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Stroke and Treatment
Zhang Xiu-mei
Department of Pharmacology,
Medicine School, SDU
E-mail: [email protected]
Tel: 88383146
2017/5/23
1
Conflict of Interest
I have no financial relationships or support from commercial
interests to disclose.
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Case
Mr Arthur Attack, 71-year-old, arrives at Accident and Emergency accompanied by
his wife. Mrs Attack says that he had just finished fried breakfast 2 hours ago and was
doing nothing in particular when suddenly, in mid-conversation, he became unable to
speak. Arthur appears perfectly aware of his surrounding but is unable to understand
anything that this wife or the doctor says to him or writes down for him. Arthur has
difficulty in speaking, and when he does speak, the speech is unintelligible. On
examination, he is found to weigh 108kg and is hypertensive. Neurological examination
reveals increased reflexes and some weakness of his right arm and face;
somatosensation on the right side of his face and arm is also absent. His doctor tells his
wife that he has just had a stroke, and he is immediately prescribed a drug called
Alteplase(tPA)). Ten days later, there has been some improvement in his condition. All
sensation has returned and he is now able to understand verbal and written commands.
However, he is still unable to speak properly, and the motor symptoms remain.
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Question
1. What are the main causes of stroke?
2. What is the blood supply to the brain?
3. How does the main arterial blood supply relate to the main
functional areas of the cerebral cortex?
4. What are the mechanism underlying cell injury in stroke and
how does this influence treatment?
5. What is the prognosis for this patient?
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Objectives
1. Pathophysiology of the ischemic stroke.
2. Drugs for acute stroke prevention.
3. Drugs in the treatment of ischemic stroke.
4. Drugs for chronic cerebrovascular disease and sequelae of
stroke.
5. Drugs under research.
6. The problems in the drug treatment of stroke.
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Stroke
Stroke(cerebrovascular disease, CVD) is one of the three
leading death pathogenesis in both World and China, which is
characterized by “three high” , that is “high incidence, high
mortality, high deformity”. Acute brain ischemia is the
primary cerebrovascular diseases, whose death rate is next
only to the malignancy.
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About one third of patients
with acute ischemic stroke
died no longer after
acurence, and the survival
got disabled because of
hemiplegia偏瘫, aphasia失
语 and other sequelae,
losing work ability and
even unable to take care of
themselves.
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Stroke
全国每年新发脑卒中约200万人；
每年死于脑卒中约150万人,存
活的患者数（包括已痊愈者）
约700万！
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目前我国农村中风死亡率首次超过城市
农村居民在20世纪90年代初脑卒中死
亡列第三位，90年代后期升至第二位。
并且我国中风患者中中青年的比例已经
升至10％，且农村中风死亡率超过城
市。
WHO结果显示，中国脑卒中发病率排名世
界第一，比美国高出一倍，我国国民死因
调查显示，脑卒中已成为中国居民的第一死
因，也是所有单病种中致残率最高的疾病，
存活患者中，约3/4致残。
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10月29日是“世界卒中日”
“世界卒中日”是由世界卒中组织（World Stroke Organization）设立
的，是为了在全球范围内加强公众对脑卒中的认识。
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“世界卒中日”
2010
主题:“六分之一”，
即全世界每六个人
中有一人可能在一
生中罹患卒中；每
六秒钟就有一人死
于卒中；每六分钟
就有一人因 中风而
永久致残。
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2011
2012
主题都是“关注脑卒中，立
即行动”！
口号:
“防治脑卒中越早越好”、
“早期发现并控制危险因素，远离
脑卒中”。
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Stroke
According to etiology stroke can be classified as:
Hemorrhagic
1.
stroke
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2.
Ischemic
stroke
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Isc-stroke
80%~85%
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Hae-stroke
15%~20%
Brain ischemia is the main type of stroke, 80%~85%
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Ⅰ. Pathophysiology of Ischemic Stroke and the
Animal Model Preparations
(Ⅰ) Pathophysiology of ischemic stroke
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Time therapeutic window—（pathology/pharmacology）
Manifestation Energy disturbance，
EAAT/FT，
Ca2+ over-load，
cell death
Apoptosis，
Inflammation
Therapy Thrombolytic,
in 3 hr (about
1%-2% effective）
Neuron protective
agents, in 24 hr.
Acute period
stroke
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In 24 hr
Anti-inflmmatory
agents, neuron
protective agents
Subacute period
One week
Brain remodeling
(neuron regenesis ,
synapse formation,
revascularization,
glial scar formation )
nervous function
recovery
unknown
Chronic period
After 1 week
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Impairment of function（penumbra, reparable）
Structure lesion (
irreparable )
min~hours
Energy disorder
hours~days
EAA toxicity
inflammation
Cell death
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days~months
Compensatory function recovery,
brain remodeling
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Ischemic brain injury is a complicated pathological
process. Its pathogenesis involve energy disturbance,
excitoxicity, free radical damage, neuron apoptosis,
inflammation and calcium over-load, and so on.
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The change of neuron ion balance induced by ischemia
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The vascular inflammatory change induced by brain ischemia/reperfusion
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Cerebral ischemia/reperfusion
no energy
damage of Na-K-ATPase
acidosis
Infarction surrounding
depolarization
release of glutamine
NMDA&AMPA receptor
calcium overload
chondriosome injury
Activation of NOS,
esterase, protease, et al
Apoptosis
iNOS
Programming cell death
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Inflammation
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1. Energy Disturbance
ATP is the main energy source of the brain, which is produced
by oxidation-phosphorylation and glycolysis. The weight of the
brain accounts for 2% of the body weight, the volume of CBF
accounts for 15%~20% of the output, while its energy
utilization，cell integration account for 40% and its nerve
impulse transmission accounts for 60% of the whole body.
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If the brain blood flow is interrupted, ATP can maintain only
for 1 minute. Spontaneous activity will disappear in 15
seconds, and ATP will be exhausted in 5~15 minutes.
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2. Excitotoxicity
(excitatory amino acid, EAA)
Excitatory amino acid exerts excitatory effect on the CNS.
Glu is the main-amino acid in the CNS, which has extensive
and potent excitatory effect on the cerebral cortex, and
maintains the normal signal transmission of the neuron.
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Excitatory amino acid
Structure:
a group of free acidic amino
acid with two carboxyl and
one amino.
Including Glu and Asp and
so on.
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Source, release and uptake
Source of Glu：
Synapse突触体
Neuron 神经元
Gliocyte metabolic pool 胶质细胞代谢池
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Mechanism of Glu release
Ca2＋-dependent release
In general, glutamic acids are released by exocytosis from
presynaptic Ca2+-dependent vesicle. When the cell
depolarizes, Ca2+ channel opens, and Ca2+ afflux occurs, then
with ample ATP, glutamic synaptic vesicle fuse with plasma
membrane, and Glu is released by exocytosis.
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Mechanism of Glu release
Ca2＋-dependent release
Shortly after brain ischemia, ATP is deceased, or exhausted,
then Ca2+-ATP enzyme is inhibited, so Ca2+ efflux from synapse
cytoplasm decreases and Ca2+ concentration increases;
meanwhile Glu can active NMDA-R-mediated Ca2+ channel,
inducing Ca2+ afflux, increase of Ca2+ concentration, and Ca2+dependent Glu release.
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Mechanism of reuptake
Glu is uptook by nerve endings and uptaking system in the
neurogliocyte. Glu uptaken into neurogliocyte is converted
into glutamine by glutamine synthetase, then glutamaine is
transferred back to nerve endings and transformed into
glutamate by de-aminozation, which termed “glutamate-
glutamine cycle”.
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（1）Cerebral distribution of EAA receptor:
Cortex,
Hippocampus,
Striatum,
Septal(中膈)
Amygdala (杏仁核)
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Striatum（纹状体）
Amygdala （杏仁核）.
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(2) Subtypes of EAA receptor
a. NMDA receptor [N-methyl-D-aspartate(N-甲基-D-门冬氨酸)receptor]
b. AMPA receptor [α-methyl–3–hydroxy–5–methyl- 4 –
isoazolepropionic acid(α-甲基–3–羟基–5–甲基异恶唑-4-丙酸)，quisqualate
使君子氨酸)] receptor
① ionstropic receptor: (Qi)AMPA-R
② metobotropic receptor: [(Qm)mGlu-R,1- aminocyclopentane1，3-dicarbozylic acid(1-氨基-环戊基-1，3-二羧酸(ACPD受体)] receptor
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c. Kainate(海人藻酸)receptor
d. L-AP4 receptor[L-2-amido-4-phosphoracyl butyric
acid(L-2-氨基-4-磷酰丁酸)receptor
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Typical agonist, antagonist for different EAA
receptor subtypes and their effects
Subtype
Selective agonist
Selective antagonist
NMDA
NMDA
D-AP5
Kainate
Kainate
CNQX, DNQX
AMPA(Qi)
AMPA
NBQX
mGlUR(Qm) transACPD
L-AP4
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Effects
Open Na+, K+, Ca2+ channel
Open Na+/K+ channel
Produce intracellular IP3, DAG
L-AP4
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(3) EAA and stroke
Brain ischemia often causes neuronal damage, but hypoxia
and intermediate metabolites deficiency are not direct injury
factors. During brain ischemia, large amount of excitatory
amino acid (EAA) are released from ischemic neurons, which
play a key role in neuronal damage.
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PCP, 苯环己哌啶
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Characteristics of glutamic acid toxicity
1) Toxicity occurs fast.
2) Injury mediated mainly by Ca2+ in afflux.
3) Can be blocked by receptor antagonists.
4) Self-spreading.
5) Different neurons has different sensitivity.
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3.Calcium Over-load and Stroke
(1) Activate Ca2+-dependent protease, XD→XO.
(2) Activate PLA1 and PLA2, AA↑.
(3) Neurotransmitter release↑.
(4) Mitochondrial oxidative uncoupling, cell respiratory
depression.
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4. Oxygen Free Radical and Stroke
free radical
·O2- → ·OH
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Free radical is a generic name of atom, molecule, ion
or radical who have one or more unpaired electrons
in the outer layer of their electron orbit.
At present, during free radicals that inducing or
exacerbating brain ischemic damage, oxygen free
radical and NO are studied most.
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Oxygen free radicals
Refers free radicals induced by oxygen.
Including：Superoxide anion (O2-), hydroxyl free radical
(OH) , lipid peroxide (LO-, LOO-), oxidation metabolites of
NO (NO2, ONOO-), etc.
Reactive oxygen species (ROS):
hydrogen peroxide (H2O2)
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and
‘O2
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NO is a sort of gas with no
negative charge, with free
radical property, acting as
intracellular and intercellular
signal and as a
neurotransmitter. It has
unpaired electron, so can easily
disperse through the cell
membrane.
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Main reasons for free radical production during brain
ischemia/reperfusion:
(1)Disturbance of energy metabolism.
(2)Increase of xanthine oxidase formation.
(3)Activation of neutrophils.
(4)Increased activity of arachidonic acid metabolism-related
enzymes.
(5)Activation of NOS.
(6)Spontaneous oxidation of compounds (hemoglobin,
catecholamine, sulphydryls, cytochrome P450 reductase)
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(1)Xanthine-xanthine oxidase pathway
Ca2+
Ca2+ dependent protease
XD
ATP
ADP
AMP
XO
hypoxanthine xanthine
O2- XO
uric acid
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(2) Metabolic pathway of arachidonic acid
Ca2+
Phospholipase A2
COX, lipoxidase
Membrane
phospholipid
AA
PGs ,LTs
O2.-
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(3) NO pathway
EAA
NMDA receptor
Introcellular
Ca2+
NO synthase
NO
.O 2
ONOO－
H＋
ONOOH
ONO + .OH
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(4) NADPH oxidase pathway on the neutrophil
membrane
Complement C3,
LTS and endotoxin
Oxygen uptake by macrophage
Activity of NADPH oxidase
O2 is reduced into .O2-
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5. RAS and stroke
Importance is increasingly attached to the effect of
renin-angiotensin system (RAS) during the process of
stroke
Drugs acting on RAS have potential value in the
prevention and therapy of stroke.
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AGT
Renin
AngⅠ (1-10)
ACE
Chymase
etc.
ACE2
AngII(1-8)
amido-peptidase A
Endopeptidase
AngⅢ（2-8）
AT1
(359)
AT2 (363)
amido-peptidase N
AngⅣ(3-8)
IRAP
AT4
Ang（1-7）
1.Contract blood vessel +
release aldosterone：
increase blood pressure
2.Promote cell proliferation
and hypertrophy
cardivascular reconstruct
Release NO,
partly antagonize
the effect of AT1
receptor
Mas
AT3
胰岛素调节的氨肽酶受体
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Renin-angiotensin System(RAS)
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RAS in the brain
All family members of RAS present in the brain:
Angiotensinogen, renin, ACE, AngⅡ and angiotensin
receptors.
AngⅡ can be generated by classical pathway, or by
direct hydrolysis of angiotensinogen
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RAS in the brain
（1）Regulate brain blood flow
（2）RAS and cerebrovascular atherosclerosis
（3）AngⅡ and nerve regeneration and tissue repair
（4）Impact on fibrinolytic system
（5）AngⅡ and cytokine and inflammation
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RAS & Targets
Renin-I
Angiotensinogen
Renin
Non-ACE*
Pathways
Angiotensin I
↑
↓release
Bradykinin
Substance P
Enkephalins
ACE
Angiotensin II
↑
ACEI
Inactive
Fragments
Losartan
Angiotensin II Receptors
A-II blockade
Sub-type AT1 AT2
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6．Arachidonic Acid（AA）Metabolism and Stroke
PGs increase during brain ischemia or brain trauma,
and may exert pathological effect.
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Arachidonic acid（AA）metabolism and stroke
(1) PGH2, PGG2, PGF2α, TXA2, LTB4, LTD4, LTC4 cause
vascular constriction，some PGs promote platelet
aggregation, increase vascular permeability.
a. Contract brain blood vessel，decrease local blood flow,
aggravate brain ischemia;
b. Promote platelet aggregation，release of 5-HT and CA, etc；
c. Increase capillary vessel permeability, cause exosmosis of
plasmic content；
d. Intracellar cAMP decrease, cGMP increase, energy
metabolism is disturbed。
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Arachidonic acid（AA）metabolism and stroke
(2) Oxygen free radical is produced, causing damage
to bio-membrane.
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Membrane phospholipids
phospholipase A2
glucocorticoid
lipoxygenase
Arachidonic acid
COX
PGI2 synthetase
(vascular endothelium)
5-HPETE
PGG2
PGH2
iosmerase
leukotrienes
NSAIDs
PGI2
reductase
PGE2
PGF2α
TXA2 synthetase
(platelet)
TXA2
Allergy
inhibit platelet aggregation induce inflammation vasoconstriction platelet aggregation
vasodilation
cause fever and pain bronchial constriction vasoconstriction
bronchial constriction hyperalgesia
vasodilation
vaslular permeability
hyperalgesia
Induce inflammation
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Metabolism of AA and mechanism of drugs
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7. NO and Ischemic Stroke
NO produced at different time or by different NOS have different
effects on the brain
Superearly stage after stroke, NO produced in endothelial cells
help ameliorating microvasculature disturbance
At late stage of stroke, cNOS and iNOS generate abundant NO,
which have cytotoxicity to neurons, and can aggravate stroke.
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Mechanism of NO on brain blood vessel
(1) NO mediate the excitoxicity of glutamic acid.
(2) NO act on iron-containing proteins to induce toxicity.
(3) NO cause damage to DNA.
(4) NO cause release of abundant DA which induce neurotoxicity.
(5) NO cause cytotoxicity by oxygen free radical.
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NO and ischemic stroke
At early stage of stroke, rapid increase of NO stimulates
vasodilation and so increases brain blood flow.
After reperfusion，NO increases again to dilate blood vessel,
but aggravates brain damage.
During reperfusion,
NO reacts with ·O2- to produce
peroxide, which can induce oxygen radicals that have potent
cytotoxicity.
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8. Inflammation and Cell Adhesion
Molecules and Stroke
During stroke and reperfusion, free radicals cause damage,
induce inflammation. Excessive inflammatory response not only
disturb local blood flow, but also exert direct damage to tissue
structure, which is a primary reason for ischemic brain damage.
Inflammatory cells (leukocyte, monocyte-macrophage, and so
on), cytokine（TNF、IL-8、ICAM-1、PAF-1, and so on) are
involved in the inflammatory response of ischemic brain tissue.
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Monocyte-macrophage and their chemokines with brain ischemia
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Leukocyte and stroke
The surface of neutrocyte and EC can excrete integrin,
selectin and cell adhesion molecules, mediating
intercellular adhesion.
In physiological state, superficial adhesion molecules,
affinity of the two cell types is weak, so leukocyte
scarely adhere to endothelia cells.
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Leukocyte and Stroke
During stroke, local leukocytes are activated by a
lot of
diffusible inflammatory mediators (such as LTB4,TNF, IL-8,
PAF, H2O2, and so on) released from injury tissues, and the
amount and activity of adhesion molecules are significantly upregulated, so intercellular adhesion is strengthened, inducing
firm adhesion of leukocytes to endothelia cells.
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leukocyte induces toxicity after adhesion
(1) Mechanically blocks microvasculature, inhibits blood flow of
ischemic brain.
(2) The simultaneously activated leukocytes can release large
amount of toxic ROS and proteolytic enzymes, inducing regional
cerebrovascular injury, with increased vascular permeability and
aggravated brain edema.
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Leukocyte and Stroke
(3)Toxins released from leukocytes can cause further
damage to survival neurons and gliocytes, aggravating
brain injury.
(4)Leukocytes also release some inflammatory
mediators and cytokines, aggravating inflammatory
response, attracting more leukocytes into the tissue,
creating a vicious cycle, so resulting in a though
damage of the tissue.
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Cytokines and Stroke
Cell adhesion molecules and Stroke
ICAM-1 is a ligand of lymphocyte function associated antigen-1(LFA-1),
belonging to the immunoglobulin superfamily
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PFA and stroke
Platelet activating factor (PAF) is a arachidonic acid metabolismrelated endogenous active phospholipids and lipid mediator.
There are substantial PAF existing in the brain, PAF receptor and
signal transduction system located in neurons and endothelial
cells. During brain ischemia or brain trauma, PAF level in the
brain tissue markedly increases.
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IL-8 and stroke
Interleukin-8 (IL-8) is a low-molecular-weight polypeptide
synthesized by multiple cells. It can chemotact and activate
neutrophils and regulates the adhesion of neutrophils and
endothelial cells, playing an important role in the inflammation.
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IL-8 and stroke
Recently, it is discovered that IL-8 is involved in the pathological
changes of stroke.
IL-8 level in the brain significantly increases in 6h after TIA /
reperfusion. And antagonist of IL-8 can significantly alleviate
brain edema, reduce infarct size. So it is thought that brain
reperfusion injury can induce IL-8 production.
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9. Apoptosis and Stroke
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Judgement for apoptosis
(1)With the morphological features of apoptosis.
具备凋亡的形态特点
(2)In situ end labeling positive.
原位末端标记法阳性
(3)Electrophoresis showed "DNA ladder"-like model.
电泳时呈现“DNA梯”样模式
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Possible mechanisms for ischemic neuronal
apoptosis
(1) Free radical and NO.
(2) Excitatory amino acid.
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（Ⅱ）Pathological Models of Stroke
1. Animal Model of Focal Cerebral Ischemia–Middle Cerebral
Artery Occlusion（MCAO）
Dogs, cats, rabbits, rats: ligation through the temple or orbital
cavity, oppression or embolization of the middle cerebral artery.
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大鼠局灶性脑缺血再灌注损伤模型制备
10%水合氯醛3ml/kg ip麻醉，大鼠仰卧位固定，取颈部正中切
口，钝性分离各层组织，暴露左侧颈总动脉（CCA），分离至颈
内（ICA），颈外（ECA）动脉分叉后一段，在ECA发出约0.8cm
处结扎。结扎CCA近心端，在其上做一锲形切口，将尼龙线自切
口处轻轻插入CCA，经颈内，颈外动脉分叉部进入ICA，继续向
前推进，直到ICA颅内分叉部阻断流入大脑中动脉（MCA）的血
流。此处距颈总动脉分叉部约17mm。逐层缝合，尼龙线留约1cm
于皮外。缺血1h后，将尼龙线轻轻抽出即可使动脉恢复再通，
实现灌注。
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MCAO model
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动 物 模 型(MCAO)
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2．Animal Model of Global Ischemia
(1) Animal model of forebrain ischemia by two vascular
occlusion (2VO) (dispersed uncomplete brain ischemia): occlude
bilateral common carotid artery and control the blood pressure
under 50mmHg by bloodletting.
Simulate shock, cardiac pump disfunction or severe stenosis or
occlusion of cerebral vessels complicated with brain disorder
caused by low perfusion.
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Models of Stroke
(2)Animal model of global ischemia by 3VO: occlude basilar
artery and bilateral common carotid artery of the rat.
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Models of Stroke
(3) Animal model of complete global ischemia by 4VO: occlude
bilateral vertebral artery and bilateral common carotid artery
of the rat.
(4) Hypertensive brain injury：reno-vascular hypertension
stroke model (RHS) and brain injury caused by vasoconstrictor.
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（Ⅲ）Determination of Cerebral Blood Flow
1. Microballoons method.
2. Arterio-venous oxygen difference method.
3. 3H, 133Xenon clearance method.
4. Determination of cerebral vascular diameter.
5. Ultrasound Doppler and laser Doppler techniques.
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（Ⅳ）Study for Blood-brain Barrier (BBB)
1. Morphological study
(1) Electron microscope
and light microscope.
(2) CT, MRI and PET.
(3) Tissue or cell culture.
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2．Functional Examination
(1)Permeability of BBB: brain water content, determination of
paint, brain edema fluid analysis and isotopic tagging.
(2)Delivery function study of BBB.
3．Combined study of the morphology and function.
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Ⅱ Drugs for Acute Stroke Prevention
According to amount of clinical Meta analysis, some effective
treatment may decrease morbidity of the ischemic stroke.
For the treatment of primary diseases
Hypotensive agents
Antidiabetes mellitus drugs
Antithrombotic therapy in atrial fibrillation
Lipid-regulating agents（Statins）
Affect blood coagulation
Antiplatelet agents: aspirin
Aspirin plus dipyridamole
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(I)Drugs in the Prevention of Stroke
1. Statins
Effective in the I and II prevention of stroke by many
Meta analysis.
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86
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Simvastatin on the types and severity of stroke Meta-analysis
2. Anti-platelet Agents
Aspirin, clopidogrel氯吡格雷, ticlopidine噻氯匹定 and
dupyridamole双嘧达莫 can prevent brain thrombosis formation.
Aspirin with dipyridamole may have synergism.
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(II)Drugs in the Treatment of Ischemic Stroke
Thrombolytic therapy：
Few drug(tPA), therapeutic window narrow, unsafe.
Neuroprotective agents：
Many kinds of drugs, ineffective clinically.
Promote neuron recovery：
In early stage, valuable for more study.
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1. Neuroprotectives
2. Drugs for the brain metabolism.
3. Free radical scavengers.
4. NOS inhibitors.
5. Anti-ICAM agents.
6. Anti-infllamotry agents.
7. Endocelin receptor antagonists.
8. Thrombolytics.
9. Drugs for reducing brain edema
and intracranial pressure.
10. Others.
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Neuroprotectives
1. CCB
2. EAA receptor antagonists
3. Glutmate release inhibitors
4. GABA receptor agonists.
5. Adenosin transport inhibitors
6. Phospholipidase inhibitors
7. Ganglioside(GM1)
8. Neurotrophin
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(III) Drugs for the Treatment of Brain Edema
1. Glucocorticoid
Ameliorate vascular brain edema, but is invalid for cellular brain
edema. Dexamethasone is in common use.
2. Dehydrant agents
Hypertonic glucose, mannitol, sorbitol, urea. Effective for
cytotoxitic edema, but may rebound.
3. Blood dilution
Low molecular weight dextran is in common use. It can reduce
pressure volume blood cell, and increase CBF。
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（IV）Calcium Channel Blockers
Nimodipine is the protype of this group. it is a lipid soluble
L-type channel blockers of dihydropyridines.
It can inhibit excessive Ca2+ entry into plasma and mitochondria,
and so inhibit intracellular calcium overload .
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Effects of Ca2+ Channel Blockers on Cerebral Vessel
1．Favorable effects
① Prevent or inhibit spasm of main cerebral artery, cerebral
blood vessel dilatation.
② Dilate pia mater vessel, increase CBF
③ Scavenger oxygen free radical, protect ischemic brain.
2．Unfavorable effects
①Increase tissue susceptibility to ischemic injury.
②Reduce mean arterial pressure (MAP).
③Increase intracranial pressure.
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Nimodipine
Pharmacological effects on cerebrovascular
1. Cerebrovascular dilation
(1)Dilation of normal vascular
(2)Increase brain blood flow of ischemic animal.
(3)Vascular protection for subarachnoid hemorrhage
2. Alleviate brain ischemia, ameliorate cerebral circulation,
inhibit Ca2+ over-load by direct effect on neuronal tissues.
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Clinical Uses
a.Acute and chronic stroke
b.Subarachnoid
hemorrhage (SAH)
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(V) Vascular Dilators
Paraverine罂粟碱, cyclandelate环扁桃酯, buphenine布酚
宁, naftidrofuryl萘呋胺酯and other drugs are not
recommended because of their blood flow-stealing
phenomenon.
PGI2 can dilate cerebral blood vessel, inhibit platelet
aggregation.
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（VI）Antiplatelet Drugs
1．Cycloxygenase inhibitors（COXI）
Aspirin is frequently used.
COX in platelet is sensitive to low dose of aspirin, which
irreversibly acetylates and blocks the active site of platelet COX .
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Aspirin
1. Antiplatelet effect
Mechanisms
(1) Low dose inhibits platelet COX-1,↓TXA2 synthesis。
① Platelet can’t synthesize COX，so the inhibition effect of
Asp for platelet COX can last 5~7d，but for endothelial
COX it only lasts 1-1.5d.
② Deacetylation of Asp occurs before its entry into systemic
circulation, which inactivate COX-1.
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30
530
530
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(2) Enhance the inhibition effect of leukocyte for
activating platelet.
Leukocyte-mediated NO/cGMP-dependent mechanism
may be involved.
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2. Prevention of Atherosclerotic Stroke
(1) Inhibit platelet aggregation.
(2) Inhibit thrombosis.
(3) Improve EC function of injured blood vessel: ↑vascular
dilatation effect of Ach.
(4) Protect LDL from oxidation.
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3．Ischemic Stroke and TIA
（1）Acute stage therapy
IST、CAST试验证实，Asp可显著降低脑卒中患者再次发生脑血
管意外，以及以死亡和非致死性脑卒中为综合终点的危险性，
并不增加出血性脑卒中危险性。
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（2）Secondary prevention二级预防
脑卒中或短暂性脑缺血发作者长期服Asp可降低脑卒中再发生的危险性，非
致死性脑卒中和血管性事件亦降低。小剂量Asp与双嘧达莫合用疗效增加。
缺血性卒中初次发作后早期应用小剂量阿司匹林（50mg/d）能够显著降低卒
中再发的风险。 建 议：
（1）单独应用阿司匹林的剂量为50～150mg/d，分2次服用；
（2）也可使用小剂量阿司匹林（25mg）加双嘧达莫缓释剂（200mg）的复
合制剂（片剂或胶囊），2次/d；
（3）对阿司匹林不能耐受者可选用氯吡格雷（波立维），75mg/d.
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（3）Primary prevention一级预防
尚无定论。
有报道，Asp对预防缺血性脑卒中无益，反可增加出血性脑卒中
发生的危险性。
欧美国家心脏血管学会推荐剂量
急性治疗（AMI、不稳定心绞痛、血栓闭塞性脑卒中） 开始160-325mg/d,
以后75-160mg/d。
心脑血管病二级预防：160-325mg/d
心脑血管病一级预防：未确定，高危者75-160mg/d。
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1.1978加拿大报告，585例TIA，阿司匹林325mg qid,26mon，
TIA和缺血性脑血管病降低19%。
2.Hass(1988)噻氯匹定1529例，3年卒中发生率17%，阿司匹林
1540例，卒中发生率19%。
3.Bellavance用噻氯匹定和阿司匹林5.3年，对可逆性脑缺血
发生率噻氯匹定优于阿司匹林。
4.美国、加拿大协作组证明阿司匹林和双嘧达莫预防脑缺血作
用相似。
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5.荷兰TIA试验 TIA患者口服阿司匹林3Omg与283mg降低卒中和
急性心梗作用相似，分别为14.7%和15.2%。
6.1994年抗血小板协作组 抗血小板治疗(口服阿司匹林75～
325mg)5837人，安慰剂对照5870例，1～3年内治疗组血管事件发
生率18%，对照组22.2%，非致死性卒中发生率给药组8.2%，对照
组10.2%，组间有明显差异。
分析剂量与疗效、性别等因素，证明75mg与325mg之间无差异，
提出每日口服75～100mg，可起慢性预防作用。
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Aspirin
Contraindications
Asthma, gastric ulcer, gastrointestinal hemorrhage,
hemophilia, retinal hemorrhage and CHF.
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Wonderful drug—Aspirin
阿司匹林历史悠久。1853年法国人Gerhardt用水杨酸与醋酐合成了乙酰水杨酸，但未
能引起重视；1898年德国化学家Felit Hoffmann重新进行合成，并为他父亲治疗风湿
性关节炎，取得成功；1899年由德国Bayer公司上市，并取名为阿司匹林（Aspirin）。
1999年3月6日德国Bayer公司在全世界范围内庆祝阿司匹林的百岁生日，114年来全世
界的人们大约服用了数十亿片阿司匹林，主要用于解热、镇痛、抗炎抗风湿，近年又
在防治心、脑血管疾病、延缓衰老、抗肿瘤等方面发挥重要作用。阿司匹林是20世纪
诸多发明中的最辉煌篇章。
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Treat colon cancer by aspirin
Related to down regulation of PIK3CA signaling by inhibiting
COX-2.
New Engl J Med, 2012,10,27 (IF53.298)
Short-term effects of daily aspirin on cancer incidence, mortality,
and non-vascular death: analysis of the time course of risks
and benefits in 51 randomized controlled trials.
Lancet，2012，Apr 28;379(9826):1602-12 (IF38.278)
Effect of daily aspirin on risk of cancer metastasis: a study of
incident cancers during randomized controlled trials.
Lancet，2012 Apr，28;379(9826):1591-601 (IF38.278)
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A view of a Bayer AG building covered to look like an aspirin box
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Antiplatelet
drugs
2. Phosphodiesterase inhibitors
Dipyridamole双嘧达莫
Paraverine罂粟碱
3.TXA2 synthase inhibitors
TXA2 synthase inhibitors are under clinical study, such as OKY1555, OKY-1581, dozoxiben苯酸咪, UK37248, UK38485, and so
on.
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Antiplatelet
drugs
4. Specific inhibitors of platelet activation by ADP
Ticlopidine噻氯匹定, clopidogrel（氯吡格雷，波立维）
Block fibrinogen combine with receptors, inhibiting α granule
secretion induced by ADP, increase PGI2, decrease TXA2
formation.
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Antiplatelet
5. Platelet GPⅡb/Ⅲa receptordrugs
blockers
Abciximab( e7E3Fab, Reopro)
Monoclonal antibody of glycoprotein(GP, 血小板表面糖蛋白)
GPⅡb/Ⅲa, block fibrinogen combine with receptors, antiplatelet.
Fibrinogen is the ligand of GPⅡb/Ⅲa receptor, inducing platelet
aggregation. Blockade of GPⅡb/Ⅲa receptor may prevent
embolism or re-embolism of narrowing coronary artery and
carotid artery, more effective than aspirin.
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(ⅤII) Anticoagulants and Thrombolytic Drugs
Anticoagulants mainly include warfarin and heparin.
Application of thrombolytic drugs:
Fibrinolytic therapy is aimed at thrombolysis, restoration of
blood perfusion, reversion of ischemic brain tissue. It is should be
administrated before necrosis of brain tissues, furthermore, the
dose and its contact time with thrombus must be in accordance.
It also reduce blood viscosity, improve bypass circuit, retrieve
penumbra of the brain ischemic zone.
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Two main categories of fibrinolytic agents
1. Non-directional fibrinolytic agents
Streptokinase(SK)and urokinase(UK)
SK: t1/2=18～83m，systemic fibrinolytic effect is distinct.
UK: t1/2=10～l5m，Systemic fibrinolytic effect is weaker than
SK.
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Thrombolytic Drugs
2. Directional fibrinolytic agents
(1) Single-chain urokinase
High affinity for plasminogen in thrombus.
t1/2=3.5～8m，activity can maintain for hours.
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(2)Anistreplase (anisoylated plasminogen streptokinase
activator complex, ASPAC, 阿尼普酶)
ASPAC can combine with fibrin automatically, and then is
converted to plasminogen activator by hydrolysis and
deacetylation, generating plasmin纤溶酶 on the surface of
thrombus to exert a regional thrombolytic effect. Half-life of
BRL-26921 now in clinical use is 40m，and its thrombolytic
activity is 10 times potenter than SK.
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(3) Tissue-type plasminogen activator(tPA)
Second generation, directly activate plasminogen, t1/2=2～8min.
Alteplase(human recombinant tissue-type plasminogen activator,
rt-PA)
Activity can be maintained for 1～2h，has high affinity for
fibrinolysin in thrombus, has no distinct systemic fibrinolytic
effect.
Siteplase西替普酶, nateplase那替普酶.
Third generation, reteplase, 瑞替普酶:Effective, rapid, and
compliance
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Ⅲ Drugs for Chronic Stroke and its Sequela
(Ⅰ) Ergots
Dihydroergotoxine(hydergine)
Their cerebrovascular effect may due to its interaction with
receptors of many neurotransmitters such as NE, E, 5-HT, DA.
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Effects on brain blood vessel
1. Dilate brain blood vessel (including capillary vessel)，inhibit
platelet aggregation, improve cerebral circulation and
anti-oxidation.
2. Improve brain metabolism.
3. Inhibit phosphodiesterase.
Uses：Cerebral arteriosclerosis, sequela of stroke, sequela of
head injury and cerebral spasm and periphery vascular diseases.
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(Ⅱ) Ginkgo bilaba extracts
Ginkgo bilaba extracts(GBE) contain many kinds of flavone and
lactone. Flavone can dilate blood vessel and cleave free radical,
and lactone is a nature antagonist of platelet-activating factor
(PAF) .
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Mechanisms
①Improve cerebral circulation.
②Antagonize PAF. GBE contain four kinds of lactones, of which
lactone B is the most important PAF antagonist.
③Prevent membrane injury from free radical.
Uses：Brian arteriosclerosis,
sequela of stroke,
neuropsychiatric symptoms caused by the elderly neurologic
dysfunction. Uses are similar to that of dihydroergotoxine.
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(Ⅲ) Vincamine长春胺 and vinpocetine
长春西汀(Japanese trade name CALAN)
t1/2 of vincamine is short. Aethroma-30 is its releasecontrol tablet.
Vincamine and vinpocetine(VP) are modifiers of
brain circulation and metabolism, having protective
effect for brain ischemia, VP is potenter than vincamine.
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Mechanisms
① Improve brain circulation.
②Stimulate brain metabolism.
③Protect ischemic brain.
Uses：They are mainly used for sequela of stroke and
brain arteriosclerosis and other neurologic dysfunctions.
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(Ⅳ) Idebenone(AVAN,艾地苯醌)
Brain metabolism stimulant and psychiatric symptoms
modifier.
Effects on cerebral blood vessel:
(1)Improve brain function, enhancing learning and memory of
animal suffer from global or focal ischemia.
(2)Improve metabolic disorders caused by brain ischemia or other
dysfunction.
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Mechanisms
①Activate mitochondrial respiratory function, increase
ATP synthesis, reduce lactic acid production, alleviate
cell injury induced by acidic toxicity.
②Inhibit production of lipid peroxide in mitochondria,
alleviate mitochondria edema.
③Increase Ach in brain tissue.
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Uses:
Sequela of stroke and cerebral arteriosclerosis
Clinical studies indicate that it can improve affective
disorders, behavior and intelligence disturbance of
patients who suffer from cerebral arteriosclerosis and
sequelae of stroke, with a 75%~81% efficiency.
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(Ⅴ) Pyrrolidones
Piracetam (普拉西坦, 脑复康), oriracetam奥尼西坦,
promiracetam and aniracetam阿尼西坦are used in clinically .
These compounds are stimulants of brain metabolism and
modifiers of brain function.
Usualy used for stroke, sequela of brain trauma, and elderly
neurologic dysfunctions.
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(Ⅵ) Befemelane,二苯美伦
Japanese trade name is Celeport, Alnert，a brain metabolism
stimulant.
Pharmacological action and indications are similar to piracetam,
but is stronger.
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Effects on bran blood vessel
(1)Enhancing learning and memory ability.
(2)Protect ischemic brain.
(3)Stimulate brain metabolism.
Clinical use
Similar to piracetam, used for sequela of stroke and cerebral
arteriosclerosis and elderly neurologic dysfunctions.
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(Ⅶ) Other drugs
1．Cyclandelate环扁桃酯
2．Citilcholine胞二磷胆碱
3．Pentoxifylline己酮可可碱
4．Propentofyllin丙戊茶碱
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Other drugs
5. Duxil都活喜
Contain 30mg almitrine阿米三嗪 and l0mg raubasin萝芙辛per
tablet.
6. Cerebrolysin脑活素
Pig brain extract, contain multiple amino acids and small peptides.
7. Naftidrofuryl萘呋胺酯
Brain metaboliam stimulantion and cerebraovascular dilation
effect. 100～200mg/d , PO.
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Ⅳ Drugs Under Research
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2. Free radical scavengers
(Ⅰ) Oxygen Free Radical Scavengers
1. Inhibitors for free radical production
Calcium-channel blockers, allopurinol (XOI)
2. Oxygen Free Radical Scavengers
(1)·O2- scavengers
Superoxide dismutase (SOD)
VitC: ·O2- → H2O2
Catalase: H2O2 → H2
(2)·OH scavengers
Mannitol, glucose, captopril.
(3)’O2 scavengers
Histamine
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(Ⅱ) Antagonists of Excitatory
Amino Acid Receptor
According to action site, they are classified as:
(1)Competitive antagonist acting on glutamate binding site.
(2)Partial antagonist acting on glycine site.
(3)Noncompetitive receptor channel blocker.
(4)Polyamine site antagonist.
(5)Selective subunit antagonist.
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Antagonists of excitatory amino acid receptor
（1）Selfotel: 在I、Ⅱ期临床试验中曾显示出很好的安全性和
耐受性，但Ⅲ期临床结果显示，治疗组死亡率明显高于对照组，
在脑缺血治疗中高剂量可能有神经毒性作用，无效、毒性。
（2）Glycine is a modulator of NMDA receptor
ACEAl021, GVl50526 have been approved safe in stage
Ⅱ clinical research, and further clinical observation is
necessary.
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Antagonists of excitatory amino acid receptor
(3)Noncompetitive receptor channel blockers are divided into two
groups according their action characteristics:
a. Irreversible receptor channel blockers
AR-R15896
b. Reversible receptor channel blockers
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EEAR antagonists
Memantine美金刚
作为金刚烷胺类似物，已用于术
后脑修复、AD等神经退行性疾病的
治疗。呈现低亲和力，阻断NMDA受
体通路的作用与MK-801相当，对血压、体温等无
影响，是目前较具优势的神经保护剂。
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(4)Polyamine site antagonists
Some potential compounds such as IEM-1754，IEM-1755，
IEM-1752 under research.
(5)Selective subunit antagonists
Some potential compounds such as Ro25-6981, Ro63-1908 under
research.
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with antagonists of excitatory amino
acid receptor
① Weak action, variability.
② Sensitivities are different in different brain regions.
③ Safety problem.
近来的证据表明，谷氨酸兴奋性毒性理论仅适用于短暂的缺血急
性期，在缺血后期应用NMDA受体阻断剂不利于神经元存活。
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Inhibitors for glutamic acid release
Lubeluzole芦贝鲁唑：Effective in acute ischemia stroke
attack 6h, iv 10mg/d X 6d.
BW-619C89
BW-1003C87
R87926
Under investigation.
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GABA receptor agonist
GABAＡagonist, under I clinical trial.
Muscimol蝇蕈醇
Chlormethiazole氯美扎酮
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(Ⅲ)Ganglioside (GM1)
Ineffective
(Ⅳ)Neurotrophic Factors (NTF)
Under experimental study.
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The failure of drug clinical trials for treatment
of stroke examples
Mechanisms
Drugs
Clinical trials results
CCB
Many agents
Ineffectiveness
Ca2+chelating agent
DP-b99
Under IIB trial
Selfotel
无效，毒性反应。
Aptiganel (Cerestar)
III期试验中止，缺证据。
镁
2个前期试验完成，2个正在进行。
Dextrophan
II期无效。
地佐环平（MK-801）
因副作用而中断。
YM872
正在进行。
ZK200775 (MPQX)
IIA期因中枢抑制作用中止。
GAvestinel (GV150526)
2个II期试验无效。
谷氨酸受体拮抗剂
NMDA拮抗剂
AMPA拮抗剂
甘氨酸位点拮抗剂
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The failure of drug clinical trials for treatment
of stroke examples
其他通道阻滞剂/调节剂
GABA受体激动剂
Clomethiazole
RCT完成，无效。
地西泮
III期多中心试验正在进
行。
Fosphenytoin
III期多中心试验无效。
Sipartrigine
无效。
Maxipost (BMS-204352)
III期试验无效。
5-HT1A受体拮抗剂
Repinotan
III期试验无效。
自由基清除剂
Tirilazad
无效。
Ebselen
多中心RCT：1个月有效，
3个月无效。
NXY-059
III期试验最后无效。
钠通道阻滞剂
钾通道激活剂
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The failure of drug clinical trials for treatment
of stroke examples
Enlimomab (anti-ICAM)
III期RCT：恶化。
LeukArrest, Rovelizumab
(Hu23F2G)
III期试验中止。
RNIF (recombinant neutrophil
inhibitory factor)
TNHH(recombinant neutrophil
inhibitory factor and hirulog
hybrid
因不良反应作用，欧洲III
期试验中止。
临床实验中（中国）。
UK-279,276
安全/可耐受，进行中。
单神经节苷脂
生长因子
阿片受体拮抗剂
磷脂酰胆碱前体
GM1
促红细胞生成素（EPO）
无效。
前期试验有改善作用。
2个试验为阴性。
5个试验的Meta分析，仅有
亚组改善。
预防性应用抗生素
左氧氟沙星
Piracetam
抗炎症药
其他机制
2017/5/23
机制未知
Nalmefene
Citicoline
无效。
III期RCT无效。
147
The failure of drug clinical trials for treatment
of stroke examples
星形胶质细胞调节剂
Arundic acid (ONO-2506) 北美II期结束；日本仍在
进行。
血液稀释剂
白蛋白
I期试验：可耐受；III期
试验正在进行。
促进红细胞生成
EPO；carbamylated
EPO；human chorionic
gonadotropin (hCG) +
epoetin alfa (EPO)
II/III期，尚未发表。
自由基清除剂
Edaravone (依达拉奉)
在日本上市。
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（V）Anti-inflammation
Possible pass-way
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（VI）Drugs Acting on RAS
(1)Dilate cerebral vessels, improve blood supply of the ischemic
zone，restore the auto-regulation for cerebral blood flow.
(2)Inhibit the action of AngⅡ in promoting AS, increase vascular
lumen/wall ratio, reverse vascular remodeling.
(3)Stimulate fibrinolytic system in blood plasma inhibit
thrombogenesis.
(4)Improve energy metabolism of brain ischemia.
(5)AT1-receptor antagonist can promote neuron reparation and
regeneration after focal cerebral ischemia-reperfusion.
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(VII)Some Potential Valuable Drugs
1. Drugs to regulating brain remodeling
(1)Drugs promoting regeneration of neuron and nervous net
formation.
(2)Drugs regulating angiogenesis, restore blood flow of ischemia
area.
(3)Drugs inhibiting formation of glial scar.
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(4)Improve energy metabolism of brain ischemia.
(5)AT1-receptor antagonist can promote neuron reparation and
regeneration after focal cerebral ischemia-reperfusion.
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2. Statins
Acetyl-CoA：
乙酰辅酶A
HMG-CoA：
羟甲基戊二酸单酰辅酶A
Mevalonate：
甲羟戊酸
他汀类药物除了降低胆固醇的
作用外，还能抑制中间产物的
合成，可影响多种细胞通路，
从而产生多方面有益的药理作
用。
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Pleiotropic effects of statins on vessel
154
Case
Mr Arthur Attack, 71-year-old, arrives at Accident and Emergency accompanied by
his wife. Mrs Attack says that he had just finished fried breakfast 2 hours ago and was
doing nothing in particular when suddenly, in mid-conversation, he became unable to
speak. Arthur appears perfectly aware of his surrounding but is unable to understand
anything that this wife or the doctor says to him or writes down for him. Arthur has
difficulty in speaking, and when he does speak, the speech is unintelligible. On
examination, he is found to weigh 108kg and is hypertensive. Neurological examination
reveals increased reflexes and some weakness of his right arm and face;
somatosensation on the right side of his face and arm is also absent. His doctor tells his
wife that he has just had a stroke, and he is immediately prescribed a drug called
Alteplase(tPA)). Ten days later, there has been some improvement in his condition. All
sensation has returned and he is now able to understand verbal and written commands.
However, he is still unable to speak properly, and the motor symptoms remain.
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Question
1. What are the main causes of stroke? Risk factors?
2. What is the blood supply to the brain?
3. How does the main arterial blood supply relate to the main
functional areas of the cerebral cortex?
4. What are the mechanism underlying cell injury in stroke and
how does this influence treatment? How to treat?
5. What is the prognosis for this patient?
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V The Problems in the Drug Treatment of Stroke
1. Angiemphraxis：血管再通时间窗窄，溶栓治疗不良反应严重，重在预防。
2. Complex in Pathogenisis：各种因素均有利弊两重性，注重内在保护因素。
3. Inflammation/immunoactivity：既是损伤因素，也可能是保护机制。
4. Regeneration：缺血后期的脑重构、可塑性、功能恢复需重点研究。
5. Predictability of Animal Model：需改进动物实验，注重长期变化、行为学
变化。
6. Blood-brain Barrier
7. Foundation experiment and clinical experiment results lack of consistency.
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Summary and Prospect
 脑缺血损伤涉及多个环节，治疗药物应包含多靶点；内在神
经保护机制及慢性期脑重构/功能恢复值得关注。
 预防原发疾病能降低缺血性脑卒中的发生，他汀类药物及抗
血小板药预防卒中效果肯定。
 溶栓治疗作用肯定，但时间窗窄，易并发出血；神经保护药
临床疗效尚不能证明，但值得期待。
 缺血性卒中是脑血管病的主要类型，迄今仍缺乏对大多数病
人均有效而安全的治疗方法及药物，这种状况促使抗脑缺血
药物成为一个持续的研究热点。
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Summary and Prospect
脑缺血后病理生理改变复杂，且多种因素密切相关，重建血供、
抗炎、保护血管内皮细胞、保护神经元的药物显示一定疗效；在
有效治疗的用药时间内联合应用不同作用机制的药物可取得协同
作用，同时可降低药物不良反应；改进动物模型以确切反映人类
缺血亚型，以此寻找有效抑制多种病理生理改变环节的药物是今
后的研究方向。
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