抗中枢退行性疾病药
抗帕金森病药
PARKINSONISM (Paralysis Agitants)
Parkinsonism is characterized by a combination of rigidity,
bradykinesia, tremor, and postural instability that can occur for
a wide variety of reasons but is usually idiopathic. The
pathophysiologic basis of the idiopathic disorder may relate to
exposure to some unrecognized neurotoxin or to the
occurrence of oxidation reactions with the generation of free
radicals. Studies in twins suggest that genetic factors may also
be important, especially when the disease occurs in patients
under age 50. Parkinson's disease is generally progressive,
leading to increasing disability unless effective treatment is
provided.
The normally high concentration of dopamine in the
basal ganglia of the brain is reduced in
parkinsonism, and pharmacologic attempts to
restore dopaminergic activity with levodopa and
dopamine agonists have been successful in
alleviating many of the clinical features of the
disorder. An alternative but complementary
approach has been to restore the normal balance of
cholinergic and dopaminergic influences on the basal
ganglia with antimuscarinic drugs. The
pathophysiologic basis for these therapies is that in
idiopathic parkinsonism, dopaminergic neurons in
the substantia nigra that normally inhibit the output
of γ-aminobutyric acid (GABA)ergic cells in the
corpus striatum are lost.
Schematic representation of the
sequence of neurons involved in
parkinsonism.
Top: Dopaminergic neurons (color)
originating in the substantia nigra
normally inhibit the GABAergic
output from the striatum, whereas
cholinergic neurons (gray) exert an
excitatory effect.
Middle: In parkinsonism,
there is a selective lossof
dopaminergic neurons (dashed, color).
Fate of orally
administered levodopa
and the effect of
carbidopa, estimated
from animal data. The
width of each pathway
indicates the absolute
amount of the drug
present at each site,
while the percentages
shown denote the
relative proportion of the
administered dose. The
benefits of
coadministration of
carbidopa include
reduction of the amount
of levodopa diverted to
peripheral tissues and an
increase in the fraction
of the dose that reaches
the brain.
一、左旋多巴及其增效剂
1.左旋多巴（L-dopa)
药理作用与机制
左旋多巴可使 80% PD 病人症状明显改善。
其中20%的病人可恢复到正常运动状态。起病初
期用药疗效更为显著，用药后患者感觉良好，抑
制和淡漠症状改善，服药后先改善肌强直和运动
迟缓，后改善肌震颤，由于情绪好转，能关心周
围环境，思维清晰敏捷，听觉口语学习能力明显
改善，生活质量明显提高。
特点
① 奏效慢，用药2 ~ 3周后才出现体征的改善，
1~6个月后获得最大疗效。
② 对轻症及年轻患者疗效好，对重症及年老患
者疗效差。
机制
L-dopa属DA的前体药，本身无药理活性，
脑内转化为DA，补充了纹状体中DA的不足，提
高中枢DA神经功能，抑制胆碱能神经功能，产
生抗震颤麻痹的作用。
体内过程
口服后主要在小肠经主动转运系统而迅速
吸收。进入中枢量不到1%，99%在外周经脱
羧换化为DA是引起不良反应的主要原因。因此，
提出与外周多巴脱羧酶抑制剂合用达到增效，
减少不良反应，还可减少左旋多巴的用量。
临床应用
1. 帕金森病治疗 广泛用于各种类型PD病人，运动
障碍症状不明显者一般不用。对抗精神病药物所
致锥体外系症状无效。病人长期用药效果有较大
个体差异。服药6年后，约半数病人失效。
2．肝昏迷辅助治疗 肝昏迷病人，由于肝功能障碍，
血中苯乙胺、酪胺升高，在神经细胞内经β-羟化
酶作用生成苯乙醇胺和 章胺（伪递质）妨碍正常
神经功能。用左旋多巴后，转化为NA恢复正常神
经功能，病人逐渐转为清醒。
鱼
不良反应
大多是由于左旋多巴在体内生成DA所致。
1．胃肠道反应 厌食、恶心、呕吐、腹部不适。是由于DA兴奋延脑催
吐化学感受区所致。继续治疗，由于产生耐受性，胃肠道反应可减
轻。
2．心血管反应 部分病人出现体位性低血压反应，表现头晕，偶见晕厥。
少数病人心律失常(DA兴奋心脏β1受体) 。
3．不自主异常运动 如咬牙、吐舌、点头、做怪相及舞蹈样动作，发生
率约40~80%，多在长期用药后出现，主要是由于DA补充过度，
须减量。少数病人长期用药后，可出现“开关现象”，表现为突然
多动不安(开)，转为全身产生强直不动(关)，二者交替出现，机制
尚无完满解释。
4．精神障碍 与DA过度兴奋中脑一边缘系统DA受体有关。
2.外周多巴脱羧酶抑制剂
卡 比 多 巴 （ Carbidopa） 、 苄 丝 肼
（benserazide）
外周多巴脱羧酶抑制剂，不易通过血脑屏障。
单独应用对PD无治疗作用，主要与左旋多巴按一
定比例制成复方左旋多巴制剂供临床应用，可增加
血和脑内L-dopa达3 ~ 4倍。
信尼麦（sinemet, 心宁美）
左旋多巴 : 卡比多巴=10 : 1（100mg :
10mg）
复方苄丝肼（美多巴，Madopar）
左旋多巴 : 苄丝肼=4∶1（100mg∶25mg）
联合用药主要优点
1、提高左旋多巴疗效（增效）
2、减少外周副作用（减毒）
3、减少左旋多巴用量（70 ~ 80%）
3. COMT抑制剂
L-dopa代谢有两条途径：
L-dopa DA 3-OMD（3-O-甲基
多巴）
而3-OMD又可与L-dopa竞争转运载体而影响L-
dopa的吸收和进入脑组织（生物利用度降低）
-co2 COMT
硝替卡朋（硝替卡朋（nitecaponenitecapone））
托托 卡卡 朋（朋（tocaponetocapone））
安托卡朋（安托卡朋（entocaponeentocapone））
可增加纹状体中L-dopa和DA。当与卡比多巴
合用时，只抑制外周COMT，增加L-dopa生物利
用度，而不影响脑内COMT（不易通过血脑屏障）。
抗老年性痴呆药
Downsized Target
A tiny protein called ADDL could be the
key to Alzheimer's
Scientific American 2004
Scientists have long suspected that the protein
clumps and tangles identified by Alois Alzheimer in
1907 somehow cause the disease that bears his
name, probably by killing neurons. Now some
researchers are blaming a much smaller form of
protein, one that apparently produces memory
deficits merely by binding to neurons and disrupting
their ability to transmit signals. The search has begun
for an antibody that would destroy these tiny
proteins--or ADDLs--thereby preventing the onset of
Alzheimer's disease and possibly even reversing the
early symptoms.
The discovery of ADDLs explains glaring
anomalies in the conventional thinking about
Alzheimer's, which holds that fragments of amyloid
precursor protein, produced by normal neurons,
aggregate into sticky, insoluble plaques that damage
neurons. The problem with this theory is that virtually
every older person carries some amyloid plaque, but
only a few develop Alzheimer's. Conversely, those with
Alzheimer's often have relatively few plaques. Another
proposed culprit is the presence of tangles of tau
protein, which form inside neurons and coincide with
the collapse of microtubules that support the cell body
and transport nutrients. The tau tangles correlate
much better with the disease but tend to appear later,
suggesting that they are a consequence, not a cause.
In 1994 Caleb E. Finch, a
neurogerontologist at the University of
Southern California, attempted to create
amyloid plaque by mixing a solution of amyloid
precursor protein fragments with clusterin, a
substance produced at higher levels in the
brains of people with Alzheimer's. The
clusterin did not trigger the formation of
amyloid plaques, but the resulting solution
profoundly disrupted the ability of the neurons
to transmit signals.
Finch reported this finding to Grant A. Krafft and
William L. Klein, two colleagues at Northwestern
University, who set out to discover what was in the
solution. Using an atomic-force microscope, they
obtained extraordinary pictures of globules no one had
ever seen. "They looked like little marbles," Krafft
recalls. "It turned out these globules contained only a
few of the amyloid peptide building blocks, whereas
the long fibrils contained thousands, if not millions, of
these subunits." The three scientists decided to call
the substance ADDL, which stands for amyloid beta-
derived diffusible ligand. (The molecule is derived
from amyloid precursor protein; it diffuses throughout
the brain instead of aggregating into fixed plaques; as
a ligand, it attaches to receptors on neurons.)
Klein developed an antibody that revealed how ADDLs
attach to dendrites in the hippocampus, thereby disrupting
signals needed to produce short-term memories. And last
summer Klein, Krafft, Finch and their colleagues found huge
quantities of ADDLs in postmortem brains from people with
Alzheimer's, whereas brains from normal patients were virtually
free of ADDLs. What is more, they discovered that neurons of
mice functioned normally once the ADDLs were removed.
The obvious solution to treat Alzheimer's disease, in
Krafft's opinion, is to remove the ADDLs or prevent them from
forming. Attempts to eradicate amyloid plaques are misguided,
he believes, and any attempt to intervene after neurons have
started to die comes too late to do much good. "It's pretty clear
to me that we're wasting about 90 percent of the Alzheimer's
research budget on things that are worthless," he says.
While crafting their theory, Krafft, Klein and
Finch acquired patent rights to ADDLs and formed
their own corporation, Acumen Pharmaceuticals,
which recently formed a partnership with Merck. "By
partnering with Merck, Acumen can get the antibody
and vaccine products to market much faster than if we
tried to do it by ourselves," Krafft explains.
Merck has committed up to $48 million to
Acumen for the right to develop an antibody against
Alzheimer's and another $48 million if it succeeds in
bringing to market a viable vaccine. That money, plus
funding from other investors, will enable Acumen to
devise three other ADDL-based strategies for
preventing Alzheimer's, as well as diagnostic tests that
would reveal early signs of the disease.
