CN107569476A - Pharmaceutical composition containing Acetylshikonin and its application in pulmonary hypertension medicine - Google Patents
Pharmaceutical composition containing Acetylshikonin and its application in pulmonary hypertension medicine Download PDFInfo
- Publication number
- CN107569476A CN107569476A CN201710822165.0A CN201710822165A CN107569476A CN 107569476 A CN107569476 A CN 107569476A CN 201710822165 A CN201710822165 A CN 201710822165A CN 107569476 A CN107569476 A CN 107569476A
- Authority
- CN
- China
- Prior art keywords
- acetylshikonin
- pharmaceutical composition
- pulmonary hypertension
- composition containing
- medicine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention relates to a kind of new pharmacological action of traditional Chinese medicine monomer composition Acetylshikonin, belong to pharmaceutical technology field.It includes the Acetylshikonin of the effective dose containing treatment in need and pharmaceutically acceptable carrier or auxiliary material, in addition to shares manufactured pharmaceutical composition in any proportion with other materials, for prevent, alleviate and/or pulmonary hypertension and its medicine of complication in.Acetylshikonin in the present invention is the monomeric compound extracted in Asian puccoon, toxicity is low, raw material resources is extensive, with good applicating and exploitation prospect, it is a kind of traditional Chinese medicine monomer of preferable new treatment hypoxic pulmonary hypertension, can be applied to prepare the product of prevention and treatment pulmonary hypertension.
Description
Technical field
The present invention relates to a kind of new pharmacological action of traditional Chinese medicine monomer composition Acetylshikonin, and in particular to one kind contains second
The pharmaceutical composition of acyl alkannin and its application in pulmonary hypertension medicine, belong to pharmaceutical technology field.
Background technology
Pulmonary hypertension (Pulmonary Artery Hypertension, PAH) is a kind of between malignant tumour and chronic
Malignant disease between disease, it is the clinical syndrome with the characteristics of the rise of pulmonary vascular resistance progressive, it is mainly characterized by by lung
Parteriole shrinks, blood vessel hyperplasia causes pulmonary vascular resistance to raise with reconstructing, and causes right ventricle plump, can finally cause patient to die from
Right heart failure.As shown by data, the average age that the disease is made a definite diagnosis is only 36 years old, if treated not in time, the life span of patient is put down
There was only 2.8 years, it is only better than prognosis in hcc, it is all poorer than other malignant tumour prognosis.Therefore, the disease is known as the " heart by medical field
Cancer in angiosis ", " disease for still perplexing world medical circle so far ".Pulmonary hypertension haemodynamics diagnostic criteria is：
Under quiescent condition, right cardiac catheter detection mean pulmonary arterial pressure >=25mmHg.
The basic pathology process of pulmonary hypertension is that Pulmonary Vascular shrinks (Pulmonary vasoconstriction, HPV)
With pulmonary artery remodeling (Pulmonary vessel remodeling, PVR).Research prompting anoxic is the important of pulmonary hypertension
Inducement.Anoxic can result in the unbalance of smooth muscle cell proliferation and apoptosis, cause pulmonary artery tube wall thickening, tube chamber to reduce, blood vessel
Compliance increase, pulmonary artery spasm are so-called pulmonary arterial vascular reconstruct, and extend with hypoxic exposure and aggravate, and cause pulmonary artery
High pressure.The progress on Hypoxic Pulmonary Hypertension mainly includes at present：1. anoxic is by raising endothelin -1 (ET-1), blood
Endothelial tube growth factor (Vascular endothelial growth factor, VEGF), Angiotensin II
(Angiotensin II, Ang II), serotonin (serotonin, 5-HT), tumor necrosis factor-alpha (Tumornecrosis
Factor- α, TNF-α) etc. growth factor, cell factor expression, cause pulmonary hypertension；2. anoxic by hypoxia inducible because
It is small that -1 α of son (Hypoxia inducible factor-1, HIF-1 α) stimulates arteria pulmonalis smooth muscle cells (PASMCs) to produce blood
Plate derivative growth factor (Platelet-derived growth factor, PDGF), ET-1 etc., cause pulmonary artery remodeling, lead
Cause pulmonary hypertension；3. anoxic is thin by stimulating the active oxygen (ROS) to be played an important role to pulmonary artery remodeling, HIF-1 α, activation T
The factors such as the karyon factor (Nuclear factor of activated T cells, NFAT), regulate and control the expression of Kv passages, draw
Play pulmonary hypertension.It recent studies have shown that the possible same Notch3 of pulmonary hypertension, BMP II receptors (BMPR2) and live
Change the variation of the gene such as plain receptor-like kinase enzyme (ALK1) and peroxisome proliferator-activated receptor (PPAR), Rho kinases
The factors such as the exception of signal path are relevant.
PAH target therapeutic agent mainly has 3 classes, including prostacyclin analogs, endothelin-receptor antagonists at present
(endothelin receptor antagonists, ERA) and PDE5 (phosphodiesterase, PDE-5)
Inhibitor, its application can obviously improve the life span and survival state of patient.The development and application of three class targeted drugs is being worked as
Play important function in preceding PAH treatment, but due to the side effect that can not be overcome and to fail its therapeutic effect satisfactory；
PAH target therapeutic agents are mostly import medicine, expensive, are not included in basic medical insurance Drug catalogue, cause PAH patient to grow
The tremendous economic pressure of phase joint medication.Therefore, Chinese Traditional Medicine advantage is played, is found in safety, economic treatment PAH
Medicine, the prognosis and its quality of life of raising to improvement PAH patient are significant.
Acetylshikonin (acetylshikonin), No. CAS is 24502-78-1, is the master isolated from plant Asian puccoon
Active component is wanted, is fat-soluble very strong naphthalene Quinone Pigments.Inventor has found Acetylshikonin can to reduce PAH big by studying
The right ventricular systolic pressure and right ventricle plumpness index of mouse, mutually it is concerned about available for caused by preventing and treating pulmonary hypertension and pulmonary hypertension
Vascular diseases.
Asian puccoon is the traditional Chinese medicine that Chinese Pharmacopoeia is included, and medicinal source is the dry root of comfrey.Active ingredient master
Will be naphthoquinones class dye compound include Acetylshikonin (acetylshikonin), beta-hydroxyisovalerylshiderivative (β-
Hydro-xyisovalerylshikonin), alkannin (shikonin), β, β '-dimethylacrylshikonin (β, β '-
Dimethylacrylshikonin) etc..2010 editions《Chinese Pharmacopoeia》Described in Asian puccoon cool blood, promoting blood circulation, detoxify promoting eruption.With anti-
Bacterium, anti-inflammatory, antiviral, antitumor etc. act on.
Acetylshikonin (formula I), it is the main anticancer component of Asian puccoon.Modern pharmacology research shows, Acetylshikonin
With many pharmacological activity, including scavenging activated oxygen, prevent superoxide dismutase (SOD) from reducing, play anti-oxidant
Effect；Suppress the activity of acyl-CoA, reduce cholesterol level, cardiovascular system is shielded；Reduce blood pressure, anti-blood
Bolt and suppression platelet aggregation effect；Strengthen protein kinase B (PKB) activity, play para-insulin bioactivity, prevent and treat glycosuria
Disease and its complication；In addition generation of the Acetylshikonin by suppressing new born microvessels plays cancer suppressing action, but so far,
We do not have found the correlative study report of Acetylshikonin treatment pulmonary hypertension.
The content of the invention
The purpose of the present invention is overcome the deficiencies in the prior art part, there is provided a kind of drug regimen containing Acetylshikonin
Thing and its application in pulmonary hypertension medicine；It specifically develops a kind of medicine resource of Asian puccoon, to the active ingredient of Asian puccoon
The function of anti-pulmonary hypertension of Acetylshikonin is studied, the results showed that the composition can effectively reduce anoxic pulmonary artery height
The pulmonary artery pressure of rat is pressed, improves pulmonary artery remodeling, reduce inflammation damage, is expected to be used for the prevention of pulmonary hypertension and controls
Treat.
According to technical scheme provided by the invention：Pharmaceutical composition containing Acetylshikonin, containing having for treatment in need
1~100mg/kg of dosage Acetylshikonin and pharmaceutically acceptable carrier or auxiliary material is imitated, in addition to other materials with any
Ratio shares manufactured pharmaceutical composition.
In the present invention, according to route of administration, the Acetylshikonin pharmaceutical composition can be in be selected from following formulation：Piece
Agent, capsule, granule, solution, spray, drops, supensoid agent, pulvis, emulsion, pill, liposome, various controlled release agents
Type and targeting preparation.
The Acetylshikonin pharmaceutical composition of the present invention can use known method to prepare, using several approach to subject
Using the approach such as including but not limited to intracutaneous, parenteral, oral, air flue is interior, intraperitoneal, subcutaneous, vein.
The Acetylshikonin pharmaceutical composition of the present invention is optional to be carried by the way that any conventional method is one or more
Body and/or excipient are prepared.Therefore, Acetylshikonin and its pharmaceutically acceptable derivative especially can be formulated as sucking or blow
Enter (by mouth or nose) or oral, containing change, parenteral.
Acetylshikonin pharmaceutical composition can also use solution, suspension, emulsion, pill, capsule, pulvis, various
Controlled release agent.These preparations by the Acetylshikonin containing effective therapeutic dose, preferably purified form, and appropriate carrier,
In the form of providing to the appropriate administration of patient.
In the present invention, the Acetylshikonin of the purified form refers to substantially pure Acetylshikonin, especially pure
Acetylshikonin of the degree more than 95%.
Described product includes medicine, food, health products.
The effective dose of Acetylshikonin is the pharmaceutical composition of single dose in described pharmaceutical composition.
The carrier be in pharmaceutical composition, it is in addition to Acetylshikonin compound, can be used for be diluted, fill out
The pharmaceutic adjuvant or excipient fill, bond, lubricating, being disintegrated, seasoning etc., including but not limited to suspending agent, filler, wetting agent,
Binder, disintegrant；Wherein auxiliary material includes but is not limited to as filler or the following material of excipient：Water, sorbierite, sweet dew
Alcohol, fructose, lactose, xylitol, glucose, sodium chloride；Following material including but not limited to as pH value regulator：Phosphate
Buffer solution, sodium citrate, citric acid, watery hydrochloric acid, acetate buffer, sodium carbonate, sodium hydroxide；It may also include but be not limited to make
For the following material of preservative：Potassium sorbate, sodium benzoate, methyl p-hydroxybenzoate, propylparaben；It can also wrap
Include but be not limited to the following material as stabilizer and antioxidant：Vitamin C, vitamin E, sodium sulfite；It may also include but not
It is limited to the following material as taste conditioning agent：Fructose, maltitol, Steviosin, sucrose, saccharin sodium, essence；It can also wrap in addition
Include other conventional, appropriate additives.
The preparation method of the pharmaceutical composition containing Acetylshikonin, step are as follows：
(1) drug solution preparing：It is according to weight ratio by Acetylshikonin compound, sorbierite and citric acid with water for injection
10: 3: 1 stirrings adjust pH to 6.8-7.6 to being completely dissolved, using sodium acid carbonate, and then injecting water to overall solution volume is
200-250 times of Acetylshikonin quality；
(2) decoction decolourizes：The decoction room temperature prepared is decolourized with medical activated carbon, filtering decarbonization, gained filtrate is with 0.22 μ
The miillpore filter filtrate refined filtration in m apertures is degerming, is dispensed with the ampoule or cillin bottle to have sterilized；
(3) preparation：Required formulation is made in packing solution obtained by step (2) as needed, is produced containing Acetylshikonin
Pharmaceutical composition.
By Acetylshikonin be used for prevent, alleviate and/or pulmonary hypertension and its medicine of complication in, its administration interval
At least 12h.
The pharmaceutical composition containing Acetylshikonin there is no Acetylshikonin compound in application
It is prominent release in mammal, particularly people inside pharmacokinetic characteristic.Using when, Acetylshikonin compound covalently connects
The compound in reservoir is connect, the compound is preferably polymer gel, more preferably hydrogel, the polymerization being most preferably hydrated
In thing matrix.
Pulvis pin preparation process is as follows：The decoction dispensed is cooled to -46 DEG C with 1 DEG C/min of speed, insulation freezing
5 hours；13.3Pa is evacuated to, is then warming up to 30 DEG C with 3 DEG C/h of speed, then 50 are warming up to by 5 DEG C/h of speed
DEG C, then freeze-day with constant temperature 6 hours, that is, obtain Acetylshikonin freeze-dried powder.
Phase time between the administration of pharmaceutical composition is at least about 12 hours, for example, at least 16 hours, typically at least
24 hours.
Joint hypoxemia (10% is subcutaneously injected using vascular endothelial growth factor receptor antagonist SU5416 (20mg/kg)
O2) induce and establish male Sprague-Dawley rat pulmonary hypertension model.General signs rate is recorded, is passed through during experimental endpoints
Electrocardiogram is recorded, measure sero-enzyme, organ index, pulmonary circulation and systemic circulation blood flowing dynamics change, detects 5- hydroxyls in lung tissue
Tryptamines level and histomorphological changes, judge prevention and/or treatment of the Acetylshikonin to Hypoxic Rats pulmonary hypertension
Effect.
The features of the present invention has spy with advantage in the monomer component-Acetylshikonin extracted in conventional Chinese medicine alkannin
The pharmacological action that the opposite sex delays the rise of pressure of pulmonary circulation and had no significant effect to body circulation；Significantly reduce Hypoxic Pulmonary Hypertension
Mortality of animals, there is the right heart failure mitigated caused by Hypoxic Pulmonary Hypertension, improve that right ventricle is plump and increase symptom
Pharmacological action；With reducing, serotonin in lung tissue is horizontal, alleviates the pharmacological action of lung parteriole reconstruct, can be applied to make
Standby prevention and/or treatment hypoxic pulmonary hypertension and its product of complication.
Acetylshikonin can be prepared by known methods to obtain in the present invention.
Beneficial effects of the present invention：The pharmaceutical composition of Acetylshikonin provided by the invention can effectively reduce anoxic lung
The pulmonary artery pressure of arterial hypertension rat, improve pulmonary artery remodeling, reduce inflammation damage, is expected to be used for the prevention of pulmonary hypertension
And treatment.
Brief description of the drawings
Influence of Fig. 1 Acetylshikonins to Hypoxic Pulmonary Hypertension hemodynamics.
Including：Right ventricular systolic pressure (right ventricular systolic pressure, RVSP), B- diastolic pressures
(diastolic blood pressure, DBP), C- systolic pressures (systolic blood pressure, SBP), D- hearts rate
(heart rate, HR).
Influence of Fig. 2 Acetylshikonins to Hypoxic Pulmonary Hypertension rat organ index.Lung weight in wet base/body weight (mg/
Kg), weight (mg/mg), D- right ventricle plumpness index (the right hearts of B- right ventricle weight in wet base/body weight (mg/kg), the right heart weight in wet bases of C-/whole-heartedly
Room weight/(left ventricle+interventricular septum)), mg/mg)
The influence horizontal to 5-HT in Hypoxic Pulmonary Hypertension lung tissue of rats of Fig. 3 Acetylshikonins.
The improvement result that Fig. 4 Acetylshikonins reconstruct to Hypoxic Pulmonary Hypertension induced lung thin vessels.
A- Normal groups；B- pulmonary hypertension model control groups；C- Bosentan groups；D- Acetylshikonins (1mg/kg)；
E- Acetylshikonins (2mg/kg)；F- Acetylshikonins (10mg/kg).
The improvement result that Fig. 5 Acetylshikonins thicken to Hypoxic Pulmonary Hypertension Pulmonary Arterioles of Rat Exposed.
A- Normal groups；B- pulmonary hypertension model control groups；C- Bosentan groups；D- Acetylshikonins (1mg/kg)；
E- Acetylshikonins (2mg/kg)；F- Acetylshikonins (10mg/kg).
Embodiment
Further illustrate that Acetylshikonin prevents and/or treated hypoxic pulmonary hypertension in vivo with reference to the present invention
And its pharmacological action and the medicinal usage of complication.
Following embodiments illustrate the present invention in more detail, are not any limitation of the invention.
Embodiment 1
The preparation method of the pharmaceutical composition containing Acetylshikonin, step are as follows：
(1) drug solution preparing：It is according to weight ratio by Acetylshikonin compound, sorbierite and citric acid with water for injection
10: 3: 1 stirrings adjust pH to 6.8-7.6 to being completely dissolved, using sodium acid carbonate, and then injecting water to overall solution volume is
200-250 times of Acetylshikonin quality；
(2) decoction decolourizes：The decoction room temperature prepared is decolourized with medical activated carbon, filtering decarbonization, gained filtrate is with 0.22 μ
The miillpore filter filtrate refined filtration in m apertures is degerming, is dispensed with the ampoule or cillin bottle to have sterilized；
(3) preparation：Required formulation is made in packing solution obtained by step (2) as needed, is produced containing Acetylshikonin
Pharmaceutical composition.
By Acetylshikonin be used for prevent, alleviate and/or pulmonary hypertension and its medicine of complication in, its administration interval
At least 12h.
Pulvis pin preparation process is as follows：The decoction dispensed is cooled to -46 DEG C with 1 DEG C/min of speed, insulation freezing
5 hours；13.3Pa is evacuated to, is then warming up to 30 DEG C with 3 DEG C/h of speed, then 50 are warming up to by 5 DEG C/h of speed
DEG C, then freeze-day with constant temperature 6 hours, that is, obtain Acetylshikonin freeze-dried powder.
The foundation of the Rats of Pulmonary Hypertension model of embodiment 2
SU5416 is a kind of fat-soluble small molecule VEGF (vascular endothelial growth
Factor, VEGF) receptors signal transduction inhibitor.Research finds that SU5416 combines Chronic sustained hypoxia (10%O2) induction is greatly
Mouse pulmonary hypertension model can preferably simulation people pulmonary hypertension occur when Pulmonary Vascular clump sample lesion.SU5416 joints are chronic to hold
Continuous anoxic can make rat pulmonary artery mean pressure (mean pulmonary arterial pressure, mPAP), RVSP, the right side for 3 weeks
Heart plumpness index (right ven-tricular hypertrophy index, RVHI), lung parteriole WT% and flesh degree
Significantly increase, luminal stenosis, obvious Pulmonary Vascular remodeling is presented, show that the SU5416 joint more simple normal pressures of chronic hypoxia are chronic low
Oxygen can more effectively induce and establish reliable pulmonary hypertension model.The present embodiment is big using SU5416 joint chronic hypoxia inductions
The animal model of mouse pulmonary hypertension, measure Rats Organs and Tissues index, hemodynamic index and histomorphological changes, judges
Purposes of the Acetylshikonin in prevention and/or treatment pulmonary hypertension and its complication product is prepared.
Embodiment selects male SD rat 120,180~220g of body weight, is randomly divided into 6 groups, every group 20.It is normal right
According to group, model control group, Bosentan group (30mg/kg, gastric infusion), the basic, normal, high dosage group of Acetylshikonin (1mg/kg,
2mg/kg, 10mg/kg, gastric infusion), successive administration surrounding, once a day.Normal group administration the previous day subcutaneous administration is same
ML normal saline, remaining each group start with DMSO solvents dissolving SU5416 in experiment, and it is the molten of 4mg/mL to be made into concentration
Liquid, inject, rat is placed in normal pressure low oxygen case, daily Constant hypoxia 8h, weekly 6d by 20mg/kg singles abdominal subcutaneous, altogether
Meter 3 weeks, prepare pulmonary hypertension model in rats.Continuous record each group rats death situation, calculates survival rate.As a result show (attached
Table 1), each dosage group of Acetylshikonin and positive drug group can significantly reduce rats death caused by pulmonary hypertension, improve life
Deposit rate.
Influence of the Acetylshikonin of table 1. to Rats of Pulmonary Hypertension survival rate
Influence of the Acetylshikonin of embodiment 3 to Rats of Pulmonary Hypertension hemodynamic index
After calculating survival rate, 10% chloraldurate 0.2mL/kg anesthetized rats, blunt separation right side vena jugularis externa, using warp
Allusion quotation right cardiac catheter detects rat right ventricular pressure, records and counts each group systolic pressure average value.Body circulation result is shown (as schemed
1), heart rate, systolic pressure and the equal no significant difference of diastolic pressure between each group.Illustrate that medicine has no significant effect to body circulation.Right ventricular pressure
Power result (such as Fig. 1) shows that model group right ventricular pressure significantly raises compared with normal group, illustrates modeling success, positive drug and acetyl are purple
Careless each dosage group of element can significantly reduce right ventricular pressure compared with model group, illustrate that SU5416 joints can be improved slowly using Acetylshikonin
The haemodynamics of the Rats of Pulmonary Hypertension of property hypoxia inducible.
Influence of the Acetylshikonin of embodiment 4 to Rats of Pulmonary Hypertension organ index
After haemodynamics detection terminates, rat is put to death, cuts heart rapidly, it is clean in the normal saline flushing of precooling,
Filter paper records lung and whole-heartedly weight after blotting residual moisture.Atrium is cut along auricle lower edge, record left and right ventricles merge interventricular septum
Weight, cut right ventricle and weigh.It is wet to calculate each group lung weight in wet base/body weight (mg/kg), right ventricle weight in wet base/body weight (mg/kg), the right heart
Weight (mg/mg) and right ventricle plumpness index of weight/whole-heartedly (right ventricle weighs/(left ventricle+interventricular septum), mg/mg).As a result show
(such as Fig. 2), each dosage group of Acetylshikonin can improve the caused lung of pulmonary arterial pressure rise and increase again, and positive drug group and acetyl are purple
Careless element can significantly reduce the right heart weight in wet base/body weight of Rats of Pulmonary Hypertension, right heart weight in wet base/whole-heartedly weight and right ventricle compared with model group
Plump index (right ventricle weight/(left ventricle+interventricular septum)), illustrates that Acetylshikonin can improve caused by pressure of pulmonary circulation rise
Right ventricle compensatory it is plump, mitigate the injury of lungs caused by pulmonary hypertension.
The influence horizontal to 5-HT in Rats of Pulmonary Hypertension lung tissue of the Acetylshikonin of embodiment 5
After rat is put to death, lung is taken.Clip lung tissue about 0.1g, 1mlPBS grinding cracking is added, is homogenized 15 minutes on ice,
Centrifugation, takes supernatant.According to 10 times of dilutions of preliminary result.5- hydroxyls in the detection supernatant dilution of commodity in use ELISA kit
Tryptamines -1 (serotonin, 5-HT) is horizontal.5-HT is strong vasoconstrictive factor.Pulmonary hypertension is often received with blood vessel
The contracting factor such as 5-HT is over-expressed for a long time, can not only be caused Pulmonary Vascular to shrink, be can also result in pulmonary artery remodeling.Implement 4 results
Show (such as Fig. 3), 5-HT levels are significantly raised in model group lung tissue, and positive drug and each dosage group of Acetylshikonin can show
The 5-HT levels in (P ＜ 0.001) Rats of Pulmonary Hypertension lung that reduce are write, mitigate the contraction of lung parteriole and thus secondary lung petty action
Arteries and veins reconstructs.
Embodiment 5：Influence of the pathologic examination Acetylshikonin to Rats of Pulmonary Hypertension
Rat unilobar lung tissue is separated, is fixed with 4% paraformaldehyde, serial section after FFPE, carries out HE dyes
Color.As a result (accompanying drawing 4) being shown, control rats lung parteriole endothelial cell continuity is fine, and tube wall is thin, and cell distribution is uniform,
Tube chamber is big and thickness is consistent；Pulmonary hypertension model group Pulmonary Arterioles of Rat Exposed endothelial cell continuity is destroyed, and cell has swollen
Swollen denaturation, necrosis even come off, and the obvious hyperplasia of tunicae media vasorum smooth muscle cell, pipe thickness increases considerably, and Lumen Area shows
Work diminishes；Compared with model group, each dosage group of Acetylshikonin and positive drug group lung parteriole endothelial cell continuity are fine, pipe
Wall thickness has reduced, Lumen Area increase.Light microscope detects, and carries out statistics credit to lung parteriole vessel wall thickness
Analysis.Every group takes 5 rats, and every rat takes external diameter to survey its internal-and external diameter, use is following in 50-200mm 20 lung flesh type parterioles
Formula estimates Pulmonary vascular cell thickness：Vessel wall thickness %=(artery outer diameter-vessel diameter)/artery outer diameter × 100%.As a result
Show that SU5416 joint chronic hypoxias can induce obvious Pulmonary Vascular Remodeling, each dosage group of Acetylshikonin and positive drug group
The obvious Pulmonary Vascular Remodeling for inhibiting Rats of Pulmonary Hypertension, as a result as Fig. 5 is shown.
Whole animal evaluating drug effect test result indicates that, compared with pulmonary hypertension model group, Acetylshikonin can be bright
It is aobvious to reduce pressure of pulmonary circulation and body circulation items hemodynamic index is had no significant effect.Acetylshikonin is relieved the right heart
Room hypertrophy symptom, improve heart function, hence it is evident that mitigate pulmonary edema symptom, while reduce the content of 5-HT in lung tissue, avoid lung small
Phenomenon is reconstructed caused by artery contracts last.Improve the changes in histopathology caused by pulmonary hypertension, delay tissue non-
Reversible lesion.
In summary, there is Acetylshikonin specificity to delay the rise of pressure of pulmonary circulation and body circulation is had no significant effect
Pharmacological action；Significantly reduce the mortality of animals of pulmonary hypertension；With mitigate pulmonary hypertension caused by right heart failure,
Improve right ventricle plumpness and increase symptom, prevention, alleviate and/or treat heart injury, heart failure caused by pulmonary hypertension
Pharmacological action；With reducing, serotonin in lung tissue is horizontal, alleviates the pharmacological action of lung parteriole reconstruct.Acetylshikonin
For the monomeric compound extracted in conventional Chinese medicine Asian puccoon, have the advantages that toxicity is low, relatively easy by converting extraction process；Its
Raw material resources is common, has good applicating and exploitation prospect, be a kind of preferably new treatment pulmonary hypertension and its
The traditional Chinese medicine monomer of complication, it can be applied to prepare prevention and/or treatment pulmonary hypertension and its product of complication.
Claims (9)
1. the pharmaceutical composition containing Acetylshikonin, it is characterized in that：1~100mg/kg's of effective dose containing treatment in need
Acetylshikonin and pharmaceutically acceptable carrier or auxiliary material, in addition to manufactured medicine group is shared in any proportion with other materials
Compound.
2. the pharmaceutical composition containing Acetylshikonin as claimed in claim 1, it is characterized in that described pharmaceutical composition is selected from such as
Under formulation：Tablet, capsule, granule, solution, spray, drops, supensoid agent, pulvis, emulsion, pill, powder, fat
Plastid, various controlled release agent types or targeting preparation.
3. the pharmaceutical composition containing Acetylshikonin as claimed in claim 1, it is characterized in that described pharmaceutical composition is by appointing
What conventional method is prepared with one or more carriers and/or excipient, especially can be formulated as sucking or is blown into, by mouth or
Nose, or orally, containing change, parenteral.
4. the pharmaceutical composition containing Acetylshikonin as claimed in claim 1, it is characterized in that：The Acetylshikonin is pure second
Acyl alkannin, purity are more than 95%.
5. the pharmaceutical composition containing Acetylshikonin as claimed in claim 1, it is characterized in that：Acetyl in described pharmaceutical composition
The effective dose of alkannin is the pharmaceutical composition of single dose.
6. the pharmaceutical composition containing Acetylshikonin as claimed in claim 1, it is characterized in that：The carrier is in drug regimen
It is in addition to Acetylshikonin compound, the medicine that is diluted, fills, bonding, lubricating, being disintegrated, seasoning etc. can be used in thing
With auxiliary material or excipient, including but not limited to suspending agent, filler, wetting agent, binder, disintegrant；Wherein auxiliary material include but
It is not limited to the following material as filler or excipient：Water, sorbierite, mannitol, fructose, lactose, xylitol, glucose,
Sodium chloride；Following material including but not limited to as pH value regulator：Phosphate buffer, sodium citrate, citric acid, dilute salt
Acid, acetate buffer, sodium carbonate, sodium hydroxide；It may also include but be not limited to the following material as preservative：Sorbic acid
Potassium, sodium benzoate, methyl p-hydroxybenzoate, propylparaben；It may also include but be not limited to as stabilizer and resist
The following material of oxygen agent：Vitamin C, vitamin E, sodium sulfite；It may also include but be not limited to as the following of taste conditioning agent
Material：Fructose, maltitol, Steviosin, sucrose, saccharin sodium, essence；It additionally can include other conventional, appropriate additions
Agent.
7. the preparation method of the pharmaceutical composition containing Acetylshikonin described in claim 1, it is characterized in that step is as follows：
(1) drug solution preparing：With water for injection by Acetylshikonin compound, sorbierite and citric acid according to weight ratio be 10: 3
: 1 stirring adjusts pH to 6.8-7.6 to being completely dissolved, using sodium acid carbonate, and it is acetyl then to inject water to overall solution volume
200-250 times of alkannin quality；
(2) decoction decolourizes：The decoction room temperature prepared is decolourized with medical activated carbon, filtering decarbonization, gained filtrate is with 0.22 μm of hole
The miillpore filter filtrate refined filtration in footpath is degerming, is dispensed with the ampoule or cillin bottle to have sterilized；
(3) preparation：Required formulation is made in packing solution obtained by step (2) as needed, produces the medicine containing Acetylshikonin
Compositions.
8. application of the Acetylshikonin in pulmonary hypertension medicine, it is characterized in that：Acetylshikonin is used to prevent, alleviated
And/or in pulmonary hypertension and its medicine of complication, its administration interval is at least 12h.
9. application of the Acetylshikonin as claimed in claim 8 in pulmonary hypertension medicine, it is characterized in that：It is specifically that acetyl is purple
Careless element is used to suppress pulmonary arterial vascular reconstruct reconstruction and right ventricular hypertrophy caused by anoxic.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710822165.0A CN107569476A (en) | 2017-09-13 | 2017-09-13 | Pharmaceutical composition containing Acetylshikonin and its application in pulmonary hypertension medicine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710822165.0A CN107569476A (en) | 2017-09-13 | 2017-09-13 | Pharmaceutical composition containing Acetylshikonin and its application in pulmonary hypertension medicine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107569476A true CN107569476A (en) | 2018-01-12 |
Family
ID=61036506
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710822165.0A Withdrawn CN107569476A (en) | 2017-09-13 | 2017-09-13 | Pharmaceutical composition containing Acetylshikonin and its application in pulmonary hypertension medicine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107569476A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116148471A (en) * | 2022-11-01 | 2023-05-23 | 中南大学 | Biomarker for pulmonary arterial hypertension and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101194920A (en) * | 2006-09-29 | 2008-06-11 | 杭州贺博生物技术有限公司 | Lithospermum and application of its active ingredient in preparing medicament for treating tumour stem cell |
| CN101474151A (en) * | 2009-01-21 | 2009-07-08 | 石河子大学医学院第一附属医院 | Alkannin microemulsion composition |
| CN106176703A (en) * | 2015-05-25 | 2016-12-07 | 中国医学科学院药物研究所 | Salvianolic acid A medicinal usage in preparation prevention and/or treatment pulmonary hypertension |
-
2017
- 2017-09-13 CN CN201710822165.0A patent/CN107569476A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101194920A (en) * | 2006-09-29 | 2008-06-11 | 杭州贺博生物技术有限公司 | Lithospermum and application of its active ingredient in preparing medicament for treating tumour stem cell |
| CN101474151A (en) * | 2009-01-21 | 2009-07-08 | 石河子大学医学院第一附属医院 | Alkannin microemulsion composition |
| CN106176703A (en) * | 2015-05-25 | 2016-12-07 | 中国医学科学院药物研究所 | Salvianolic acid A medicinal usage in preparation prevention and/or treatment pulmonary hypertension |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116148471A (en) * | 2022-11-01 | 2023-05-23 | 中南大学 | Biomarker for pulmonary arterial hypertension and application thereof |
| CN116148471B (en) * | 2022-11-01 | 2024-05-07 | 中南大学 | Biomarker for pulmonary arterial hypertension and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2002540144A (en) | Use of pyridoxine compounds for the treatment of cardiovascular and related pathologies | |
| SCHNECKLOTH et al. | Effects of serotonin antagonists in normal subjects and patients with carcinoid tumors | |
| CN108348481A (en) | Medicinal application of the dammara alkyl compound in treatment myocardial hypertrophy and pulmonary hypertension | |
| CN106177960B (en) | Angiotensin receptor antagonist and the compound of enkephalinase inhibitor and application thereof | |
| WO2021160192A2 (en) | Use of kaurane compounds in preparation of drug for prevention and treatment of sepsis and multiple organ failure | |
| CN104138377A (en) | A pharmaceutical composition treating severe high-altitude diseases | |
| JP6462147B2 (en) | HSP90 inhibitory peptide conjugate and its application in tumor therapy | |
| CN104906111B (en) | Pharmaceutical composition prepared from hydroxytyrosol for treating liver injury and preparation process of pharmaceutical composition | |
| TWI464147B (en) | Use of indolyl and indolinyl hydroxamates for treating heart failure or neuronal injury | |
| EP3777871A1 (en) | Traditional chinese medicine composition for preventing and/or treating ischemic reperfusion injury | |
| Letts et al. | Effects of intra-coronary administration of leukotriene D4 in the anaesthetized dog | |
| CN106474479B (en) | Angiotensin receptor antagonist and the compound of Creatine Phosphate Sodium and application thereof | |
| CN107569476A (en) | Pharmaceutical composition containing Acetylshikonin and its application in pulmonary hypertension medicine | |
| CN1997358A (en) | The use of kauranes compounds in the preparation of medicament | |
| Simonsen | Haemodynamic effects of ICI 118,587 in cardiomyopathy. | |
| CN103340844A (en) | Application of gamatine in preparing drug resisting high PTH | |
| CN109771411A (en) | Dihydroquercetin is used to prepare the purposes in the drug for the treatment of fatty liver | |
| JPS6129927B2 (en) | ||
| WO2021135665A1 (en) | Application of tetrahydrocannabivarin in prevention and/or treatment of pulmonary arterial hypertension | |
| Stone et al. | Study of the role of 5-hydroxytryptamine (serotonin) and histamine in the pathogenesis of pulmonary embolism in man | |
| CN112755015A (en) | Application of PT2385 in preparation of medicine for preventing and treating pulmonary hypertension | |
| Tang et al. | Saikosaponin A ameliorates inflammatory response by modulating P38MAPK pathway in rats with depression and myocardial ischemia | |
| CN103622985B (en) | The effect of amarogentin treatment pulmonary hypertension and application thereof | |
| TWI794847B (en) | Composition for reducing metabolic syndrome and application thereof | |
| CN103083323A (en) | Application of fasudil hydrochloride in preparation of medicament for promoting in-vivo survival and repair of mesenchymal stem cells and preparation of fasudil hydrochloride |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20180112 |
|
| WW01 | Invention patent application withdrawn after publication |