Transcript 张宝荣_MDS

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Baorong Zhang M.D.
Professor and Chair
ZJU Department of Neurology
and ZJU Brain Center
(email: [email protected])
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Movement disorder disease is induced by basal ganglia
damage with different kind causes, such as : toxin,
degeneration, infalmanntary, infarction , genetics, ect.
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It comprise a spectrum of abnormalities that range
from the hypokinetic disorders (of which Parkinson's
disease is the best-known example) at one extreme to
the hyperkinetic disorders (exemplified by Huntington's
disease and hemiballismus) at the other.
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Parkinson’s disease
Huntington’s disease
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Wilson disease
Multiple system atrophy:
SND,OPCA,SDS
Dystonia
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Restless Leg Syndrome
Psychiatric diseases (OCD)
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Tremor:
Video. PD.avi
a rhythmic oscillatory movement
best characterized by
its relationship to voluntary motor
activity
Intension: cerebellar
rest : PD(4-6 Hz)..PDbrother 012.mpg
 action: Essential and cerebellar
 postural: metabolism(8-12 Hz)
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Chorea: denotes rapid irregular muscle jerks
that occur involuntarily and unpredictably in
different parts of the body(Video:)HDchorea.MPG
 Tic: Sudden,repetitive,stereotyped,purposeless
brief actions,gestures,sounds
 and words that emerge from a background of
normal motor activity.
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Spasticity: continue clonic contraction,
upper motor neuron( hereditary spastic
paraplegia,HSP)
Myoclonus: a single sudden jerk or a short
series occurring in slow : CJD(CreutzfeldtJakob disease(Prion disease), AIDS
dementia complex
Athetosis :
 in contrast to chorei form movements
 these are slower
 writing,resembling the actions
 like a worm or snake
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Dystonia
 sustained muscle contractions
 often causing twisting movements
 or abnormal postures
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General consideration
Causes
Pathogenesis
Clinical findings
Different diagnosis
treatment
“帕金森病”的由来
---伦敦医生Parkinson
James Parkinson
1817
History of Parkinson´s disease (PD)
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First described in 1817 by an English physician,
James Parkinson, in “An Essay on the Shaking
Palsy.”
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The famous French neurologist, Charcot, further
described the syndrome in the late 1800s.
Jame parkinson’s founding
 Biochemistry founding
 MPTP
 Mutaion of Gene
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全球约400万帕金森病患者
 一般在55岁以上的人群中患病率在1%以上
 65岁以上的老人中患病率高到2%。
 近期的一项调查显示中国65岁以上人群PD患病
率接近1.7％，与西方国家接近(Zhang ZX
etal)
 因此在中国大陆至少有约200万PD患者，远远
超过欧美主要国家PD患者人数的总和
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Epidemiology of PD
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The most common movement disorder
affecting 1-2 % of the general
population over the age of 65 years.
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The second most common
neurodegenerative disorder after
Alzheimer´s disease (AD).
World Health Organization estimates for
incidence and prevalence follow:
wemen: 4.9/100,000
men: 5.8/100,000
0-19 years: 0.0/100,000
20-64 years: 3.9/100,000
65 years and over: 49.3/100,000
wemen: 6/100,000
men: 8/100,000
0-19 years: 0/100,000
20-64 years: 6/100,000
65 years and over: 70/100,000
There’s about 200,000 PD patient in China.
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May be less prevalent in China and other Asian
countries, and in African-Americans.
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Prevalence rates in men are slightly higher
than in women; reason unknown, though a
role for estrogen has been debated.
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Genetics
Age
Sex
Environmental
Toxin
Injury
Infection
Vascular
Idiopathic causes:
Primary PD(75%):idiopathic Parkinson's disease
1.5 men/women ratio
Main risk factor : age
Young onset: before 50 y.o.
Rare familiar forms: genetic clues
PARK 1-8
1.
Park1: alpha-synuclein dominant: mutation
2.
Park2: Parkin, mainly recessive;
3.
4.
5.
6.
7.
8.
Park3 (Chr 2p13 dominant) [1998]
Park4: alpha-synuclein dominant: gene duplication
Park5: UCHL1, possibly dominant)
Park6: PINK1, recessive
Park7 (Chr 1p33-p34; recessive)
Park8: LRKK2-dardarin
More genes?
Exposure
variable
Cases
Controls
OR+
>20
74
14
32
199
21
20
1.0
1.5
4.5
0
1-19
>20
89
7
24
218
13
9
1.0
1.2
6.4
Years
used
Herbicides/p 0
esticides
1-19
Paraquat
+
Odds ratio, adjusted for age, gender, smoking
*Liou HH, et al. Neurology 1997;48:1583-8
Secondary PD (25%):
Vascular disease
Infectious and postinfectious
Postencephalitic
Neurosyphilis
AIDS
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Toxins:Manganese ,Cyanide
Methanol ,Carbon ,monoxide
MPTP,Pesticides
Medications:Neuroleptics ,
Dopamine-depleting agents
Calcium-channel blockers
Valproic acid
Fluoxetine
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Hypoparathyroidism with basal ganglia
calcification , Hypothyroidism and
hyperthyroidism
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Miscellaneous:
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Repeat trauma (notably from boxing)
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Structural lesions:
Tumors ,Infarctions ,Hydrocephalus
Neuropathology of PD
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Eosinophilic, round intracytoplasmic inclusions called
lewy bodies and Lewy neurites.
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First described in 1912 by a German
neuropathologist - Friedrich Lewy.
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Inclusions particularly numerous in the substantia
nigra pars compacta.
Functional neuroanatomy of PD
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Substantia nigra: The major origin of the dopaminergic
innervation of the striatum.
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Part of extrapyramidal system which processes
information coming from the cortex to the striatum,
returning it back to the cortex through the thalamus.
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One major function of the striatum is the regulation of
posture and muscle tone.
Neuropathology of PD: Lewy bodies
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Not limited to substantia nigra only;
also found in the motor nucleus of the vagus nerve,
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the hypothalamus, the nucleus basalis of Meynert
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the cerebral cortex, the olfactory bulb and the autonomic
nervous system.
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Confined largely to neurons; glial cells only rarely affected.
Diagnosis of PD
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Clinical examination
No disease-specific biological marker available
Positron Emission Tomography (PET) or
Single-photon Emission Computed
Tomography (SPECT) with dopaminergic
radioligands
Exclusion of several causes of secondary
Parkinsonism
Chronic, progressive neurodegenerative disease
Primary symptoms:
 Resting tremor
 Rigidity
 Bradykinesia
 Gait disturbance
Illustration of Parkinson's disease
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Motor signs
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Non-motor signs
Tremor
 Akinesia
 Rigidity
 lose of postural reflexes
 Reduced arm swing
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Masked faces
Strooped Posture / Shuffling Gait
Low Speech Volume (Hypomimia)
Micrographia(Small Handwriting)
Postural Instabilty(Ususally Late)
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Orthostatic Hypotension
Hyposomia
Urinary Incontinence
Sleep Behaviour Disorder
Dementia (Late)- In 40-80% at some
stage of PD
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depression
constipation
Pain
Dementia
Slowed Thinkung
Anxiety / Pain attacks
RBD
DyskinesiaDYSKINEIA1.MPG
Peak dyskinesia
Biphasic dyskinesia
dystonia
Motor-fluctuation
Wearing off phenomina
On-off phynomena
0n-delay
Motor dyskineia(confortable)
peak dyskinesia2.MPG
PD-Motor and non-motor.avi
(unconfortable)
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Completely off: Severe PD-OFF 031.avi
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ON time decreased
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OFF time increase: 翁采琴 129.avi
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On delay
The Unified Parkinson's Disease Rating Scale
(UPDRS)
Evaluated by interview and clinical assessment in the following
categories:
Mentation, behavior, and mood
Activities of daily living
Motor
Complications of therapy
Hoehn-Yahr Stage
Schwab and England Activities of Daily Living
Scale
为了鉴别血管源性帕金森综合征（Vascular Parkinsonism,VP）
尚无统一的诊断标准，曾经命名：
arteriosclerotic parkinsonism,
arteriosclerotic pseudo-parkinsonism
lower-body parkinsonism
在100例临床诊断PD中，病理证实3例系腔隙性脑梗引发的VP, 无路易小体
（Hughes, 1992）
VP的临床特点：
下肢受累为主（步态不稳、易跌倒）
容易合并痴呆
常为对称性强直
震颤少见
多数多巴制剂等治疗效果不显著
MR: 基底节区慢性缺血灶。急性缺血引发的VP罕见
起病前过去的6个月内使用过下列药物
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经典的神经阻滞剂
 氟哌啶醇
 奋乃静、维思通等动眼危
象.wmv
 氯丙嗪
 舒必利
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钙离子拮抗剂：西比灵
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利血平
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……
流行性甲型脑炎（昏睡性脑炎，
Encephalitis lethargica）
因为舌蝇传播的一种昏睡性脑炎，19151926年大流行
临床表现为：高热、咽喉红肿、头痛、昏
睡、眼球运动障碍、帕金森症候群。
以帕金森症候群为主要表现的称为MSA-P
（占80%）
以小脑症状为主要表现的称为MSA-C（占
20%）
原发性帕金森病与进行性核上性麻痹的鉴别
进行性核上性麻痹
原发性帕金森病
临床表现对称性
对称
起病不对称
步态障碍,跌倒
病程早期即出现
病程早期极少出现
眼球上、下视
不能
能
姿位反射
早期出现损害
正常
躯干姿位
呈伸展位
行走时呈屈曲位
行走时摆臂动作
可有
病程早期行走时即无
面容
惊恐面容
面部表情减少
眨眼
3-5次/分钟
10-14次/分钟
静止性震颤
不常见
常见
肌张力障碍和强直的部位
更多出现在躯干
更多出现在肢体
手部变形
无
有特征性的手部变形
对左旋多巴的反应
无或差
好
左旋多巴诱导的异动症
极少
经常
“剂末”、“开关”现象
不常见
常见
PSP临床诊断..psp2.MPG标准(NINDS-SPSP)
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临床特点
 皮层症状：失用、皮层感觉缺失、异己手等
 锥体外系症状：不自主运动、帕金森综合征、
肌张力障碍等
 影像特点（磁共振FLAIR相）
 非对称性皮质萎缩，中央区皮质下白质高信号
 非对称性大脑脚萎缩，中脑被盖萎缩
女, 62Y, Feeling change and no emotion
one year
 Speeche slow
 Cognitive decline
 MMSE为17分（Parimary school education）
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Modopar test：
After UPDRS motor score is the same as
before 40
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Video
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3
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Early treatment:
Hypotention
nause,vomiting
Hallucination
Precaution:individual dosage,little
by little
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Dyskinesias
Motor fluctuation
Depression
Insomia
Pain
Dementia
Constipation
Parkinson's disease is a chronic disorder that
requires broad-based management including
patient and family education,
 support group services
 general wellness maintenance
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physiotherapy, exercise, and nutrition.
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Medications or surgery can just provide relief from
the symptoms.
What is the desired goal of pharmacological
therapies for Parkinson’s disease?
- Produce more output from the striatal dopamine neurons
I. increase dopamine synthesis capacity
II. direct activate post-synaptic receptors
III. inhibit dopamine metabolism
IV. alter the interaction/balance with other
neurotransmitters
V. dopamine releasers
VI. L-DOPA peripheral metabolism inhibitors
•
Main Line Agents:
• L-DOPA plus carbidopa (Sinemet®)
• dopamine receptor agonists (ropinirole,
pramipexole )
• MAO B Inhibitors (rasagiline , selegiline)
•Lower Efficacy/Second Line or Adjuvant Agents:
anticholinergics (benztropine, trihexyphenidol)
• DA reuptake Inhibitor (amantadine)
• COMT Inhibitor (entacapone)
Dopamine Agonists
The dopamine-agonists bromocriptine, pergolide,
pramipexole, ropinirole , cabergoline, apomorphine,
and lisuride, are moderately effective.
 Dopamine agonists initially act by stimulating some
of the dopamine receptors.
 Dopamine agonists can be
useful for patients experiencing
on-off fluctuations and
dyskinesias as a result of high
doses of L-dopa.
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D1 家族
D2 家族
受体亚型
受体亚型
D1 D5
D2 D3 D 4
D1, D2 subcortical
D3, D4, D5 cortical
 1st generation agonists
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(ergot derivatives*)
 bromocriptine
 pergolide
(D2 agonist)
(D2/D3 agonist)
 2nd generation agonists: (non-
ergot)
 ropinirole
(D2/D3 agonist)
 pramipexole (D2 agonist)
 rotigotine
(D3/D2/D1 agonist)
 Other Dopamine Agonists
 short-acting non-ergoline
agonist
 apomorphine( D1 and D2
receptors )
 Other Dopamine Agonists
 short-acting non-ergoline
agonist
 apomorphine( D1 and D2
receptors )
MAO-B inhibitor:
Selegiline
Rasagiline
COMT inhibitor:
entacapone
Amantadine
block DA reuptake,glutamate
receptors
A2A antiagonist: clinical trial
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帕金森病运动并发症是帕金森病重要症状，
应该早期诊断、早期治疗
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早期帕金森病起始治疗推荐使用非麦角类
多巴胺受体激动剂，以推迟左旋多巴使用，
延迟运动并发症的发生
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1872: Meigs and Mason
Academy of Medicine
 adult-onset
 progression
 tendency to insanity and
suicide
 inheritance pattern.
 Hereditary Chorea.
• “I have drawn your attention to
George Huntington
this form of chorea gentlemen, not
that I considered it of any great
practical importance to you, but
merely as a medical curiosity, and
as such it may have some interest.”
Huntington Disease: Historical Aspects
First described by George Huntington in 1872 in families in
East Hampton, Long Island
“ Over fifty years ago, in riding
with my father on his
professional rounds, I saw my
first cases of ‘that disorder’,
which was the way in which the
natives always referred to the
dreaded disease….we suddenly
came upon two women,
mother and daughter, both tall,
thin, almost cadaverous, both
bowing, twisting,
grimacing…my medical
education had its inception.
From this point on my interest
in the disease has never wholly
ceased.”
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Huntington disease,HD：
is transmitted as autosomal dominant trait
With complete penetrance.Both sexes are
equally affected.
VIEDO- HDfamily1.avi1 HD2.MPG
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Genetics characteristics：
Gusella etal (cell,1993) identified the gene_IT15,
IT15 with exon 67:
 IT15 gene code:PloyQ(Huntingtin, Htt）:
1972-Centennial
Ramon Avila-Giron
 El Mal de San Vito
 165 families studied in 4
towns
 Of the 1352 people, 28
had HD
 203 people in those
families had died with
HD
 A sailor (A.D.) involved
in dividivi trade with
Germany probably
introduced HD in this
region between 1860
and 1870
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Dystonia and parkinsonism
predominate
Seizures
Typically paternal inheritance due to
anticipation; expansion of CAG repeat
Faster progression (duration 5-15 years)
1979- First American expedition to
Maracaibo led by Dr. Nancy Wexler
 1981- First of annual trips to the
region
 1983- Discovery of the HD gene
marker on chromosome 4
 1993- Identification of IT-15
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Motor
Cognitive
•Frontal-Executive
•Attention
•Planning
•Memory
•Visuospatial
•Eye movements
•Chorea
•Dystonia
•Gait and balance
•Dysarthria and
dysphagia
•Parkinsonism
Psychiatric
•Depression
•Anxiety
•OCD
•Psychosis
CoQ10, Creatine,
Mitochondrial
BN 82451
Ethyl-EPA,
lipoic acid
dysfunction
Remacemide,
Excitotoxicity
Riluzole
Transglutaminase
Aggregate
Inhibitors:
Cystamine
PolyQ toxicity
aggregation inh:
Congo red
Intrabodies,
Genetics
siRNA
Proteasomal and
lysosomal
dysfunction
HDAC Inhibitors:
Transcriptional
SAHA, sodium butyrate
dysregulation
Caspase-mediated
Caspase Inhibition:
Minocycline
cell
death
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Wilson (1912) describe: is a
degeneration induced by Cu
metabolism disorder with liver
cirrhosis and basal ganglia
dysfunction
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Autosomal genetics
Genetics mapping 13q14-21
Ceruloplasmin decreased
Pathology: deposit in Brain ,liver,
kidney and corneal,
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Age; 4-50 Y
Basal ganglia symptoms
Psychological symptoms: no
motivation, intelligence decline
personality change
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Liver dysfunction
K-F ring
Kidney function failure
Skin color change
Bone degeneration: fracture
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1.Ceruloplasmin reduced (200mg/L)
2.K-F ring
3.MRI
4.X ray in Bone
5.Blood cu decrease and urine cu
increase in 24h
 Principle:
 lower cu food, lessen cu absorbed
 increased cu export
 symtomatic treatment
Zinc sulfate:50-150mg/d,tid or qid
D-penicillamine：1-1.5g/d
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20mg/d for child
 Traditional Chinese medicine
 Liver transplantation
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原则：低铜饮食、减少铜吸收、增加铜排出和
症状治疗
 饮食：避免高铜饮食：豆类；坚果类（花生、
胡桃；蔬菜（菠菜、茄子、葱）；瓜果类如南
瓜；薯类（芋头、山药）；蕈类（香菇及其他
菇类）、软体动物（乌贼、鱿鱼、牡蛎）、贝
类（蛤蜊、蛏子、淡菜、河蚌）、螺类、虾蟹
类、腊肉、动物的肝和血、巧克力、可可、咖
啡、蜜糖、中药的龙骨、牡蛎、蜈蚣、全蝎等。
此外，含铜量较高的食物还有牛肉、各种干果
等。勿用铜制的食具及用具。
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适宜日常摄食的含铜量低的食物：如精白米、精
面、鸡蛋、鱼、猪肉、瘦鸡鸭、小白菜、藕、芹
菜、橘子、苹果、桃子、牛奶等。
 （3）高氨基酸或高蛋白饮食，有利于铜的排泄
 3。阻止肠道铜的吸收
 锌剂: 50-150mg/d,tid or qid
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青霉安：1-1.5g/d 20mg/d for child