CN107569509B - The purposes of xenon or xenon-133 gas mixture in the preparation for preparing treatment epilepsy - Google Patents
The purposes of xenon or xenon-133 gas mixture in the preparation for preparing treatment epilepsy Download PDFInfo
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- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 0.000 title claims abstract description 74
- 229910052724 xenon Inorganic materials 0.000 title claims abstract description 73
- 206010015037 epilepsy Diseases 0.000 title claims abstract description 64
- 238000011282 treatment Methods 0.000 title claims abstract description 21
- 239000000203 mixture Substances 0.000 title claims abstract description 13
- FHNFHKCVQCLJFQ-NJFSPNSNSA-N Xenon-133 Chemical compound [133Xe] FHNFHKCVQCLJFQ-NJFSPNSNSA-N 0.000 title claims abstract description 10
- 229940106670 xenon-133 Drugs 0.000 title claims abstract description 10
- 230000004900 autophagic degradation Effects 0.000 claims abstract description 11
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- 230000002401 inhibitory effect Effects 0.000 claims abstract description 5
- 210000004027 cell Anatomy 0.000 claims abstract description 4
- 230000000803 paradoxical effect Effects 0.000 claims abstract description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 239000007789 gas Substances 0.000 claims description 13
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 12
- 239000001301 oxygen Substances 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 230000002708 enhancing effect Effects 0.000 claims description 3
- 238000010248 power generation Methods 0.000 claims description 3
- 239000003814 drug Substances 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 5
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- 206010059866 Drug resistance Diseases 0.000 abstract description 3
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- 238000012545 processing Methods 0.000 description 22
- 241001465754 Metazoa Species 0.000 description 16
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- 230000001154 acute effect Effects 0.000 description 12
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- 230000006698 induction Effects 0.000 description 9
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 7
- 210000004556 brain Anatomy 0.000 description 7
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 7
- 230000003556 anti-epileptic effect Effects 0.000 description 6
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- 241000700159 Rattus Species 0.000 description 4
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- 102000003952 Caspase 3 Human genes 0.000 description 3
- 108090000397 Caspase 3 Proteins 0.000 description 3
- 239000001961 anticonvulsive agent Substances 0.000 description 3
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- 238000012360 testing method Methods 0.000 description 3
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- 208000001654 Drug Resistant Epilepsy Diseases 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
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- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000002651 drug therapy Methods 0.000 description 2
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- 206010067484 Adverse reaction Diseases 0.000 description 1
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- 208000017667 Chronic Disease Diseases 0.000 description 1
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- 231100000869 headache Toxicity 0.000 description 1
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- 239000011261 inert gas Substances 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention discloses a kind of purposes of xenon or xenon-133 gas mixture in the preparation for preparing treatment epilepsy.Particularly, the present invention relates to such xenon purposes, wherein epilepsy is the autophagy function that xenon can inhibit neuron paradoxical discharge, enhance cell, to realize the inhibiting effect to epilepsy occurrence and development caused by neuron paradoxical discharge.System of the present invention is found that xenon or xenon-133 gas mixture have significant treatment and neuroprotection to epilepsy for the first time; solve the problems such as drug resistance, the uncertainty of operative treatment epilepsy that oral epilepsy drugs generates; and the safety of epilepsy is verified in the use as anesthetic; therefore, the present invention provides new thinking and medicine for the treatment of epilepsy.
Description
Technical field
Purposes that the present invention relates to xenons in preparing therapeutic gas, is controlled more particularly to xenon or xenon-133 gas mixture in preparation
Treat the purposes in the preparation of epilepsy.
Background technology
Epilepsy (epilepsy) is one of of short duration cerebral disorder caused by the electric discharge of cerebral neuron paroxysmal abnormality
Kind chronic disease.It is shown according to Chinese epidemiologic data, the overall illness rate of domestic epilepsy is 7.0 ‰, annual morbidity 28.8/
It is 4.6 ‰ to have the activity epilepsy illness rate of breaking-out in 100000,1 year.There are about 9,000,000 or so epilepsy trouble for estimation China accordingly
Person, wherein 500~6,000,000 be movable Patients with Epilepsy, while newly increasing epileptic about 400,000 every year, Chinese epilepsy
The second largest common disease of headache is only second to as neurology department.
Mainly there are drug therapy and surgical intervention two ways for the treatment of epilepsy at present, wherein drug therapy faces
Both sides problem, on the one hand, antiepileptic adverse reaction is serious, involve nerve, uropoiesis, blood, digestion, movement, interior point
It the multisystems such as secretes, may occur in which nervous function damage, insanity, hematopoietic disorders, or even alpastic anemia occur；Another party
Antiepileptic is used for a long time in face, and there are about the patients of one third to generate drug resistance to antiepileptic, becomes intractable epilepsy
The probability that epilepsy, wherein temporal epilepsy develop into intractable epilepsy is more than 50%, the situation that partial epilepsy patient pasts medical help occurs,
As a great problem of clinical treatment.
The surgical intervention of epilepsy is to cut off epileptogenic focus point by operation, is the radical treatment of epilepsy.But since epilepsy has
More stove points, the features such as stove point is indefinite, many epileptics are not appropriate for operative treatment, and often perform the operation and can not all keep away
It destroys normal brain tissue with exempting from, and finally damages normal brain function.In addition cerebral injury is one of Important cause of disease of epilepsy, so
Recurrent seizures again after the patient with operation of significant proportion is performed the operation several years, therefore operative treatment is also greatly limited.
Xenon is a kind of nonmetalloid, colourless, odorless, tasteless, chemical property pole torpescence.Xenon is in medical field master at present
If as uses such as deep anaesthesia agent, Medical ultraviolets.One kind is disclosed in patent " adjuvant containing xenon " (CN1665542A)
Adjuvant containing xenon, wherein xenon role are to improve drug supply of the active constituents of medicine to body part, especially brain.
But do not treat the report of epilepsy as therapeutic gas about xenon also at present.
Invention content
In view of the above shortcomings of the prior art, the purpose of the present invention is to provide a kind of xenons or xenon-133 gas mixture to prepare
Treat the purposes in the preparation of epilepsy.
The present invention is for the first time the study found that xenon can significantly shorten after epilepsy the discharge period, by inhibiting neuron
Electric discharge inhibit the occurrence and development of epileptics.Based on above-mentioned discovery, the present invention proposes following technical solution：
The purposes of xenon or xenon-133 gas mixture in the preparation for preparing treatment epilepsy.
The preparation is therapeutic gas, does not include the preparation as adjuvant.
Preferably, the preparation is the preparation for treating the epilepsy caused by neuron extremely power generation.
Preferably, the preparation is the preparation for inhibiting neuron paradoxical discharge.
Preferably, the preparation is the preparation for enhancing cell autophagy function.
Preferably, the xenon of 35-70% (percentage by volume) is contained in the preparation.
Further, oxygen and/or nitrogen and/or air are in addition contained in the preparation.
Further, the xenon of 35-70% (percentage by volume), 30% oxygen are contained in the preparation, surplus is
Nitrogen.
It is further preferred that the oxygen containing 70% xenon, 30% in preparation.
The present invention is the study found that the percentage by volume of xenon is 35-70% in preparation, the percentage by volume of oxygen is fixed as
30%, when the percentage by volume of xenon is less than 70%, remaining is nitrogen；Then the preparation of the composition to the therapeutic effect of epilepsy compared with
It is excellent；If adjusting the ratio of xenon in preparation, the xenon ratio of (being higher than 70%) excessively high in preparation or too low (being less than 35%) are all
The therapeutic effect to epilepsy can be reduced.
Beneficial effects of the present invention：
System of the present invention is found that xenon or xenon-133 gas mixture have significant treatment and neuroprotection to epilepsy for the first time,
Solve the problems such as drug resistance, the uncertainty of operative treatment epilepsy that oral epilepsy drugs generates, and the safety of epilepsy
It is verified in the use as anesthetic, therefore, the present invention provides new thinking and treatment for the treatment of epilepsy
Drug.
Description of the drawings
The accompanying drawings which form a part of this application are used for providing further understanding of the present application, and the application's shows
Meaning property embodiment and its explanation do not constitute the improper restriction to the application for explaining the application.
Fig. 1：Xenon processing to animal epilepsy each grade residence time influence.
Fig. 2：Influence of the xenon processing to discharge period after epilepsy animals (ADD).
Fig. 3：Each group representativeness electroencephalogram after xenon processing.
Fig. 4：Xenon processing induces KA the influence of epilepsy acute seizures model apoptosis.
Fig. 5：Xenon processing induces KA the influence of acute seizures model autophagy.
Specific implementation mode
It is noted that following detailed description is all illustrative, it is intended to provide further instruction to the application.Unless another
It indicates, all technical and scientific terms used herein has usual with the application person of an ordinary skill in the technical field
The identical meanings of understanding.
It should be noted that term used herein above is merely to describe specific implementation mode, and be not intended to restricted root
According to the illustrative embodiments of the application.As used herein, unless the context clearly indicates otherwise, otherwise singulative
It is also intended to include plural form, additionally, it should be understood that, when in the present specification using term "comprising" and/or " packet
Include " when, indicate existing characteristics, step, operation, device, component and/or combination thereof.
Term explanation：
Heretofore described " preparation for the treatment of epilepsy ", refers to the system as main active in epilepsy therapy
Agent, and the preparation as adjuvant not comprising ancillary drug curative effect.
As background technology is introduced, the report of epilepsy is not treated as therapeutic gas about xenon also in the prior art
Road, the present invention is based on experimental studies, it is proposed that a kind of new application of xenon or xenon-133 gas mixture in treating epileptics.
Present invention research finds that inert gas xenon can significantly shorten the duration discharged after epilepsy, to KA inductions
The Apoptosis that acute seizures cause has very strong inhibiting effect, this unexpected discovery is controlled so that preparing
The preparation for treating the epileptics caused by neuron extremely power generation is possibly realized.
Correspondingly, the preparation of the preparation containing xenon present invention focuses primarily on the purposes of xenon for treating epilepsy and for treating epilepsy
On.
On the basis of the present invention, by simple Inhalation in Treating, different types of epilepsy can be treated.Xenon is logical
Respiratory system is crossed to absorb and be transported to brain by its purposes confirmation as anesthetic.It can equally deduce using xenon pair
The organ of human body does not have damage effect, this is because it is used as anesthetic has done many corresponding experiments.Xenon can be with
By various technology applications, these technologies are selected according to place to use.For example, the inhalation device of inhalation anesthesia is had been used for
Use clinically.If using cardiopulmonary artery shunt or other artificial respiration apparatus, xenon can be introduced directly into machine
In without other equipment.In mobile give first aid to, when such as carrying out Primary treatment to patient, simpler sucking can be used
Device, this inhalator during inhalation mix xenon and surrounding air, and making for xenon concentration and xenon is adjusted by simple mode
With the time to adapt to the requirement for the treatment of.
In order to enable those skilled in the art can clearly understand the technical solution of the application, below with reference to tool
The technical solution of the application is described in detail in the embodiment of body.
Test material used in the embodiment of the present invention is the test material of this field routine, can pass through commercial channel
It is commercially available.
Embodiment 1：The antiepileptic action of xenon is studied
1. test method：
(1) intracerebroventricular injection classics animal epileptic model KA prepares acute seizures model, is inhaled respectively after KA administrations
It is primary to enter different component gas.The oxygen (KA groups) of the oxygen (xenon group) of 70% xenon/30% and 70% nitrogen/30% continuously sucks
2h records behaviouristics and eeg data.
(2) the acute seizures model of KA inductions gives the oxygen treatments applied one of 70% xenon/30% immediately after KA administrations
Secondary (xenon group), another group to give the oxygen treatments applied of 70% nitrogen/30% primary (KA groups)；Mortality of animals is counted after 7 days.
2. test result：
Xenon processing is to animal in the influence the result is shown in Figure 1 of epilepsy each grade residence time, and as seen from Figure 1, KA is lured
In the acute seizures 60min led, KA groups animal (n=13) is respectively in accumulated dwelling time at different levels：I grade：
3.15min；II grade：1.54min；III grade：10.54min；IV grade：19.38min；V grade：25.23min.And xenon processing group (n
=10) animal does not have 3-5 grades of breaking-outs, is respectively in the residence time at different levels：I grade：3min；II grade：0.4min；III grade：0min；
IV grade：0min；V grade：0min.The experimental results showed that xenon processing significantly suppresses the acute seizures of KA inductions.**P<
0.01,***P<0.001。
Xenon processing induces the influence of the epilepsy animals death rate to the results are shown in Table 1 KA.
Table 1：Xenon processing induces KA the influence of the epilepsy animals death rate
As can be seen from Table 1, xenon group does not have animal dead, and the death rate of KA groups has up to 23.08% compared with KA groups
Significant difference.***P<0.001.
Xenon processing is shown in Fig. 2 to the influence result of discharge period after epilepsy animals, has Fig. 2 it is found that the urgency that KA is induced
Property epileptic attack 60min in, it is 48.15min to add up ADD, and xenon processing group (n=10) is 7.8min, hence it is evident that is less than KA groups
(n=13).***P<0.001.
The representative electroencephalogram of each group after xenon processing is as shown in figure 3, A is the acute seizures animal of KA inductions in figure
Representative brain Electrical change；B is that xenon handles animal representativeness brain electricity (in 10 animals 7 epilepsy do not occur then discharge).
To sum up, behaviouristics data analysis found that the breaking-out of KA group animal seizures with 4-5 grade it is serious break out greatly based on, and xenon
7 do not have Epileptic seizure behavior grade in processing animal 10, and 3 epileptic attack of short time 1-2 grade compared with light grade occur, do not have
3-5 grades of breaking-outs (Fig. 1)；And rats death rate is reduced to 0% (table 1) from 23.08%.Brain electricity analytical also confirms that and KA groups compare
(48.15min), xenon significantly shorten discharge period (7.8min, P after epilepsy<0.001, Fig. 2).Fig. 3 is representative brain
Electrograph.Experimental result confirms that xenon has powerful antiepileptic action.
Embodiment 2：Influence of the xenon processing to Apoptosis is given in epileptic process
This experimental studies have found that, in the rat epilepsy model of intracerebroventricular injection KA induction, different time points (for 24 hours, 3d,
7d), intracerebral multiple regions (such as cortex, hippocampus), Actived caspase-3/GAPDH (classical apoptosis index) apparent increases (P
<0.05,P<0.01and P<0.001), KA induces the Acute Epilepsy Rats continuously sucking oxygen 2h of 70% xenon/30%, intracerebral sea
The regions such as horse, cortex Actived caspase-3/GAPDH significantly reduce (P<0.001) (Fig. 4).In Fig. 4, A is that KA inductions are insane
Epilepsy different time points apoptosis changes；B is different time points apoptosis variation after xenon processing；C is that KA induces epilepsy different time points
Apoptosis mutation analysis；D is different time points apoptosis mutation analysis after xenon processing.As shown above, in the big breaking-out of KA inductions
Epilepsy model different time points (for 24 hours, 3d, 7d), intracerebral apoptosis index Actived caspase-3/GAPDH are apparently higher than
Shame groups；And xenon processing is obviously reduced apoptosis (C：Cortex；P：Pear-like layer；H：Hippocampus).*P<0.05,**P<
0.01and***P<0.001。
Experimental result confirms that the Apoptosis that xenon causes the acute seizures that KA is induced has very strong inhibition to make
With.
Embodiment 3：Xenon processing induces KA the influence of acute seizures model autophagy
Originally experimental studies have found that, the rat acute epileptic attack of KA inductions, different time points (for 24 hours, 3d, 7d), intracerebral is each
Region II/GAPDH of LC3 (II/LC3 of LC3 I or II/GAPDH of LC3 are often used in evaluation autophagy level) do not have significant change；But
After xenon processing, the regions such as cortex, hippocampus II/GAPDH of LC3 significantly increase (P<0.001), wherein xenon is handled 3 days, cortex
II/GAPDH of LC3 are 21.79 times (Fig. 5) of KA groups；In Fig. 5, A is that KA induces epilepsy different time points autophagy changes of function；B is
Different time points autophagy changes of function after xenon processing；C is Different brain region, different time points, the variation of each group autophagy index.As above
Shown in figure, in the big breaking-out epilepsy model different time points (for 24 hours, 3d, 7d) of KA inductions, intracerebral different zones (C：Cortex；P：Pears
Shape cortex；H：Hippocampus), xenon processing can significantly increase autophagy function.***P<0.001.
It is experimentally confirmed that xenon generates powerful neuroprotection and antiepileptic action by enhancing cell autophagy function.
The foregoing is merely the preferred embodiments of the application, are not intended to limit this application, for the skill of this field
For art personnel, the application can have various modifications and variations.Within the spirit and principles of this application, any made by repair
Change, equivalent replacement, improvement etc., should be included within the protection domain of the application.
Claims (5)
1. purposes of the xenon-133 gas mixture in preparing treatment preparation of epilepsy caused by neuron extremely power generation, feature exist
In the preparation contains the xenon of percentage by volume 35-70%, and surplus is oxygen and/or nitrogen and/or air.
2. purposes according to claim 1, which is characterized in that the preparation is the system for inhibiting neuron paradoxical discharge
Agent.
3. purposes according to claim 1, which is characterized in that the preparation is the system for enhancing cell autophagy function
Agent.
4. purposes according to claim 1, which is characterized in that the xenon containing percentage by volume 35-70% in the preparation
Gas, 30% oxygen, when xenon percentage by volume be less than 70% when, surplus is nitrogen.
5. purposes according to claim 1, which is characterized in that the preparation by percentage by volume 70% xenon, 30%
Oxygen composition.
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| DE19910986C2 (en) * | 1999-03-11 | 2001-06-07 | Aga Ab | Use of xenon in the treatment of neurointoxication |
| FR2863169B1 (en) * | 2003-12-08 | 2006-02-10 | Air Liquide Sante Int | ARGON-BASED INHALABLE GAS MEDICINE FOR THE TREATMENT OF NEURO-INTOXICATIONS |
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Denomination of invention: Use of xenon or xenon gas mixture in the preparation of preparations for the treatment of epilepsy Effective date of registration: 20211214 Granted publication date: 20180921 Pledgee: Yantai financing guarantee Group Co.,Ltd. Pledgor: BINZHOU MEDICAL University Registration number: Y2021980014859 |
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Granted publication date: 20180921 Pledgee: Yantai financing guarantee Group Co.,Ltd. Pledgor: BINZHOU MEDICAL University Registration number: Y2021980014859 |