CN109364050A - Application of the Idebenone in preparation treatment pulmonary hypertension drug - Google Patents
Application of the Idebenone in preparation treatment pulmonary hypertension drug Download PDFInfo
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Abstract
The invention discloses application of the Idebenone in preparation treatment pulmonary hypertension drug.The invention belongs to biomedicine technical fields.The present invention constructs pulmonary hypertension disease rat model by monocrotaline (Monocrotaline) induction.By intraperitoneal injection Idebenone after, observe Rats of Pulmonary Hypertension model fur, diet, activity, death situations such as.As a result, it has been found that, Idebenone (shown in Formulas I), which has, significantly improves pulmonary hypertension animal pulmonary artery remodeling, mitigate right ventricle plumpness and right heart failure, the life quality (improving feed, inflow) for improving pulmonary hypertension animal, improves the effect of the survival rate of pulmonary hypertension animal.Therefore, proposition of the invention will make Idebenone have broad application prospects in terms of preventing and treating pulmonary hypertension disease.
Description
Technical field
The present invention relates to Idebenone (Idebenone, 6- (10-hydroxyindenyl) -2,3-dimethoxy-5-
Methyl-1,4-benzoquinone) a kind of new application, in particular to Idebenone is in preparation treatment pulmonary hypertension drug
Application.The invention belongs to biomedicine technical fields.
Background technique
Pulmonary hypertension (Pulmonary Artery Hypertension, PAH) i.e. pressure of pulmonary circulation is higher than normal disease
Reason state is the cardiovascular disease for being only second to coronary heart disease and hypertension.Most of patient will die of right heart failure in 2~3 years,
" cancer in cardiovascular disease " is known as by medical field.Since nearly 20 years, researcher develops some drugs successively makes patient's
Prognosis and Survival make moderate progress, however so far pulmonary hypertension still without effective cure method, can only temporarily delay or
Person prevents disease progression.
Anoxic be pulmonary hypertension morbidity major incentive, basic pathology process be anoxic Pulmonary Vascular shrink, reconstruct and
Adventitial fibrosis.Pulmonary artery remodeling includes that Pulmonary Vascular new life and pulmonary artery medial smooth muscle thicken, and Pulmonary Vascular new life is by pulmonary artery
Damage, pulmonary artery endothelial cell proliferation and migration cause, pulmonary artery thickening in the middle by Proliferation of Pulmonary Artery Smooth Muscle Cells excessively with
Apoptosis inhibitor causes, and leads to occlusive lesion, and pulmonary artery pressure and pulmonary vascular resistance increase, and right ventricular afterload increases,
It is even dead so as to cause right ventricle failure.Pulmonary artery remodeling is that the pathologic basis of PAH continuing disease progression and its drug are treated
Imitate the main reason for bad.
Mitochondria (mitochondria) is the main place that cell carries out biological oxidation and energy conversion, provides cell
80% of energy needed for vital movement, it plays a significant role in cell metabolism and physiological function.Substantially all PAH pathology mistakes
The participation of equal mitochondrial in journey.Under low oxygen conditions, the mitochondrial electron transport chain sense of arteria pulmonalis smooth muscle cells (PASMC)
By the decline of partial pressure of oxygen, the active oxygen in mitochondria source generates reduction, so as to cause the valtage-gated potassium on regulation plasma membrane from
Subchannel is open, and the calcium ion increased in final cytoplasm shrinks PASMC and then Pulmonary Vascular is caused to shrink.Meanwhile PAH patient
The Mitochondrial Shape of PASMC is abnormal, and mitochondrial function is suppressed.These are all prompted by correcting abnormalities or reactivating
Mitochondria may reverse the pathologic process of PAH.
Since the nineties in last century, with the understanding of pathogenesis and various pathways of drug action to pulmonary hypertension
With understanding, drug therapy is made great progress.During preventing and treating the occurrence and development of PAH, agents are answered in clinic
With: 1. calcium channel blocker, nifedipine, diltiazem and Amlodipine；2. prostacyclin and the like, vein according to
Forefront alcohol, subcutaneous injection formulation treprostinil, oral preparation shellfish prostacyclin suck preparation according to Lip river prostacyclin；3. endothelium
Hormone receptor antagonists Bosentan；4. inhaled nitric oxide (NO) or sublingual administration Isosorbide Nitrate；5. phosphodiesterase inhibits
Agent Dipyridmole, silaenafil etc..The invention of these drugs is played an important role in the treatment of current PAH with applying.
But it is very big that the side effect due to that can not overcome and expensive medical expense receive the clinical application of these therapeutic agents
Limitation.For example, calcium channel blocker can cause low blood pressure, ventilation-perfusion mismatch, Cardiac depression effect, patient it may also occur that
The adverse reactions such as headache, flushing, palpitaition；Prostanoid drug pharmacological properties are unstable, and it is red that part can be generated after subcutaneous injection
Rash occasionally has headache, nausea and diarrhea；Endothelial receptor antagonist will lead to male reproductive function atrophy or infertility, or occur potential
The side effects such as hepatotoxicity wind agitation, anaemia and oedema；It is of short duration to suck NO action time, only several minutes, needs one persistently to suck
Device just can be promoted clinically, and suck also genotoxic potential；The side effect of phosphodiesterase inhibitors includes head
Bitterly, nose is bleeding, cheek be red and indigestion etc..Therefore these existing drug therapy prospects and pessimistic, find new medicine
Object is current urgent problem to be solved.
Idebenone (Idebenone, 6- [10- hydroxydecyl] -2,3- dimethoxy -5- methyl-1,4- benzoquinones, 6-
[10-hydroxyindenyl] -2,3-dimethoxy-5-methyl-1,4-benzoquinone) it is a kind of mitochondria activation
Agent oppresses related central nervous system degenerative disease with oxidation clinically mainly used for treating, such as Parkinson's disease, A Erzi
The silent disease in sea, multi-infarct dementia, brain local anemia and cerebral senility etc., can improve the utilization rate of intracerebral glucose, promote ATP raw
At, have the function of compared with strong anti-oxidation and remove free radical.It may be simultaneously used in cosmetic formulations, have and remove freely
Base, anti-lipid peroxidation inhibit inflammation, inhibit DNA damage, light protection, mitigate the cosmetic industries such as pigmentation.This
Outside, there are also antitumor actions for Idebenone, but have not yet to see it and be used for pulmonary hypertension (Pulmonary Arterial
Hypertension, PAH) research report.
Effect of the present invention research Idebenone to pulmonary hypertension, the results showed that it is dynamic that the compound can be effectively improved lung
Arteries and veins high pressure animal pulmonary artery remodeling mitigates right ventricle plumpness and right heart failure, and the life quality for improving pulmonary hypertension animal (improves
Feed, inflow), the survival rate of pulmonary hypertension animal is improved, therefore can be used as the medicine of a kind of novel prevention and treatment pulmonary hypertension
Object, the prevention and treatment for pulmonary hypertension.
Summary of the invention
The object of the present invention is to provide Idebenone (Idebenone, 6- [10- hydroxydecyl] -2,3- dimethoxy -5-
Methyl-1,4- benzoquinones, 6- [10-hydroxyindenyl] -2,3-dimethoxy-5-methyl-1,4-benzoquinone)
In the application of prevention and treatment pulmonary hypertension disease.
Present invention employs following technological means in order to reach the goals above:
The present invention constructs pulmonary hypertension disease rat model by monocrotaline (Monocrotaline) induction.It is logical
Situations such as crossing after stomach-filling gives Idebenone, observing fur, the diet, activity, death of Rats of Pulmonary Hypertension model.As a result it sends out
Existing, Idebenone can significantly improve the reconstruct of monocrotaline-induced pulmonary hypertension Pulmonary Vessels in Rats, mitigate right ventricle plumpness and
Right heart failure improves the life quality (improving feed, inflow) of pulmonary hypertension animal, improves the existence of pulmonary hypertension animal
Rate, the i.e. present invention have found that Idebenone (Idebenone) has the function of preventing and treating pulmonary hypertension disease by research.
Therefore, on the basis of the studies above, the invention proposes Idebenones to treat pulmonary hypertension drug in preparation
In application, the chemical structural formula of the Idebenone (Idebenone) is shown in formula I:
Wherein, pulmonary artery remodeling and mitigation of preferred, described Idebenone by mitigation patients with pulmonary hypertension
The right ventricle plumpness of patients with pulmonary hypertension and right heart failure achieve the purpose that treat pulmonary hypertension.
Detailed description of the invention
Fig. 1 is blank group, Idebenone group, monocrotaline model group and monocrotaline+Idebenone treatment group not
With survival rate when number of days, illustrate that Idebenone can be improved the survival rate of pulmonary hypertension animal；
Fig. 2 is blank group, Idebenone group, monocrotaline model group and monocrotaline+Idebenone treatment group not
With rat right ventricular plumpness situation when number of days, illustrate that Idebenone can significantly improve Rats of Pulmonary Hypertension right ventricle fertilizer
It is thick；
Fig. 3 is blank group, Idebenone group, monocrotaline model group and monocrotaline+Idebenone treatment group not
With rats eating amount, inflow and the changes of weight figure when number of days, illustrate that monocrotaline causes rats eating, inflow gradually
Decline can significantly inhibit the weight loss of Rats of Pulmonary Hypertension, it is big to increase pulmonary hypertension after Idebenone medication treatment
The food-intake and inflow of mouse；
Fig. 4 is dynamic for blank group, Idebenone group, monocrotaline model group and monocrotaline+Idebenone treatment group lung
Arteries and veins high pressure rat right ventricular pressure compares, and illustrates that Idebenone can reduce Rats of Pulmonary Hypertension right ventricular pressure；
* P < 0.01vs blank group；##P < 0.01vs monocrotaline model group；
Fig. 5 is that blank group, Idebenone group, monocrotaline model group and monocrotaline+Idebenone treatment group are typical
Lung thin vessels cross-sectional picture, show that Idebenone can significantly improve Rats of Pulmonary Hypertension pulmonary artery remodeling.
Specific embodiment
Further describe the present invention below with reference to specific example, the advantages and features of the present invention will be with description and more
It is clear.But these examples be only it is exemplary, it is not intended to limit the scope of the present invention in any way.Those skilled in the art answer
It should be appreciated that without departing from the spirit and scope of the invention can details to technical solution of the present invention and form repair
Change or replace, but these modifications and replacement are fallen within the protection scope of the present invention.
Application of 1 Idebenone of embodiment in treatment pulmonary hypertension
1. animal and experiment reagent:
Rat (strain: Wistar, Beijing Vital River Experimental Animals Technology Co., Ltd.'s purchase), monocrotaline
(Monocrotaline, Shanghai Yuan Mu Biotechnology Co., Ltd).
2. the foundation of monocrotaline-induced pulmonary hypertension model:
Healthy Wistar male rat 60 (160-200 grams of weight) is randomly divided into two groups according to weight homeostatic principle, i.e.,
Experimental group and control group are all raised in standard sterile feeding environment.Control rats are randomly divided into according to weight homeostatic principle
Two groups, i.e. blank group (isometric physiological saline, stomach-filling method with Idebenone group) and Idebenone group (Idebenone
200mg/kg/ days, stomach-filling method).Experimental group rats by intraperitoneal injection monocrotaline 60mg/kg is primary, after 21 days, by weight equilibrium
Principle divides 2 groups at random again, and respectively monocrotaline model group is (with monocrotaline+isometric physiology salt of Idebenone treatment group
Water, stomach-filling method) and monocrotaline+Idebenone treatment group (Idebenone 200mg/kg/ days, stomach-filling method).Observation fur,
The situations such as diet, activity, death.
The dirty and left lung of coring carries out 4% pair of polyformaldehyde and fixes, remaining lobe of the lung carries out freezing processing.Fixed heart and lung into
Row pathological staining.
3. result
The survival rate of 3.1 Idebenones raising pulmonary hypertension animal
After monocrotaline is injected 24 days, Idebenone drug treatment is carried out, each group is denoted as 0 day with this time point, Log-
Rank (Mantel-Cox) examines the survival rate (P=of different number of days pulmonary hypertension animal after display Idebenone administration
0.005)。
By the study found that the pulmonary hypertension animal that monocrotaline induces, extend successively with feeding time occur it is dead,
To injection monocrotaline 60 days, the monocrotaline model group death rate is up to 73%, and monocrotaline+Idebenone treatment group (ends
Ground benzoquinones, 30mg/kg/ days, intraperitoneal injection) death rate is only 33%, illustrate that pulmonary hypertension animal can be improved in Idebenone
Survival rate, as a result as shown in Figure 1.
It is plump that 3.2 Idebenones can significantly mitigate Rats of Pulmonary Hypertension right ventricle
The study found that the Rats of Pulmonary Hypertension that monocrotaline induces is gradually dead, draw materials, ties to dead rat
The significant right ventricular hypertrophy of animal phenotype of fruit discovery materials, Right ventricular hypertrophy index (right heart weight/Zuo Xinchong+interventricular septum) significantly increase
Add, and increased Right ventricular hypertrophy index is significantly suppressed after Idebenone medication treatment, as a result as shown in Figure 2.Illustrate Chinese mugwort ground benzene
Quinone can significantly mitigate Rats of Pulmonary Hypertension right ventricle plumpness, can correct right heart failure.
3.3 Idebenones can significantly improve the life quality of Rats of Pulmonary Hypertension
The study found that monocrotaline induces Pulmonary Hypertension, extends rat with feeding time and not only occur successively extremely
It dies, and the weight of rat is gradually reduced during the feeding process, feed, inflow are also gradually reduced.Energy after Idebenone treatment
Weight loss is enough significantly inhibited, dramatically increases feed and the inflow of rat, as a result as shown in Figure 3.
3.4 Idebenones can effectively reduce Rats of Pulmonary Hypertension right ventricular pressure
The visible right ventricular pressure of monocrotaline-induced pulmonary hypertension model significantly increases.Monocrotaline+Idebenone is controlled
Treatment group compares monocrotaline model group, and right ventricular pressure increases situation and can significantly mitigate, as a result as shown in Figure 4.
3.5 Idebenones can significantly improve Rats of Pulmonary Hypertension pulmonary artery remodeling
Monocrotaline-induced pulmonary hypertension model can lead to pulmonary artery remodeling.Monocrotaline+Idebenone treatment group phase
Than monocrotaline model group, Rats of Pulmonary Hypertension pulmonary artery remodeling situation is significantly improved, as a result as shown in Figure 5.
Claims (2)
1. application of the Idebenone in preparation treatment pulmonary hypertension drug, Idebenone (Idebenone, the 6-
[10- hydroxydecyl] -2,3- dimethoxy -5- methyl-1,4- benzoquinones, 6- (10-hydroxyindenyl) -2,3-
Dimethoxy-5-methyl-1,4-benzoquinone chemical structural formula) is shown in formula I:
2. application as described in claim 1, it is characterised in that: the Idebenone is by mitigating patients with pulmonary hypertension
Pulmonary artery remodeling and mitigate patients with pulmonary hypertension right ventricle plumpness and right heart failure come reach treatment pulmonary hypertension mesh
's.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117378563A (en) * | 2023-09-08 | 2024-01-12 | 广州市妇女儿童医疗中心 | Construction method and application of pulmonary artery high-pressure animal model |
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| WO2009124693A1 (en) * | 2008-04-09 | 2009-10-15 | Santhera Pharmaceuticals (Schweiz) Ag | Quinone derivative 2,3-dimethoxy-5-methyl-6-(10-hydroxydecyl)-1,4-benzoquinone for the treatment of respiratory illness in muscular dystrophy |
| WO2012098281A2 (en) * | 2011-01-19 | 2012-07-26 | Universidad Miguel Hernández De Elche | Trp-receptor-modulating peptides and uses thereof |
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