CN108310369A - A kind of drug delivery system for percutaneous coronary intervention (pci) - Google Patents
A kind of drug delivery system for percutaneous coronary intervention (pci) Download PDFInfo
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Abstract
The invention discloses a kind of drug delivery systems for percutaneous coronary intervention (pci) comprising：Adenosine；Infusion consumptive material for infusion；For being catalyzed excessive adenosine metabolism in body and activating the adenosine kinases of downstream AMPK accesses；Infusion consumptive material for infusion kinases.The drug delivery system can reduce the adenosine delay after the percutaneous coronary intervention (pci) of adenosine kinase mutation or the insufficient patient of activity, increase adenosine kinase activity and improve the myocardial reperfusion protective effect of adenosine to reduce myocardial reperfusion injury.
Description
Technical field
The invention belongs to field of medicaments, and in particular to a kind of suitable for the percutaneous of adenosine kinase mutation or the insufficient crowd of activity
The drug delivery system of percutaneous coronary intervention, more particularly to one kind being suitable for adenosine kinase mutation or the insufficient Acute myocardial of activity
The adenosine of Infarction Patients percutaneous coronary intervention (pci) and adenosine kinase administering drug combinations system.
Background technology
Acute myocardial infarction AMI (AMI) is a kind of serious angiocardiopathy, percutaneous coronary intervention (pci)
(percutaneous coronary intervention, PCI) have become treatment AMI important minimally-invasive treatment mode it
One, clinical studies show restores lesion myocardial blood flow for AMI patient as early as possible, can effectively reduce myocardial necrosis, prevent ventricle weight
Structure reduces arrhythmia cordis incidence and improves patient's long term prognosis heart function, reduces AMI patient's case fatality rate on the whole.But it grinds
Study carefully while confirming, can be by new ischemical reperfusion injury after the ischemic myocardium of PCI treatments restores Reperfu- sion, the damage is not only
Make the myocardial necrosis that part ischemic is survived and lose activity, additionally it is possible to involve the normal health cardiac muscle of preoperative supply of blood flow.Ischemic
Reperfu- sion (Ischemia/Reperfusion, I/R) damage has seriously affected PCI therapeutic effects, and can be in patient's cardiac muscle
Leave damage hidden danger.
Adenosine (adenosine, Ad) is a kind of endogenous purine nucleoside acid, by glucosides key connection adenine and ribose
At it is the precursor of adenylate, and is its metabolite.Classical theory thinks that adenosine mainly passes through internal a variety of adenosine receptors
Modulating vascular function, this has myocardial ischemia-reperfusion injury positive therapeutic potential.Adenosine treatment mode before is
It is pumped into through coronary artery mouth, 60 μ g/min (arteria coronaria dextra) or 90 μ g/min (arteria coroaria sinistra).Concrete operations are：It is coronal in target
Artery uses microtubular, and by guiding steel wire to reach the distal end of target coronary, adenosine is first dissolved in life before PCI Reperfu- sions
Brine (being commonly used for 20mg adenosine+50ml physiological saline) is managed, then with the rate infusion 10min of 2mg/min.Complete infusion recession
Go out microtubular, steel wire will be guided to enter target vessel again after 10min and become area, complete PCI reperfusion as treatment.But the adenosine of single component
When some patientss are treated, there are severe sinus bradycardia, sinus arrest or atrioventricular blocks etc. for treatment, this is imitated with adenosine
Fruit is detained related, another aspect, and the reduction of some patientss adenosine kinase activity influences adenosine metabolism, the adenosine treatment of single component
Myocardial reperfusion protective effect can not be played completely.
Invention content
In order to overcome the problems, such as that above-mentioned single component adenosine treatment causes many drawbacks, inventor is for adenosine in body
Physiological metabolism path has made intensive studies, it has unexpectedly been found that adenosine kinase (adenosine kinase, ADK) can be significantly
Intervene and adjust physiological metabolism of the adenosine in body, and new function can also be generated.The study found that adenosine kinase is in body
The interior main effect for playing catalysis adenosine metabolism as adenosine-phosphoric acid, can be with the excessive adenosine of rapid metabolization, and activates downstream
AMPK accesses, the latter play an important role in myocardial ischemia-reperfusion.Meanwhile ADK can influence machine by being metabolized adenosine
Body cell DNA methylation is horizontal, has great significance disease prognosis (referring to Fig. 1), for example Acute myocardial is obstructed and is suffered from
The dead percutaneous coronary intervention (pci) of person, passes through the administering drug combinations of adenosine kinase and adenosine, it is possible to expand treatment indication
Crowd especially increases adenosine kinase mutation or the insufficient crowd of activity.This new discovery constitutes the basis of the present invention.Therefore,
The purpose of the present invention is to provide a kind of adenosines for percutaneous coronary intervention (pci) and adenosine kinase drug delivery system.Specifically
For, it is described that technical scheme is as follows.
A kind of drug delivery system for percutaneous coronary intervention (pci) comprising：Adenosine；Infusion for infusion
Consumptive material；For being catalyzed excessive adenosine metabolism in body and activating the adenosine kinases of downstream AMPK accesses；For infusion
The infusion consumptive material of kinases, the drug delivery system is mutated for adenosine kinase or the insufficient crowd of activity.
In one embodiment, the adenosine kinase is people's recombinant adenosine kinases (or recombined human adenosine kinase).
It is preferred that people's recombinant adenosine kinases is people's recombinant adenosine kinases PKA-367 of ProSpec companies of Israel.
In another preferred embodiment, drug delivery system further includes the life for being respectively used to dissolving adenosine and adenosine kinase
Manage brine.
Optionally, the solution concentration that adenosine is dissolved in physiological saline is 0.4mg/ml；And/or adenosine kinase is dissolved in physiology
The solution concentration of brine is 100 μ g/ml.
In a preferred embodiment, infusion consumptive material is microtubular, more preferably carries the microtubular for guiding steel wire.
Above-mentioned drug delivery system is suitable for the patients of acute myocardial infarction or convulsion of adenosine kinase mutation or the insufficient crowd of activity
Contraction patients with coronary heart disease.
When stating drug delivery system in use, after adenosine infused, then infusion kinases.
Preferably, after adenosine infused, the then infusion kinases in same blood vessel pathway.
In a preferred embodiment, the administering mode of above-mentioned drug delivery system is：It is used in target coronary micro-
Conduit, administering mode are：Target coronary use microtubular, 20mg adenosines are dissolved in 50ml physiological saline, then with
The rate infusion 10min of 2mg adenosines/min withdraws from the infusion consumptive material for infusion after completing infusion；In same blood vessel diameter
100 μ g/ml adenosine kinase normal saline solutions are transfused with the usage amount of 1 μ g/kg weight in road.
In a preferred embodiment, above-mentioned drug delivery system is a kind of kit (kit), that is, is rendered as a kind of administration
Kit form.
When above-mentioned drug delivery system is rendered as a kind of kit, it includes be packaged in container such as sealing bottle or sealing
Adenosine in pipe, for infusion consumptive material, the adenosine kinase of infusion, for the infusion consumptive material of infusion kinases.
Experiment in vitro proves, drug delivery system provided by the invention can reduce adenosine kinase mutation or the insufficient crowd of activity
Adenosine after the percutaneous coronary intervention (pci) of patients of acute myocardial infarction is detained, and increases adenosine kinase activity, improves adenosine
Metabolism, to reduce myocardial reperfusion injury, improves the myocardial reperfusion protective effect of adenosine.
Description of the drawings
Fig. 1 is the internal adenosine metabolism schematic diagram that adenosine kinase mediates.Abbreviation therein and the correspondence of full name are：
SAM, S- adenosylmethionine；DNMT, DNA methylation transferase；SAH, AdoHcy；CH3, methyl base
Group；ADK, adenosine kinase；AMP, adenosine-phosphoric acid；The protein kinase that AMPK, AMP are relied on.
Myocardial slices TTC/Evans indigo plants contaminate after Fig. 2 shows the mouse ischemia-reperfusion of percutaneous coronary intervention (pci)
Color photo.Abbreviation therein and the correspondence of mice group full name are：WT+I/R, ischemia-reperfusion wild-type mice group；
ADK-Cre+I/R, Myocardial Ischemia-reperfusion ADK specific knockdown type mouse；WT+I/R+Ad, ischemia-reperfusion simultaneously receive adenosine
The wild-type mice group for the treatment of；ADK-Cre+I/R+Ad, ischemia-reperfusion and the myocardium ADK specific knockdowns for receiving adenosine treatment
Type mouse；WT+I/R+Ad+ADK, ischemia-reperfusion and the wild-type mice group for receiving adenosine+ADK supplementary therapys；ADK-Cre+
I/R+Ad+ADK, ischemia-reperfusion and the myocardium ADK specific knockdowns type mouse for receiving adenosine+ADK treatments.
Fig. 3 corresponds to the infarct size ratio (Infarction of cardiac muscle TTC/Evans indigo plant stained photographs shown in Fig. 2
Area ratio) column diagram.
Specific implementation mode
The present invention is described in further details below in conjunction with specific embodiment.It should be understood that following embodiment is only used for
The bright present invention is not for restriction the scope of the present invention.
The activity of adenosine kinase (ADK) can influence a variety of pathologic, physiologic phenotypes and disease of body with expression in human body
Disease, including sleep rhythm disorder, congenital hepatic dysfunction, epilepsy, alzheimer's disease and Parkinson's disease etc..DECIFER numbers
It is shown according to library, the haploinsufficiency phenomenon of ADK gene mutations comes out at the top in all gene rankings, i.e. mono- equipotential of ADK
After gene mutation, although another allele energy normal expression, this only has the ADK expression of normal level 50% to be not enough to tie up
Hold the normal physiological function of cell.Meanwhile have researches show that ADK mutation mostly to copy number variation (Copy number
Variation, CNV) it is main feature, by genetics research in recent years, educational circles thinks that ADK gene orders at least have 5
Its activity or expression can be caused to reduce to 10 CNV, for example, there is Japanese team to be found that ADK bases in 1699 patients in the recent period
Because of the new CNV mutation of an example, which can also arrive to ADK to express and reduce.In addition, ADK also has SNP mutation, such as
AK1rs1109374T>C mutated-genotypes are up to 30% in crowd's ratio, and the mutation is likely to related to the reduction of ADK activity.
In addition to intrinsic gene mutation, many patients can because the day after tomorrow obtain new factor occur ADK activity or expression reduce, it is known that factor
Including history of medications (virazole etc.), cranial vascular disease, diabetes etc..Therefore many treatment means for being suitable for common patient
It is not applied for adenosine kinase mutation or the insufficient crowd of activity, how to improve this kind of special population for conventional therapy means
Applicability is a the technical issues of must solving.Based on the discovery of the present invention, by the way that ADK is administered to extraly this kind of special population
Perhaps it can become solution route, be not restricted to the percutaneous coronary intervention (pci) of acute myocardial infarction AMI.
We are had found by the administration contrast test of Cardiac-specific ADK knock-out mices：The cardiac muscle of ADK missings cannot respond to
The percutaneous coronary intervention (pci) effect of single adenosine, again using single adenosine and without using the myocardial ischemia caused by adenosine
Without significant difference, i.e. the mouse of ADK missings is not necessarily to carry out the treatment of adenosine perfusion injury；But it being capable of active response adenosine
The administering drug combinations of the percutaneous coronary intervention (pci) of+ADK supplements, adenosine kinase and adenosine can be substantially reduced myocardial ischemia again
Perfusion injury, it was demonstrated that ADK can play significant ischemical reperfusion injury protective effect.On the other hand, the heart of wild-type mice
Flesh can respond the percutaneous coronary intervention (pci) effect of single adenosine, and myocardial ischemia can be reduced using single adenosine treatment
Reperfusion injury.
For the sake of statement conveniently, in embodiment for experiment mice, abbreviation WT represents wild type, and I/R represents ischemic again
It is perfused (Ischemia/Reperfusion), Ad represents adenosine, and ADK represents adenosine kinase, and it is special that ADK-Cre represents cardiac muscle ADK
Property knockout type.Correspondingly, Ad+ADK represents adenosine kinase and adenosine administering drug combinations.
In embodiment, wild-type mice (WT) represent adenosine kinase do not mutate, adenosine kinase activity it is normal, be with
ADK specific knockdowns (missing) type mouse (ADK-Cre) opposed model, the latter represent adenosine kinase mutation or activity not
Foot.
In the administering drug combinations system of adenosine kinase and adenosine, the dosage of adenosine is effective therapeutic dose, can refer to conventional control
Treat dosage.It can be adjusted flexibly according to treatments factors such as the constitution of administration object, weight, age, patient's condition processes.Such as
20mg adenosines, can be dissolved in 50ml physiological saline, then with 2mg glands by the acute myocardial infarction AMI adult patients of common weight
The rate infusion 10min of glycosides/min.
Correspondingly, the dosage of adenosine kinase should ensure that adenosine kinase is effectively catalyzed excessive adenosine generation in body
It thanks and activates downstream AMPK accesses.Specific adenosine kinase dosage can according to the type of adenosine kinase, source, unit of activity,
The treatments factors such as constitution, weight, age, the patient's condition process of administration object are adjusted flexibly.Such as the acute of common weight
Myocardial infarction adult patients can be with when adenosine kinase is the people recombinant adenosine kinases PKA-367 of ProSpec companies of Israel
Consider the usage amount of 1 μ g/kg weight.
The present invention drug delivery system in, for infusion infusion consumptive material can with for the defeated of infusion kinases
Note consumptive material is identical, for example is all microtubular, especially with the microtubular for guiding steel wire.But the two cannot be same, to keep away
Exempt from there is adenosine to remain in infusion consumptive material, causes adenosine kinase catalysis adenosine reaction conversion to influence therapeutic effect.
Herein, term " percutaneous coronary intervention (pci) ", " PCI ", " PCI treatments ", " PCI Reperfu- sions " or
" PCI reperfusion as treatment " can be interchanged, and the meaning that they are indicated is identical with range.
When the drug delivery system of the present invention is rendered as a kind of kit, such as sealed including at least container is packaged in
Adenosine in bottle or seal pipe, the infusion consumptive material for infusion, adenosine kinase, the infusion consumption for infusion kinases
Material.It is preferred that the kit is also packaged in the physiological saline in container such as sealing bottle or seal pipe, for dissolving respectively
They are configured to the solution of normal concentration by adenosine and adenosine kinase respectively.Obviously, kit can also include graduated cylinder.
Preferably, kit carries the label for being attached to container or being included in packaging, for listing each group respectively
At the information of part, scanning window such as bar code or Quick Response Code can be equipped on these labels.
Certainly, in the specification of description kit application method is also included within, wherein specification can be paper, e.g.
The paper of window such as Quick Response Code is downloaded with operation demonstration video APP；Specification can also be multimedia form, such as
CD, compact disk, USB flash disk etc..
In order to make the present invention more obvious and understandable, hereby with preferred embodiment, and attached drawing is coordinated to be described in detail below.This field skill
Art personnel should be appreciated that following embodiments are only used for illustrating the present invention, not limit the invention.
The percentage composition arrived involved in embodiment all refers to mass percentage unless otherwise indicated.
Embodiment
Cardiac-specific ADK knockouts type (ADK-Cre) acute myocardial infarction in mice model used in experiment is big by Fudan University
Learn attached Zhong Shan hospitals animal experimental center structure；Wild-type mice (WT) ami model by Fudan University it is attached in
Mountain hospital animal experimental center provides；Adenosine is purchased from Sigmag companies of the U.S., article No. A9251-100G；People's recombinant adenosine kinases
Purchased from ProSpec companies of Israel (PKA-367, Adenosine 5'-phosphotransferase, EC 2.7.1.20, AK,
ADK.)；Physiological saline is provided by centers for making of pharmaceutical preparations of Zhongshan Hospital Attached to Fudan Univ.
The structure of 1 mouse model of embodiment
1.1 experimental animal
ADK-Cre mouse (ADK-Cre) mouse of preparation 8-10 week old bulls C57BL/6, weight 24.5g ±
0.8g；Prepare 8-10 week old bull C57BL/6 mouse (Wildtype, WT) mouse, weight 24.2g ± 1.1g, as right
According to group.Cardiac-specific ADK knockouts type (ADK-Cre) acute myocardial infarction in mice model used in experiment is attached by Fudan University
The mountains Shu Zhong hospital animal experimental center structure；Wild-type mice (WT) ami model is cured by the attached middle mountain of Fudan University
Institute's animal experimental center provides, and the mouse purchased voluntarily is raised in the attached public health clinical center SPF animal houses of Fudan University,
It is raised in experimentation in Experimental Animal Center SPF grades of animal house of Zhongshan Hospital Attached to Fudan Univ, circadian rhythm rule, often
Diet is advised, mouse adapts to living environment and starts every intervention after 3 days, freely ingests and drink water.
1.2 mouse cardiac muscle ischemia-reperfusion injury models
This experiment mice myocardial infarction model is completed using " the crowded heart of no trachea cannula " art formula, and specific steps include：
1) mouse is placed in isoflurane anesthesia induction case and handles to deep anaesthesia；
2) mouse is taken out, is placed at surgery anesthesia mouse mask, pareordia depilation, and fixed mouse four limbs；
3) operation opening at three or four intercostal space of pareordia, blunt separation musculature expose at apex beat；
4) right hand breaks through three or the four intercostal space wall of the chest using needle holder, and left hand overstocks thoracic cavity to heart and is completely exposed to the wall of the chest
Outside, direct-view mouse heart ligatures heart left anterior descending branch coronary artery using 6-0 operation suture thread slip-knots, and outside indwelling the end of a thread and thorax；
5) unclamp left hand, also received and thoracic cavity using needle holder guiding heart, overstock thoracic cavity be discharged air that may be present with
Anti- pneumothorax；
6) it uses 4-0 operation suture threads to close operation on chest wall to be open, and uses mouse Ecg myocardial infarction model
Whether succeed, if model success, mouse lead electrocardiogram will appear apparent ST section and raise phenomenon, confirm after model succeeds in
Pull slip-knot the end of a thread after 45min completes ischemia-reperfusion injury model, retains Mouse feeder in case subsequent experimental.
2 percutaneous coronary intervention (pci) of embodiment
Myocardial ischemia-reperfusion (I/R) is shown in the step in embodiment 1, is carried with the patent wherein simulating traditional adenosine injection
The adenosine gone out+steps are as follows for adenosine kinase percutaneous coronary intervention (pci)：
(1) traditional adenosine injection
In embodiment 1 6) before step " pull slip-knot the end of a thread ", through mouse tail vein injection adenosine solution.Wherein 20mg glands
Glycosides is dissolved in formation adenosine solution in 50ml physiological saline.
(2) adenosine+adenosine kinase injection
In embodiment 1 6) before step " pull slip-knot the end of a thread ", through mouse tail vein injection adenosine solution.Then same
Pathway injection 100 μ g/ml people's recombinant adenosine kinases normal saline solutions of infusion, dosage is 1 μ g/kg weight.
3 mouse model anatomy experiment of embodiment
3.1 Evan indigo plants/TTC dyeing theories：
Evans can enter in coronary artery un-ligatured in coronary vasculature after coronary artery is paid close attention to, and be dyed to normal myocardium, and
Ischemic region blocks because of coronary artery without will present blue；
As fat-soluble photaesthesia compound, TTC (2,3,5-triphenyltetrazolium chloride) is pyridine-core in respiratory chain
The proton acceptor of glycosides structure enzyme system takes on a red color with the dehydrogenase reaction in normal structure, and Dehydrogenase activtity in ischemic tissue
Property decline, cannot react, therefore not will produce variation in pale.
3.2 TTC solution are prepared：
①0.1M Na2HPO4:14.2mg is dissolved in 1L distilled waters；
②0.1M NaH2PO4:12mg is dissolved in 1L distilled waters；
3. mixing 1. with 2. solution, it is titrated to pH7.4；
4. 1g TTC powder to be dissolved in the 3. solution of 100ml.
3.3 Evans indigo plant solution are prepared：
1g Evans blue powders end is dissolved in 100ml distilled waters；
3.4 Evan indigo plants/TTC staining procedures：
1. mouse blood is rinsed through the left apex of the heart using physiological saline, in the same injection orifice injection 2 of the left apex of the heart to 3ml volumes
1%Evans is blue, and normal myocardium in blue, do not dye by danger zone；
2. isolated heart is rinsed repeatedly with physiological saline, it is main to handle remaining Evans indigo plants solution in the chambers of the heart, be placed in-
80 DEG C of liquid nitrogen containers are rapidly frozen, laterally to cut off top atrial tissue from non-infarcted region at the top 1mm of heart ligation point；
3. ischemic region ventricular muscles are cut into 4 to be parallel to the direction of coronary sulcus, every 1~2mm of thickness.It is placed in 1% chlorination
In triphenyltetrazolium chloride (TTC) phosphate buffer (pH7.4), 37 DEG C of water-baths keep the temperature 10~15min；
4. slice is dissolved in 37% paraformaldehyde solution, fixed overnight, taken pictures using the camera of Japanese Nikon companies, as a result
See Fig. 2；
5. row infarct size detects after being fixed to stained slice using Image J softwares, Fig. 3 is as a result seen.
4 interpretation of result of embodiment
Two kinds of acute myocardial infarction AMI mouse model ADK-Cre and WT carry out adenosine (Ad) percutaneous coronary intervention (pci)s and
Carry out the myocardial ischemia-reperfusion injury stained photographs after adenosine+adenosine kinase (Ad+ADK) percutaneous coronary intervention (pci) such as
Shown in Fig. 2.For infarct size ratio statistical result (the * P ＜ 0.05vs WT+I/R of myocardium TTC/Evans indigo plants stained photographs；#
P ＜ 0.05vs ADK-Cre+I/R+Ad) as shown in Figure 3.
Referring to Fig. 2, first row is that the myocardium TTC/Evans indigo plants dyeing of ischemia-reperfusion wild-type mice group WT+I/R is shone
Piece；Second row is the myocardium TTC/Evans indigo plants dyeing of Myocardial Ischemia-reperfusion ADK specific knockdown type mouse ADK-Cre+I/R
Photo；Third row is ischemia-reperfusion and receives the myocardium TTC/Evans indigo plants of the wild-type mice group WT+I/R+Ad of adenosine treatment
Stained photographs；4th row is ischemia-reperfusion and receives the myocardium ADK specific knockdowns type mouse ADK-Cre+I/R of adenosine treatment
The myocardium TTC/Evans indigo plants stained photographs of+Ad；5th row is ischemia-reperfusion and receives the wild type of adenosine+ADK supplementary therapys
The myocardium TTC/Evans indigo plants stained photographs of mouse group WT+I/R+Ad+ADK；6th row is ischemia-reperfusion and receives adenosine+ADK
The myocardium TTC/Evans indigo plants stained photographs of the myocardium ADK specific knockdowns type mouse ADK-Cre+I/R+Ad+ADK for the treatment of.
Photo shows that the myocardial infarction area ratio of WT+I/R is the myocardial infarction area of 29.53%, ADK-Cre+I/R
Ratio is 40.26%, is shown compared with wild-type mice, and ADK missings can significantly aggravate myocardial ischemia-reperfusion injury.
The myocardial infarction area ratio of WT+I/R is that the myocardial infarction area ratio of 29.53%, WT+I/R+Ad is
18.97%, show that adenosine treatment can significantly reduce myocardial ischemia-reperfusion injury before giving wild-type mice Reperfu- sion.
The myocardial infarction area ratio of ADK-Cre+I/R is the myocardial infarction area ratio of 40.26%, ADK-Cre+I/R+Ad
Rate is 38.73%, that is, compared with the ADK depleted mices for not receiving adenosine treatment, the ADK depleted mice cardiac muscles of adenosine treatment lack
Blood reperfusion injury area shows that the cardiac muscle of ADK missings cannot respond to adenosine treatment without significant changes.
The cardiac muscle stalk that the myocardial infarction area ratio of ADK-Cre+I/R+Ad is 38.73%, ADK-Cre+I/R+Ad+ADK
Dead area ratio is 30.54%, shows that the heart lacked for ADK supplements ADK on the basis of adenosine treatment and can play significantly
Ischemical reperfusion injury protective effect, that is, the percutaneous coronary intervention (pci) of Ad+ADK is capable of effective protection ADK missing
Heart.
On the other hand, for wild-type mice, the myocardial infarction area ratio of WT+I/R is 29.53%, WT+I/R+
The myocardial infarction area ratio that the myocardial infarction area ratio of Ad is 18.97%, WT+I/R+Ad+ADK is 26%, is shown wild
Adenosine treatment can significantly reduce myocardial ischemia-reperfusion injury before type reper-fusion, and the cardiac muscle of wild-type mice can respond
The percutaneous coronary intervention (pci) of single adenosine can reduce myocardial ischemia-reperfusion injury using single adenosine treatment；
But the combination therapy effect of adenosine kinase+adenosine is not so good as to use single adenosine treatment instead, it appears that shows that adenosine kinase is not sent out
Raw mutation, the normal average individual of adenosine kinase activity use adenosine kinase ADK there is no necessary complement, reason up for into
One step is furtherd investigate.
Above-mentioned experimental result shows that adenosine provided by the invention+adenosine kinase administering drug combinations system can reduce adenosine and swash
Myocardial reperfusion injury after the percutaneous coronary intervention (pci) of the patients of acute myocardial infarction of enzyme mutant or the insufficient individual of activity,
The myocardial reperfusion protective effect of adenosine is improved, thus suitable for the percutaneous coronary intervention (pci) of acute myocardial infarction AMI.
Claims (10)
1. a kind of drug delivery system for percutaneous coronary intervention (pci) comprising：Adenosine；Infusion for infusion consumes
Material；For being catalyzed excessive adenosine metabolism in body and activating the adenosine kinases of downstream AMPK accesses；Swash for infusion
The infusion consumptive material of enzyme, the drug delivery system is mutated for adenosine kinase or the insufficient crowd of activity.
2. drug delivery system as described in claim 1, which is characterized in that the adenosine kinase is people's recombinant adenosine kinases.
3. drug delivery system as described in claim 1, which is characterized in that the adenosine kinase is ProSpec companies of Israel
People's recombinant adenosine kinases PKA-367.
4. drug delivery system as claimed in claim 1 or 2, which is characterized in that further include be respectively used to dissolving adenosine and adenosine swash
The physiological saline of enzyme.
5. drug delivery system as claimed in claim 4, which is characterized in that the solution concentration that adenosine is dissolved in physiological saline is 0.4mg/
ml；The solution concentration that adenosine kinase is dissolved in physiological saline is 100 μ g/ml.
6. drug delivery system as described in claim 1, which is characterized in that the infusion consumptive material is led with guide the micro- of steel wire
Pipe.
7. drug delivery system as described in claim 1, which is characterized in that for adenosine kinase mutation or the urgency of the insufficient crowd of activity
Property myocardial infarction patient or spastic patients with coronary heart disease.
8. drug delivery system as claimed in claim 7, which is characterized in that after adenosine infused, then infusion kinases.
9. drug delivery system as claimed in claim 7, which is characterized in that administering mode is：It is led using micro- in target coronary
Pipe, 20mg adenosines are dissolved in 50ml physiological saline, then with the rate infusion 10min of 2mg adenosines/min, complete infusion recession
Go out the infusion consumptive material for infusion；100 μ g/ml adenosines are transfused with the usage amount of 1 μ g/kg weight in same blood vessel pathway
Kinases normal saline solution.
10. drug delivery system as described in claim 1, which is characterized in that be a kind of kit.
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| CN1938285A (en) * | 2004-03-02 | 2007-03-28 | 坎皮纳斯国立大学 | 4-anilinequinazolines with adenosine-kiase inhibitor properties |
| CN101062420A (en) * | 2006-04-25 | 2007-10-31 | 沈阳守正生物技术有限公司 | Pharmacodynamics experiment method of adenosine medicine |
| US20090130092A1 (en) * | 2007-10-30 | 2009-05-21 | Pinsky David J | Nucleotide phosphate dissipation as a treatment for vascular disorders |
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| CN1938285A (en) * | 2004-03-02 | 2007-03-28 | 坎皮纳斯国立大学 | 4-anilinequinazolines with adenosine-kiase inhibitor properties |
| CN101062420A (en) * | 2006-04-25 | 2007-10-31 | 沈阳守正生物技术有限公司 | Pharmacodynamics experiment method of adenosine medicine |
| US20090130092A1 (en) * | 2007-10-30 | 2009-05-21 | Pinsky David J | Nucleotide phosphate dissipation as a treatment for vascular disorders |
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