CN104840459B - 17 allylamines 17 go purposes of the methoxy geldanamycin in the medicine for preparing treatment epilepsy - Google Patents
17 allylamines 17 go purposes of the methoxy geldanamycin in the medicine for preparing treatment epilepsy Download PDFInfo
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Abstract
The present invention relates to 17 allylamines 17 to go purposes of the methoxy geldanamycin in the medicine for preparing treatment epilepsy.Wherein described epilepsy is preferably intractable epilepsy, more preferably the invalid temporal epilepsy of drug therapy.17 allylamine 17, which removes methoxy geldanamycin, to be realized by the Glt1 albumen raised in brain tissue.Methoxy geldanamycin is gone to effectively treat the invalid temporal epilepsy of drug therapy using 17 allylamines 17, meanwhile, it is capable to which other physiological status of subject are unaffected during ensureing treatment.
Description
Technical field
The present invention relates to 17- allylamines -17- to go purposes of the methoxy geldanamycin in the medicine for preparing treatment epilepsy,
More particularly to 17- allylamines -17- goes purposes of the methoxy geldanamycin in the medicine for preparing treatment intractable epilepsy.
Background technology
Epilepsy be one group as caused by different pathogeny, caused by brain neuroblastoma member high level of synchronization paradoxical discharge, with anti-
Renaturation, ictal, transience, it is typically the stereotyped not normal syndrome being characterized of central nervous system function.Epilepsy is most
One of common the nervous system disease, according to the statistics of the World Health Organization (WHO) and international anti-epileptic alliance (ILAE),
The whole world about 50,000,000 people suffer from epilepsy, and wherein developing country accounts for 85%, there are about every year 2400000 newly make a definite diagnosis trouble
Person.
Epilepsy can be classified according to site of pathological change, disease symptom etc..First, it is related to position (focal, limitation and
It is partial) epilepsy and syndrome：1. idiopathic (relevant with the age)：Center, benign children epilepsy, the occipital lobe of temporo area spike are quick-fried
The children epilepsy of hair, primary reading epilepsy；It is 2. symptomatic：Children's chronic progressive partial epilepsy state
(Kojewnikow syndromes), the syndrome characterized by special state induces breaking-out, temporal epilepsy, frontal lobe epilepsy, top are insane
Epilepsy, occipital lobe epilepsy；3. essential epilepsy.2nd, systemic epilepsy and syndrome：1 idiopathic (relevant with the age)：Both sexes familial
Neonatal convulsions, benign neonatal convulsions, benign baby's myoclonus epilepsy, with break out greatly epilepsy, it is awake when with big hair
Make the epilepsy, other systemic idiopathys, the epilepsy with special state induction breaking-out of (GTCS)；2 hidden source property and/or symptom
Property (relevant with the age)：West syndromes (infantile spasm), Lennoi-Castaut, myoclonia astasia epilepsy, flesh battle array
Contraction absence epilepsy；3 is symptomatic：(1) no special venereal disease because：Early myoclonic encephalopathy, premature babies suppress brain with outburst
Epileptic encephalopathic, the other symptoms systemic epilepsy of electrograph；(2) special syndrome：Merge the epileptic attack of other diseases, bag
Include by breaking-out and to break out for the disease of cardinal symptom.3rd, limitation or systemic epilepsy and syndrome are not determined as：
1 has the breaking-out of systemic and limitation concurrently：Continuation spine is slow in neonate's breaking-out, baby's severe myoclonic epilepsy, slow wave sleep
Complex wave epilepsy, acquired epilepsy aphasia (Landau-Kleffner syndromes), other unascertainable epilepsies；2 not can determine that
For systemic or limitation person：Systemic or limitation generalized tonic-clonic is not determined as in clinical and electroencephalogram finding
Property breaking-out, such as sleep GTCS.4th, special syndrome：The breaking-out related to disease：Febrile convulsion, isolated breaking-out or isolated epilepsy
State, the breaking-out for occurring only at formulation metabolic or intoxication conditions, such as alcoholism, medicine, eclampsia and non-ketone hyperglycaemia.
Although new antiepileptic continuously emerges, but still the patient for having about 30% is applying enough all kinds of anti-epileptics
Breaking-out still can not be effectively controlled after medicine, turns into intractable epilepsy.Medically intractable epilepsy causes the death rate of epileptic big
Width raises, and its sudden death ratio is up to 65% in the total number of persons that epileptic attack causes death, to the social medical treatment brought, economy
Burden is significantly larger than in general epilepsy syndromes.Prolonged epileptic attack, huge psychological burden is also brought to patient, there are about
The 10%-20% concurrent phrenoblabia of patient, is mainly shown as depression and anxiety, schizophrenia, greatly reduces the life of patient
Bioplasm amount.Therefore, the pathogenesis, the new effective anti-epileptic treatment method of exploitation and medicine target for the treatment of of intractable epilepsy are illustrated
Point, the treatment gap of intractable epilepsy will be filled up, reach the target for reducing and reducing epileptic's death rate.
Temporal epilepsy is complex disease caused by a kind of nature-nurture collective effect, is most common drug refractory
Epilepsy.According to causing the difference of insane stove to be divided into Lateral Temporal epilepsy and mesial temporal lobe epilepsy, the latter's proportion highest can be to 80%.
In addition to genetic defect, patient often occur in year after birth be considered as risk factor past medical history, such as:
Febrile convulsion (whole body or local tic caused by neonate's high fever), virus infection and wound etc..
The disease generating process of mesial temporal lobe epilepsy has more obvious phasic characteristics.There is theory to think at present, suffer from
Person meets with that febrile convulsion etc. is initial to induce sexual behavior part on the basis of itself genetic predisposition, and several years of experience is even more prolonged
After incubation period (period of no epileptic attack), patient finally produces the automatic epilepsy paradoxical discharge originating from temporal lobe, is referred to as slow
Property phase epileptic attack.Incubation period is considered as the critical period for establishing spontaneous paradoxical discharge loop in the future, and clinical application
Gold period, if can find participate in incubation period promote epilepsy occur key regulatory molecule and path, it is possible to not
Prophylactic treatment is carried out to be directed to correlation molecule design targeted drug.Astroglia can pass through intake and glutamate release
Mode maintain normal glutamate levels in neural microenvironment, wherein glutamate transporter Glt1 (Glutamate
Transporter 1, also known as Excitatory amino-acid transporter 2) play most important glutamic acid removing
Function.Glt1 is a kind of specific expressed integral membrane protein of astroglia, by extracellular paddy by way of active transport
Propylhomoserin makes the aminoglutaric acid concentration in neural microenvironment maintain in normal range (NR) to transmitter loss.The glutamic acid of intracellular is in paddy ammonia
Glutamine is changed into the presence of acyl ammonia synthesis enzyme (Glutamine synthetase, GS) and enters metabolic pathway.Glt1
Neuronal hyperexcitation can also be avoided by quickly removing the glutamic acid of acceptor on postsynaptic membrane.In the presence of Glt1,
Up to 10,000 times of aminoglutaric acid concentration difference outside intracellular can be made.It is to turning in the most important glutamic acid of intracerebral that research, which has proven to Glt1,
Carrier, it is responsible for nearly 80% glutamic acid scavenging action.
Evidence shows that Glt1 unconventionality expressions in a variety of the nervous system diseases are lowered, and cause astroglia seriously to lose
Glutamic acid Scavenging activity is lost, this is probably the major reason of glutamate abnormality accumulation.For intractable mesial temporal lobe epilepsy patient
Research find that Glt1 mRNA and protein are lowered in the insane stove of cause (hardening hippocampal tissue) of patient.AD has with epilepsy
There is certain Comorbidity, multinomial research confirms also there is neure damage caused by excitatory toxicity in AD brain in patients, together
When in the postmortem brain tissue of AD patient find Glt1 protein level be decreased obviously.Research to ALS patient's postmortem brain tissue
It was found that the loss degree of Glt1 albumen is up to 90%, follow-up functional study shows, under pathological state Glt1 abnormal internalization and
Protein degradation is probably the major reason for causing its protein content deficiency.In addition, researcher is also in the mould of tuberous sclerosis
Also the phenomenon that Glt1 is lowered is observed in type mouse.
Relation of the horizontal functional study of animal between Glt1 loss and disease phenotype provides sufficient evidence.It is first
First, Glt1 transgenic mice has anti-seizure ability, show as (pilocarpine, be in the case where causing the induction of insane medicine
The activator of m-AChR, the rodent models for establishing epilepsy are can be used for by way of intraperitoneal injection),
The death rate reduction of Glt1 transgenic mice hippocampal neurons, mossy fiber sprouting degree and other hippocampal sclerosis correlation
Pathology is eased, while the idiopathic chronic epileptic attack number of Glt1 transgenic mices also reduces about 50%.On the contrary,
Method by injecting antisense RNA suppresses Glt1 expression, and the glutamic acid of mouse intracranial can be caused largely to accumulate, and induces nerve and moves back
Row venereal disease becomes, and mouse is gradually paralysed.These researchs show that astroglia is played by its specific expressed Glt1 molecule
Important neuroprotective function, Glt1 missing are enough to make nervous system Excitotoxicity occur.Therefore, astroglia is thin
The glutamate transport function of born of the same parents is to treat the potential target of intractable epilepsy.
Common antiepileptic mostly targets ion channel at present, by block voltage-dependent sodium-ion channel,
Calcium channel, or increase GABA level are overexcited to suppress nerve.Such medicine is treated to inner side patients with temporal lobe epilepsy
It is invalid, prompt it to be different from the mechanism of causing a disease of general epilepsy syndromes.From 2005, sight was gradually turned to glue by researcher
Cell plastid, more and more experimental evidence points out that the exception of astroglia rises during the temporal lobe onset of inner side at present
To key effect.Tian G.F. etc. in vitro study finds that the activation of astroglia intracellular Ca2+ oscillations can promote star glue
Cell plastid causes neuron to produce the abnormal operation current potential similar to epileptiform discharges to surrounding environment glutamate release.
Ortinski P.I. etc. research finds that proliferation of astrocytes can cause local nerve to suppress function and be damaged, and speculates star
It is a kind of possible mechanism of action that the glutamic acid buffer capacity of shape spongiocyte is impaired.It is published in Nature within 2011
Research on Medicine confirms that a large amount of glutamic acid that intracerebral glioma is discharged are that patient is occurred together the immediate cause of epilepsy.On
State experimental evidence to show, the glutamic acid regulating power of astroglia has highly important shadow to nervous system excitability
Ring.It is noted above, Glt1 albumen is lowered in the insane stove of cause of inner side patients with temporal lobe epilepsy, and zoopery confirms Glt1 genes
Homozygous knockout mouse show serious spontaneous epileptic seizures, and Glt1 transgenic mice has higher epileptic attack threshold
Value.
In summary, Glt1 abnormal missing may play critical pathogenic work during the temporal lobe onset of inner side
With, therefore using mesial temporal lobe epilepsy as research object, the medicine of targeting Glt1 anti-neuroexcitation toxicity can be looked for, had again
Wish to understand the pathogenesis of intractable epilepsy from the glutamic acid regulation and control angle of astroglia, develop new medicine.
17- allylamines -17- removes methoxy geldanamycin (Tanespimycin), and also known as 17AAG, it is a kind of effective
HSP90 inhibitor, IC50 5nM, act on and be compared to from the HSP90 of tumour cell extraction for being extracted from normal cell
HSP90 binding affinities are high 100 times.Have been demonstrated that it for having in the kinds of tumors such as liver neoplasm, colon tumor, stomach neoplasm
Good effect, but have no that it is used for the report of epilepsy.
17- allylamines -17- removes methoxy geldanamycin (Tanespimycin)
The content of the invention
By the Molecular screening of early stage, inventor has found Hsp90 (Heat Shock Protein 90, heat shock protein
90) expression rise (Fig. 1 a-c) in the astroglia in epileptogenic process.Hsp90 is a kind of Gao Feng in the cell
, there is the elevated phenomenon of abnormal expression, and play the part of under a variety of physical stress states such as tumour in degree, the molecular chaperones of wide expression
Drill important pathogenetic role.The experiment in vitro that this group is further carried out confirms that Hsp90 is overexpressed in astroglia to be pressed down
Glt1 processed protein expression level (Fig. 1 d), opposite Hsp90 inhibitor can improve protein of the Glt1 under CHX effects
Stability (CHX：Cycloheximide；Suppress intracellular protein synthesis, to the degraded situation of observing protein).This
A little experimental result promptings：The abnormal rise of astroglia Hsp90 albumen promotes Glt1 degraded, and causes astroglia
Its glutamic acid Scavenging activity of the forfeiture of cell.
Result of study prompting mentioned above, if the activity of energy targeted inhibition Hsp90 molecules may improve Glt1 egg
White matter is expressed, and plays the effect of anti-neuroexcitation toxicity.17- allylamines -17- removes methoxy geldanamycin
(Tanespimycin) be Hsp90 molecules specific inhibitor, be used for treat the malignant tumour such as leukaemia and kidney, at present
The medicine has completed clinical second phase test, and the use of medicine has clinical safety.
The present invention carries out 17- allylamines -17- using the mesial temporal lobe epilepsy model mice of digenic acid induction and removes methoxy Ge Er
The administration of moral mycin suppresses epilepsy experiment.It was unexpectedly observed that 17- allylamines -17- goes the injection of methoxy geldanamycin significantly to carry
The expression (Fig. 2) of Glt1 in normal mouse and epilepsy mouse brain is risen, and significantly inhibits epileptic attack (Fig. 4, specific experiment number
According to seeing caption).This be only epilepsy treatment provide new method, it is often more important that the 17- third found in experimentation
Enamine -17- goes effect of the methoxy geldanamycin for up-regulation Glt1 expressions, can extend 17- allylamines -17- and go first
The application of oxygen geldanamycin disease extremely related to Glt1 expression downwards.In summary, the present invention relates to a kind of 17- third
Enamine -17- goes purposes of the methoxy geldanamycin in the medicine for preparing treatment epilepsy.
Further, the epilepsy is intractable epilepsy.
Further, the intractable epilepsy is the invalid temporal epilepsy of drug therapy.
The invention further relates to 17- allylamines -17- to go methoxy geldanamycin preparing treatment and Glt1 downwards or missing phase
Purposes in the medicine of related disorders.
Further, it is intractable epilepsy that described and Glt1, which lowers or lacked relevant disease,.
Further, it is described to lower or lack relevant disease with Glt1 as the invalid temporal epilepsy of drug therapy.
Wherein intractable epilepsy is also referred to as intractable epilepsy, refers to no central nervous system progressive disease or occupancy
Lesion, but clinical delay, were treated through more than 2 years regular anti-epileptics, and major antiepileptic prescription on probation is only or shares, and reaches patient's energy
Maximum dose is resistant to, blood concentration reaches effective range, can not still control breaking-out, and influences daily life, can determine difficult
The property controlled epilepsy.Intractable epilepsy accounts for the 20%~30% of epileptic patient.The invalid temporal epilepsy of its drug treatment refers to insane
The brain areas such as amygdaloid nucleus of the paradoxical discharge of epilepsy patient originating from temporal lobe part or periphery, and controlled by two kinds of antiepileptics are regular
Failure is treated, meets above-mentioned intractable epilepsy standard, that is, belongs to intractable temporal epilepsy.
Brief description of the drawings
Fig. 1 a-1e are demonstrated by Hsp90 unconventionality expressions in insane stove is caused and raised.
Fig. 1 a are that the 2nd week mouse has the immunofluorescence of idiopathic chronic epileptic attack and hippocampal sclerosis after digenic acid is injected
Colored graph, Hsp90 expresses rise in the astroglia kytoplasm that GFAP is marked, and (GFAP and Hsp90 common location pixels are pointed out
Aobvious increase).
Fig. 1 b, the astroglia that dentate fascia in hippocampus is hardened under 400 times of mirrors is counted, as a result display is each hard
Change hippocampus there are about the positive astroglias of 45 Hsp90 and (to the hardening hippocampus of 4 mouse, be cut into slices for 4 before and after each hippocampus
Statistical result).
Fig. 1 c are the Hsp90 molecular immune histochemical staining figures compared with control hippocampus and non-hardening group hippocampus, in inner side temporo
Having the colloid like cells of substantial amounts of Hsp90 stained positives in the hardening hippocampus of leaf epileptic's surgery excision, (arrow is signified thin
Born of the same parents).
Fig. 1 d-e are that the albumen that Hsp90 suppresses Glt1 protein expression level is overexpressed in primary astroglial cells
(1 compared with 3, and Glt1 is not expressed in 293 cells, and this experiment utilizes for matter western blot test figure and block diagram
PcDNA-3.1 expression plasmids are overexpressed exogenous Glt1, therefore level upon translation occurs for regulation and control of the Hsp90 to Glt1).
Fig. 2 a-2d are that 17- allylamines -17- goes methoxy geldanamycin optimal injection dosage and the result of injection time.
Fig. 2 a-2b：Various dose 17- allylamines -17- removes shadow of the methoxy geldanamycin to Glt1 protein expressions in hippocampus
Ring.It will be seen that injection dosage is the expression quantity highest that 15mg/kg is monomer Glt1 from figure, 2.8 about compareed
Times, and Glt1 tetramers highest when injection dosage is 25mg/kg, 2.0 times about compareed.
Fig. 2 c-2d：17- allylamines -17- go methoxy geldanamycin inject after different time, Glt1 is expressed in hippocampus
Level change.From figure it will be seen that when 12 hours after injecting 17- allylamines -17- and removing methoxy geldanamycin,
Glt1 expression highest, about inject Glt1 concentration in just hippocampus 3.1 times.
Fig. 3 is the flow of drug study.
The C57/B6L mouse of 8 week old are selected, Unilateral Hippocampal injects 200ng digenic acid, carries out electrode within 5 weeks after injection
Installation and the measurement of brain electricity baseline, the base line measurement time is 20-25 days, after baseline determination, the first continuous wheel of injection 2 every time 5
Its 17- allylamine -17- removes methoxy geldanamycin.A 17- allylamines -17- is every other day injected afterwards removes methoxy Ge Erde
Mycin.The dosage of injection is 20mg/kg, is dissolved in 100 μ lDMSO.Control group injects the DMSO of same dose.Whole injection process
Coordinate eeg monitoring, analyze effect of drugs.This experiment has carried out the drug injection and eeg monitoring of 25 to 35 days altogether, and is counted with this
According to evaluation drug effect.
Fig. 4 are histamine result of the medicine to intractable epilepsy.
Injection 17- allylamines -17- is gone after methoxy geldanamycin, and the daily attack times of mouse significantly reduce, and
DMSO does not influence on epileptic attack number in itself.The definition of epileptic attack number：With obvious brain electrical anomaly, and pass through video
It was observed that the breaking-out of a limb spasm twitch occurs for mouse.Specific data corresponding with Fig. 4 are referring to table 1 below.
The data corresponding with Fig. 4 block diagrams of table 1
Embodiment
The foundation of the epilepsy mouse model of embodiment 1
1. drug injection method：Reagent：
DMSO:Dimethyl sulfoxide(Sigma,D4540-1L Lot#BCBK5723V)
17- allylamines -17- removes methoxy geldanamycin：17AAG,[17-(Allylamino)-17-
Demethoxygeldanamycin], [17- (Allylamino) geldanamycin], [Tanespimycin] (LC
Laboratories,A-688017-AAG,>99%), Geldanamycin：(LC Laboratories, G-4500)
Compound method：
(1) methoxy geldanamycin is gone to be diluted to 50mg/ml 17- allylamines -17- with DMSO, packing lucifuge is stored into -
20℃。
(2) injection concentration：20mg (is diluted, every mouse injection final volume is 50 μ l every time) with DMSO.
2. the method for building up of model mice：We use the Medial Temporal Lobe of Unilateral Hippocampal area injection digenic acid induction insane
Epilepsy model mice, the model are classical and the most frequently used intractable temporal lobe epilepsy model.Pass through the C57BL6j mouse to 8 week old
Unilateral Hippocampal injects 200ng digenic acids, induces the epileptic attack that the duration first is 3 hours or so.We note in digenic acid
5th week installation encephalic hippocampus EEG measuring electrode after penetrating, and it is electric (epileptic discharge) to record the brain originating from hippocampus.
The medicine of embodiment 2 influences on hippocampus of mice Glt1 expression
1st, experimental method
First, methoxy geldanamycin is gone to determine optimal injection using normal mouse intraperitoneal injection 17- allylamines -17-
Dosage and injection time.We have selected 5 test doses altogether：0mg/kg、2mg/kg、5mg/kg、15mg/kg、25mg/
Kg, hippocampus of mice albumen was taken at 24 hours, when discovery injection concentration is 15mg/kg, monomer Glt1 up-regulation is most obvious, is about pair
According to 2.8 times, and when injection concentration is 25mg/kg, although monomer Glt1 expression relative injection concentration is 15mg/kg
When declined, but the Glt1 expression quantity of the tetramer rise more obvious, 2.0 times (on Fig. 2) about compareed.Follow-up real
In testing, the injection concentration that we select is 20mg/kg.
And the selection of optimum injection time, we have selected 7 time points of 0h, 6h, 12h, 24h, 36h, 48h, 72h, note
It is 20mg/kg to penetrate concentration, it is found that Glt1 up-regulations are most bright when 12 hours after 17- allylamines -17- goes methoxy geldanamycin to inject
It is aobvious, 3.1 times about compareed, because at 24 hours, Glt1 up-regulation was also clearly, for 2.6 times of (Fig. 2 of control
Under), and Glt1 half-life period be more than 12 hours, while solvent DMSO also has certain toxicity to mouse.So subsequent experimental,
The injection time that we select is to inject once for every 48 hours.
2nd, experimental result
We have found that the star in the insane stove of cause and mesial temporal lobe epilepsy model mice of intractable mesial temporal lobe epilepsy patient
Hsp90 molecules raise in shape spongiocyte, and Hsp90 can suppress Glt1 expression, can by suppressing Hsp90 activity
Promote Glt1 protein expressions.By the method for intraperitoneal administration, systemic injections 20mg/kg 17- allylamines -17- removes methoxy
Geldanamycin suppresses Hsp90 activity, can significantly improve the expression for causing Glt1 at insane stove, and effectively patient is refractory
The chronic seizure disorder frequency of property mesial temporal lobe epilepsy mouse, increase the number of days of no epileptic attack.Therefore, 17- allylamines -17-
Methoxy geldanamycin is gone to be used for treating epilepsy.
Embodiment 317- allylamines -17- goes therapeutic effect of the methoxy geldanamycin to mouse model epilepsy
1st, experimental method
After baseline determination, give 17- allylamines -17- and remove methoxy geldanamycin or DMSO.Dosage period is：
The administration that 2 wheels are often taken turns 6 days is carried out first, and wherein first five day is continuously injected medicine, is not administered within the 6th day.Inject one every two days afterwards
Secondary medicine (Fig. 3).This experiment employs 13 mouse injection 17- allylamines -17- and removes methoxy geldanamycin, 8 mouse notes altogether
Penetrate DMSO.Eeg monitoring result finds that DMSO is injected in itself does not influence to inject front and rear seizure trequency, and 17- allylamines-
17- goes methoxy geldanamycin to significantly suppress epileptic attack number after injecting, and effectively alleviates epileptic attack (Fig. 4, column statistics
Figure, 1-21 groups left side column are baseline, and 1-13 groups are that 17- allylamines -17- removes methoxy geldanamycin, are on the right side of 14-21 groups
DMSO).The seizure trequency of specific every experiment mice see the table below 2-3.
The seizure frequency statistics of the every mouse of table 2.
The seizure frequency statistics of the every mouse of table 3.
2nd, experimental result
By the method for intraperitoneal administration, systemic injections 17- allylamines -17- goes methoxy geldanamycin effectively to drop
The chronic seizure disorder frequency of low epilepsy mouse.Therefore, 17- allylamines -17- goes methoxy geldanamycin insane for treating
Epilepsy.
Embodiment 417- allylamines -17- goes methoxy geldanamycin acute toxicity test
20mg/kg dosage is used to test mice, 5 days 17- allylamines -17- is continuously injected and removes methoxy geldanamycin,
Reacted by observing mouse, it is found that 17- allylamines -17- goes the toxicity of methoxy geldanamycin smaller, over the course for the treatment of to small
Mouse feed etc. is without influence, and mouse survival rate is up to 100% during off-test, and data are referring to table 4.
Table 4.17- allylamines -17- goes toxicity of the methoxy geldanamycin to mouse
Claims (3)
1.17- allylamines -17- goes purposes of the methoxy geldanamycin in the medicine for preparing treatment epilepsy, wherein the 17- third
Enamine -17- goes methoxy geldanamycin to suppress epileptic attack number.
2. purposes according to claim 1, wherein the epilepsy is intractable epilepsy.
3. purposes according to claim 2, wherein the intractable epilepsy is drug refractory temporal epilepsy.
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| CN101687808A (en) * | 2007-06-21 | 2010-03-31 | 默克专利有限公司 | indazolamide derivatives |
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| CN101687808A (en) * | 2007-06-21 | 2010-03-31 | 默克专利有限公司 | indazolamide derivatives |
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| Title |
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| Hippocampal expression of heat shock proteins in mesial temporal lobe epilepsy with psychiatric comorbidities and their relation to seizure outcome;Ludmyla Kandratavicius等;《Epilepsia》;20140919;第55卷(第11期);1834-1843 * |
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