CN105769858A - New use of phenytoin sodium - Google Patents
New use of phenytoin sodium Download PDFInfo
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- CN105769858A CN105769858A CN201610175608.7A CN201610175608A CN105769858A CN 105769858 A CN105769858 A CN 105769858A CN 201610175608 A CN201610175608 A CN 201610175608A CN 105769858 A CN105769858 A CN 105769858A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
Abstract
The invention relates to new use of phenytoin sodium. According to the new use, through injecting the phenytoin sodium into a rat body through intraperitoneal injection, improved conditions on dyskinesia of a 6-hydroxy-dopamine unilateral-lesion PD (Parkinson's Disease) rat model are observed from praxiology, so that application of phenytoin sodium in the preparation of drugs for relieving PD motor symptoms is sought. The novel drugs for treating PD, created by the invention, provide research carriers for researching the molecular mechanism of PD and dyskinesia and meanwhile provide a screening platform for the research and development of the novel drugs for treating PD.
Description
Technical field
The present invention relates to a kind of new application of dilantin sodium.
Background technology
Parkinson's (Parkinson ' s Disease, PD) it is second-biggest-in-the-world nerve degenerative diseases, it is only second to A Er
Zi Haimo disease.The whole world there are about the population of 1% and suffers from this illness, and crowd has focused largely on the elderly, greatly reduces this people
The quality of life of group and life expectancy, have resulted in serious social influence.The dopaminergic neuron of substantia nigra of midbrain compact part is lost
Losing, dopamine exhausts that the nigro-striatal dopamine pathway disorder caused is the major pathologic features of PD.PD clinical symptoms are with fortune
Dynamic symptom is main, is usually expressed as bradykinesia, static tremor, gait disorder, posture shakiness, along with the progress of the state of an illness, disease
Shape gradually aggravates.The appearance of these illnesss normally starts from the side of health, then extends to other side.Along with the state of an illness
Development, in brain, non-athletic control zone also begins to be affected, and non-motor symptoms occurs in patient, including cause sleep disordered, recognize
Know obstacle and cacesthesia etc..The most clinical pharmaceutical intervention for PD uses supplementary Dopaminergics preparation such as levodopa mostly
(Levodopa), it is the intermediate product being formed catecholamine by tyrosine, can be changed into dopamine in brain, recovers in brain
The content of dopamine.The drug effect of this medicine maintains ability relatively limited, and along with the prolongation for the treatment of time, result for the treatment of also can subtract
Weak, and there will be stronger pharmacological dependence situation, side effect is bigger.
Parkinson's research at present shows, at Parkinson's (PD) patient and the basal ganglion loop of rat model, deposits
Swing in the synchronization electroshock based on beta response, this abnormal motion barrier synchronizing electrical activity and PD patient and rat model
Hinder closely related.Research display, Voltage-gated sodium channels (voltage-gated sodium channels, VGSCs)
Key player is play in the globus pallidus of basal ganglion loop and the synchronization concussion electrical activity of subthalamic nuclei.It is so far
Only, in mammal body, 10 different VGSC a hypotype (Na are had been found thatv1.1-1.9 and NaX) and β Asia of 4 VGSC
Base (β 1, β 2, β 3, β 4).Wherein SCN1A, SCN2A, SCN3A, SCN8A(correspond to Nav1.1、Nav1.2、Nav1.3、
Nav1.6) it is present in the brain of people and mammal.VGSCs plays emphatically in the generation and transmittance process of electroneurographic signal
Act on.Along with the depolarising of cell membrane, the activation of VGSCs can cause quick instantaneous interior to sodium current, produces action potential
Rising phase.Electron microscopy observation shows 3 kinds of hypotypes Na of Voltage-gated sodium channels a subunitv1.1、Nav1.2、Nav1.6 in substrate
There is high expressed in ganglionic important core group-pallidal neuron dendron.It addition, there is research display Nav1.6 is that mouse is pale
Ball electrical activity pace-making and the key molecule quickly provided.On the other hand, clinical and laboratory research all show damage globus pallidus and
Subthalamic nuclei or give globus pallidus and the dyskinesia of PD can be effectively alleviated in subthalamic nuclei frequency deep electro photoluminescence.And study aobvious
Show that brain frequency deep electro photoluminescence depolarizes the Main Function that blocking-up is its Functional inactivation neuron to voltage-gated sodium channel
Mechanism.Therefore, blocking voltage gated sodium channel so that it is inactivation is probably the methods and strategies that PD treatment is new.
Dilantin sodium as a kind of dilantin class sodium salt being the most widely used, its pharmacological property,
Domain functional relationship analysis research comparative maturity, be mainly used in treating epilepsy, arrhythmia cordis, trigeminal neuralgia etc. and sodium from
Subchannel dysfunction relevant disease.Pharmacological research display dilantin sodium is a kind of effective Voltage-gated sodium channels
(VGSCs) blocking agent.During treatment sodium-ion channel dysfunction disease, it is possible to effectively reduce in process of depolarization thin
The interior stream of born of the same parents' extracellular sodium ion so that cell membrane potential is in stable state, improves excited threshold value, reduces the granting frequency of action potential
Rate, reaches the effect suppressing neuroelectricity to provide.Therefore, dilantin sodium is applied to the treatment of PD as Na-ion channel blocker,
Expect that it can act on the Voltage-gated sodium channels of basal ganglion core group neuron, intervene basal ganglion core group
The abnormal electrical activity that synchronizes, thus reach to alleviate and improve the symptom of PD patient.
Summary of the invention
It is an object of the invention to provide a kind of dilantin sodium answering in Parkinson's motor symptoms medicine is alleviated in preparation
With.
PD animal model is mainly: the PD rat model of the unilateral induction of 6-HAD (6-OHDA).
6-OHDA is the hydroxylation derivative of catecholamine, and its structure is similar with catecholamine, and it is many to be that one effectively causes
The never poison of bar amine neuron sex change, is widely used in the cell of selective CA never poison effect or moves
Thing PD model.The PD rat model that the present invention is induced by 6-OHDA one side, utilizes various actions to test, and observes dilantin sodium
Situation is affected for PD rat motor obstacle.
The antiepileptic that dilantin sodium is commonly used it is as a kind of clinic, it is possible to effectively suppress in place of novelty of the present invention
With the dyskinesia alleviating PD animal.With the PD rat model of efficient stable as carrier in the present invention, application Animal Behavior Science is real
Testing detection dilantin sodium impact dyskinetic on PD rat model, it is big that experimental result display dilantin sodium can be effectively improved PD
The dyskinesia of mouse model.
Accompanying drawing explanation
Fig. 1 is PD rat model, the PD rat model of lumbar injection dilantin sodium (50mg/kg) and blank group rat
Slope creep go up a slope needed for pickup time situation of creeping (Mean ± SEM) (* * represent compare with blank group P <
0.01；* represent and compare P < 0.05 with blank group；## represents that PD rat model is big with the PD model of lumbar injection dilantin sodium
Mouse compares P < 0.01；# represents that PD rat model compares P < 0.05 with the PD rat model of lumbar injection dilantin sodium,
Wherein sample size n=10).
Fig. 2 is PD rat model, the PD rat model of lumbar injection dilantin sodium (50mg/kg) and blank group rat
Slope creep pickup time situation of creeping (Mean ± SEM) needed for descending (* * represent compare with blank group P <
0.01；* represent and compare P < 0.05 with blank group；## represents that PD rat model is big with the PD model of lumbar injection dilantin sodium
Mouse compares P < 0.01；# represents that PD rat model compares P < 0.05 with the PD rat model of lumbar injection dilantin sodium,
Wherein sample size n=10).
Fig. 3 is PD rat model, the PD rat model of lumbar injection dilantin sodium (50mg/kg) and blank group rat
Slope creep that (* * represents and compares P < 0.01 with blank group the crawl time situation (Mean ± SEM) needed for going up a slope；* table
Show and compare P < 0.05 with blank group；## represents that PD rat model compares with the PD rat model of lumbar injection dilantin sodium
Relatively P < 0.01；# represents that PD rat model compares P < 0.05, wherein sample with the PD rat model of lumbar injection dilantin sodium
Amount n=10).
Fig. 4 is PD rat model, the PD rat model of lumbar injection dilantin sodium (50mg/kg) and blank group rat
Slope creep that (* * represents and compares P < 0.01 with blank group for crawl time situation (Mean ± SEM) needed for descending；* table
Show and compare P < 0.05 with blank group；## represents that PD rat model compares with the PD rat model of lumbar injection dilantin sodium
Relatively P < 0.01；# represents that PD rat model compares P < 0.05, wherein sample with the PD rat model of lumbar injection dilantin sodium
Amount n=10).
Fig. 5 is PD rat model, the PD rat model of lumbar injection dilantin sodium (50mg/kg) and blank group rat
Slope creep and go up a slope that (* * represents and compares P < 0.01 with blank group the longest every situation (Mean ± SEM)；* represent with
Blank group compares P < 0.05；## represent the PD rat model of PD rat model and lumbar injection dilantin sodium compare P <
0.01；# represents that PD rat model compares P < 0.05, wherein sample size n=with the PD rat model of lumbar injection dilantin sodium
10).
Fig. 6 is PD rat model, the PD rat model of lumbar injection dilantin sodium (50mg/kg) and blank group rat
Slope creep that (* * represents and compares P < 0.01 with blank group the longest situation (Mean ± SEM) of descending；* represent with
Blank group compares P < 0.05；## represent the PD rat model of PD rat model and lumbar injection dilantin sodium compare P <
0.01；# represents that PD rat model compares P < 0.05, wherein sample size n=with the PD rat model of lumbar injection dilantin sodium
10).
Fig. 7 is PD rat model, the PD rat model of lumbar injection dilantin sodium (50mg/kg) and blank group rat
Adjust in gait experimental adjustment step number situation (Mean ± SEM) headfirst (* * represent compare with blank group P <
0.01；* represent and compare P < 0.05 with blank group；## represents that PD rat model is big with the PD model of lumbar injection dilantin sodium
Mouse compares P < 0.01；# represents that PD rat model compares P < 0.05 with the PD rat model of lumbar injection dilantin sodium,
Wherein sample size n=10).
Fig. 8 is PD rat model, the PD rat model of lumbar injection dilantin sodium (50mg/kg) and blank group rat
Adjust adjustment step number situation (Mean ± SEM) backwards of head in gait experimental (* * represent compare with blank group P <
0.01；* represent and compare P < 0.05 with blank group；## represents that PD rat model is big with the PD model of lumbar injection dilantin sodium
Mouse compares P < 0.01；# represents that PD rat model compares P < 0.05 with the PD rat model of lumbar injection dilantin sodium,
Wherein sample size n=10).
Detailed description of the invention
PD rat model method is set up in the damage of 6-OHDA one side and experiment condition refers to Ungerstedt U:6-
Hydroxy-dopamine induced degeneration of central monoamine neurons. EurJ
Condition and the method for operating of Pharmacol 1968,5 (1): 107-110. climbing experiment refer to Xin Fang:The
stepping test and its learning process in different degrees of unilateral
striatal lesions by 6-hydroxydopamine in rats. Neurosci Res, 55(2006) 403-
409. conditions adjusting gait experimental and method of operating refer to M.Olsson:Forelimb Akinesia in the Rat
Parkinson Model: Differential Effects of Dopamine Agonists and Nigral
Transplants as Assessed by a New Stepping Test. J Neurosci,May 1995,15(5):
3863-3875.
Set up PD rat model: by Sprague Dawley(SD) rat puts into and measures its body weight in electronic scale, and then will be to it
Lumbar injection 10% chloraldurate (450mg/kg) is anaesthetized, and holds to rat is carried tail, and rat does not has action, gently pinches four limbs
After the most not reacting, rat prone position is fixed on stereotaxic instrument and (keeps hanging down of micro syringe needle handle and operation planar
Straight state).Being fixed by rat head ear bar, upper teeth is fixed on front tooth rod, and depression bar pressure is toward nasal bone.Alcohol is to rat scalp
After sterilization, cut off the hair on the rat crown, scratch the skin of each 0.5 centimeters before and after two external auditory meatus center line lines with scalpel.Make
The connective tissue membrane under skin is removed with eye scissors.Swab stick dips hydrogen peroxide (H2O2Removal fascia superficialis and periosteum is smeared, clearly after)
Appear bregma, determine bregma position.Make mouse brain keep anterior fontanelle and rear chimney level height be more or less the same in
The strict cranium prosposition of 0.1mm.Use stereotaxic instrument location medial forebrain bundle coordinate, (3.2 ± 0.1) mm, sagittal suture after anterior fontanelle
Right side (1.7 ± 0.1) mm, uses and holes to dural surface on dental burr skull, make micro syringe syringe needle the most slow
Slow lower pin is to (8.2 ± 0.1) mm under dural surface, and 1 μ l/ min slowly injects 4 μ g/ μ l 6-OHDA 4 μ l(blank group rats
6-OHDA solution is replaced with the physiological saline of equivalent), inject complete let the acupuncture needle remain at a certain point 10min, at the uniform velocity extract syringe needle, use cotton swab to dip celebrating
After big mycin smears wound, surgical thread is used to sew up a wound.Then, lumbar injection gentamicin 40,000 unit (50mg/ml,
0.6ml) to prevent and treat infection.Unilateral damage started after 1 week, at rats by intraperitoneal injection apomorphine (0.5mg/kg) each 1 time weekly
To the 4th week, its unilateral rotation of induction every time, unilateral number of revolutions reached 210r/30min, then it is assumed that be that successful 6-OHDA lures
The PD rat model led.
Administration processes: after modeling 1 week, weighs rat body weight, lumbar injection dilantin sodium (50mg/kg), every day 1 every day
Secondary, injection cycle is 4 weeks.
Animal behavioral study:
Hill climbing test: SD rat is positioned over block length 1 m, on the swash plate of width 0.3 m, overhead horizontal sextant angle 15 °, sees
Examine it to go up a slope and the motor behavior of descending at swash plate.Wherein swash plate initiates 0.1 m is SD rat motor initiating district, climbs a length of
0.9 m.Before formal experiment, being trained experimental rat, the time is 8 days, trains 30 min every day.In formal experiment,
Experiment every time (going up a slope and descending) is repeated 2 times all every days, follow-on test 3 days.
This experiment measurement index:
1. left fore/right fore pickup time respectively (initiation time, unit: s): lower limb are fixed with a hand,
Slight lifts hiding part to surface.Another hand fixes forelimb so that it is cannot freely move.The hand pine of fixing forelimb
Immediately begin to timing after opening, observe the pickup time of forelimb movements.
2. left fore/right fore climbing time (stepping time, unit: s): from start line, i.e. distance swash plate top
The position of 0.1m, motion until terminal, omnidistance long 0.9m, the time required for whole process.
3. left fore/right fore step-length (stepping length unit: cm) measures left fore/right fore step number, comes
Calculate average step length, utilize blue red ink to spread upon on left fore/right fore respectively, survey according to the distance between same color
The step-length of fixed each step, determines its standard error.
Result: (note: 6-OHDA injection side is left side brain medial forebrain bundle, arranges according to offside, and right fore is for being administered side
Domination forelimb, left fore collateral joins forelimb for strong)
As depicted in figs. 1 and 2, the right fore of 6-OHDA one side damage rat is on the upward slope and descending pickup time of climbing experiment
Being substantially higher in offside and control group (P < 0.01), after its lumbar injection dilantin sodium, the upward slope of its right fore begins with descending
The dynamic time, compared with the PD rat model not injecting dilantin sodium, presents and significantly declines (P < 0.01).6-OHDA one side is damaged
Rat left fore, does not has difference (P > 0.05) compared with control group.
As shown in Figure 3 and Figure 4, the right fore of 6-OHDA one side damage rat is when the upward slope of climbing experiment is creeped with descending
It is substantially higher between in offside and blank group (P < 0.01), but after its lumbar injection dilantin sodium, its right fore upper
Slope with descending crawl time, presents and significantly declines (P < 0.01) compared with the PD rat model not injecting dilantin sodium.6-
OHDA one side damage rat left fore, does not has difference (P > 0.05) compared with control group.
As shown in figure Fig. 5 and Fig. 6, the right fore of 6-OHDA one side damage rat is creeped with descending at the upward slope of climbing experiment
Offside to be less than and blank group (P < 0.01) in every length step by step, and after its lumbar injection dilantin sodium, it is right
The upward slope of forelimb is creeped every step by step long compared with the PD rat model not injecting dilantin sodium with descending, presents (the P that significantly gos up
< 0.01).6-OHDA one side damage rat left fore, does not has difference (P > 0.05) compared with control group.
Adjust gait test: being placed on arbitrary plane by SD rat respectively, 1 hand fixes the hind leg of rat, another 1 hand
Catch a wherein forelimb so that it is 1 forelimb is on swash plate surface, by the forelimb pointing direction caught from (forehand) forward
Become (backhand) backward, make rat finish the full distance by such mode；After Quan Bu, test is another in the same way
Side forelimb.The data obtained adjust gait exactly, the measurement index of this experiment be rat finish the full distance step number (unit:
Times).
Result: as shown in Figure 7 and Figure 8, the right fore of 6-OHDA one side damage rat is adjusting gait experimental headfirst
With offside to be less than in head step number backwards and blank group (P < 0.01), and at its lumbar injection dilantin sodium
After, its right fore headfirst with head step number backwards compared with the PD rat model not injecting dilantin sodium, present significantly
Go up (P < 0.01).6-OHDA one side damage rat left fore, does not has difference (P > 0.05) compared with control group.
Conclusion: by the observation of rat motor Behaviors survey, lumbar injection dilantin sodium can be effectively improved PD model
The movement defect of rat, at pickup time of creeping, crawl time, creeps every step by step long and adjusts on the experimental index such as gait,
Before and after administration, its damage ruined is collateral joins forelimb movements behavior and there is notable significant difference (P < 0.01).
In sum, dilantin sodium as the most common a kind of antiepileptic, as a kind of voltage gated sodium from
The blocking agent of subchannel can effectively alleviate the dyskinesia of PD rat model, and the drug therapy giving PD provides a kind of new
Thinking and strategy.
Claims (1)
1. a dilantin sodium is preparing the application alleviated in Parkinson's motor symptoms medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610175608.7A CN105769858A (en) | 2016-03-26 | 2016-03-26 | New use of phenytoin sodium |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610175608.7A CN105769858A (en) | 2016-03-26 | 2016-03-26 | New use of phenytoin sodium |
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| CN105769858A true CN105769858A (en) | 2016-07-20 |
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| CN201610175608.7A Pending CN105769858A (en) | 2016-03-26 | 2016-03-26 | New use of phenytoin sodium |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000050014A2 (en) * | 1999-02-23 | 2000-08-31 | Mylan Pharmaceuticals, Inc. | Phenytoin sodium pharmaceutical compositions |
| CN105012265A (en) * | 2015-08-19 | 2015-11-04 | 上海华源安徽锦辉制药有限公司 | Pharmaceutical composition containing phenytoin sodium compound as well as preparation method of composition |
-
2016
- 2016-03-26 CN CN201610175608.7A patent/CN105769858A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000050014A2 (en) * | 1999-02-23 | 2000-08-31 | Mylan Pharmaceuticals, Inc. | Phenytoin sodium pharmaceutical compositions |
| CN105012265A (en) * | 2015-08-19 | 2015-11-04 | 上海华源安徽锦辉制药有限公司 | Pharmaceutical composition containing phenytoin sodium compound as well as preparation method of composition |
Non-Patent Citations (2)
| Title |
|---|
| ALLESIA M. GILLESPIE,JR.: "《Manual of spectrofluorometric and spectrophotometric derivative experiments》", 31 December 1994, CRC出版社 * |
| 刘靖等: "苯妥英钠不良反应研究进展", 《现代中西医结合杂志》 * |
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