claim 2, is characterized in that: described fargesin derivant is fargesin halo, sulfonation, nitrated, hydroxylation, alkoxide, esterification products.
4. application according to claim 1 and 2, it is characterized in that: described pulmonary hypertension is that arterialness and/or the left heart are disease associated, and wherein arterialness pulmonary hypertension comprises idiopathic, hereditability, medicine and persistent pulmonary hypertension of the new-born that poisonous substance is made peace; The disease associated pulmonary hypertension of the left heart comprises the pulmonary hypertension that cardiac systolic function is incomplete, Diastolic Heart failure, valvular heart disease cause.
5. application according to claim 1 and 2, is characterized in that: described pulmonary hypertension, caused by pulmonary disease and/or hypoxia, comprises chronic obstructive pulmonary disease, Interstitial Lung Disease, sleep apnea syndrome, chronic plateau sickness.
6. application according to claim 1 and 2, is characterized in that: described pulmonary hypertension is caused by chronic thromboembolic.
7. the application according to any one of claim 1-6, is characterized in that: described medicine is using fargesin, fargesin derivant and salt thereof or solvate for single-activity composition or as one of active component.
8. application according to claim 7, is characterized in that: described medicine also comprises pharmaceutically acceptable at least one excipient.
9. the application according to any one of claim 1-6, is characterized in that: described medicine is tablet, capsule, pill, powder, granule, suspensoid, oral administration solution, powder pin or injection.
10. the application according to any one of claim 1-6, is characterized in that: described medicine is peroral dosage form, Sublingual or buccal administration dosage form, vein, subcutaneous, transdermal or intramuscular dosage form.
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| WO2016182399A3 (en) * | 2015-05-13 | 2017-01-12 | 한국생명공학연구원 | Pharmaceutical composition for preventing and treating chronic obstructive lung disease containing, as active ingredient, magnoliae flos extract, fraction, or active fraction thereof |
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| ROLFSEN WNA: "来源于天然产物的血小板活化因子拮抗剂", 《国外医药——合成药、生化药、制剂分册》 * |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016182399A3 (en) * | 2015-05-13 | 2017-01-12 | 한국생명공학연구원 | Pharmaceutical composition for preventing and treating chronic obstructive lung disease containing, as active ingredient, magnoliae flos extract, fraction, or active fraction thereof |
| CN108135954A (en) * | 2015-05-13 | 2018-06-08 | 韩国生命工学研究院 | For preventing and treating the pharmaceutical composition containing Flos Magnoliae extract, fraction or active fractions active constituent of chronic obstructive pulmonary disease |
| JP2018515528A (en) * | 2015-05-13 | 2018-06-14 | コリア リサーチ インスティチュート オブ バイオサイエンス アンド バイオテクノロジー | Pharmaceutical composition for preventing and treating chronic obstructive pulmonary disease, comprising Magnolia floss extract, fraction or active fraction thereof as an active ingredient |
| EP3295947A4 (en) * | 2015-05-13 | 2019-05-15 | Korea Research Institute of Bioscience and Biotechnology | Pharmaceutical composition for preventing and treating chronic obstructive lung disease containing, as active ingredient, magnoliae flos extract, fraction, or active fraction thereof |
| US10376553B2 (en) | 2015-05-13 | 2019-08-13 | Korea Research Institute Of Bioscience And Biotechnology | Pharmaceutical composition for preventing and treating chronic obstructive lung disease containing, as active ingredient, Magnoliae flos extract, fraction, or active fraction thereof |
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