chapter 15 anti-parkinsonism and anti-dementia drugs 抗帕金森病和老年性痴呆药
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Chapter 15 Anti-parkinsonism and anti-dementia drugs 抗帕金森病和老年性痴呆药. Anti-Pakinsonism drugs. Muhammad Ali is known around the world as one of the great sports stars of the twentieth century. He needed great energy and power to become the world boxing champion. - PowerPoint PPT PresentationTRANSCRIPT
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Chapter 15
Anti-parkinsonism and anti-dementia drugs
抗帕金森病和老年性痴呆药
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Anti-Pakinsonism drugs
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Muhammad Ali is known around the world as one of the great sports stars of the twentieth century. He needed great energy and power to become the world boxing champion.
As he grew older, though, he began to change. The energy and power began to disappear. His face lost its expressiveness. His legs lost their speed.
Muhammad Ali is sixty-four now and long retired from boxing. Yet it was not age that changed him so much. It was Parkinson's disease.
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Muhammad Ali and another celebrity with Parkinson's disease, actor Michael J. Fox, before the start of a Senate hearing on the disorder in 2002
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教皇保罗二世
希特勒
阿拉法特
邓小平
陈景润
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What is Parkinson’s disease?
A progressive nervous disease occurring most often after the age of 50, associated with the destruction of brain cells that produce dopamine, and characterized by muscular tremor, slowing of movement, partial facial paralysis, peculiarity of gait and posture, and weakness.
one of the “neurodegenerative diseases”
神经退行性疾病
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特征性症状 • rigidity 肌肉僵硬 • bradykinesia 运动徐缓• resting tremor 静止性震颤• abnormal postural reflexes 异常体位反射(姿态不稳)
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development in the past ten years about PD symptoms
deficits in the sense of smell;
fatigue;
disturbances of the autonomic nervous system which controls blood pressure, urinary bladder, bowel and sexual function;
sleep disorders;
a variety of behavioral features including anxiety and depression;
and finally neuropsychological abnormalities including dementia.
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中国 PD流行病学资料:
1986 0.047 %
2000 1.14 % (上海统计资料)
2006 2.0 % (全国统计资料)全国病人数 170 万
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发病率:
中国: 130 人 /10 万人
美国: 187 人 /10 万人
西北欧: 185 人 /10 万人
Mayo Clinic : lifetime risk of developing Parkinson's disease , 2 % for men and 1.3 % for women
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4000 年前有记载
1817,英国医师 James Parkinson首次报道
1953,确定病变部位在黑质
1960, Austria Hornykeiwicz 发现与黑质纹状体中 DA含量显著降低有关
80 % neurons loss in substantia nigra
利舍平( reserpine )耗竭 DA, 致 PD 症状
动物损毁 DA 通路,显相似症状
1961,用 L-dopa治疗取得良好的效果
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1997 年确定 4月 11 日
World Parkinson’s Disease Day
世界帕金森病日
纪念 James Parkinson 生日
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Causes: why only those neurons die?
1, Primary (原发性) , unknown
2, secondary, chemicals: Mn2++, CO, brain injury, chemicals (除草剂、杀虫剂)…
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1976 美国一名大学生自己合成 MPPP (非法毒品)享用,因制备错误,得到 MPTP 。
3 天后, PD 样症状。家人误以为得精神分裂症。医生诊断后给抗帕金森病药物
2 年后自杀,尸检发现黑质损伤。
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1982 美国加州年轻人中发生帕金森病的爆发小流行
神经内科医生了解:
都使用过一名药剂师合成的注射用毒品 MPPP
制备毒品反应条件意外有误
含有大量的 MPTP(1-methyl-4-phenyl-1 ,2, 3, 6-tetrahydropyridine)
MPTP( 甲苯四氢吡啶)造模给猴子注射,亦得病
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MPTP: 1947 synthesized for anti-Parkinsonism
primates : rigid, unable to move, dies
6 persons: PD-like, 2 died.
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animal models
lesion of substantia nigra
MPTP model
rotenone (鱼藤酮) model
…
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ACh
DA GABA
纹状体
黑质
抗 M 胆碱
补充前体促释放
抑制降解受体激动剂
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提高多巴胺能神经功能 补充 DA 前体 左旋多巴 (levodopa) 促 DA 释放 金刚烷胺 (amantadine) 抑制 DA 降解 脱羧酶 卡比多巴 (carbidopa) ;
苄丝肼 (benserazide) MAO-B 司来吉林 (selegiline) COMT inhibitors 硝替卡朋 (Nitecapon
e) DA 受体激动剂 溴隐亭 (bromocriptine) 培高利 (pergolide)
降低中枢胆碱能功能 苯海索 (tribexyphenidyl)
治疗 PD 的药物
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左旋多巴 (Levo-dopa)
pharmacokinetics
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MAOCOMT
MAOBCOMT
HO
C C NH2
H
HH
H H
H
NH2CC
HO
HO
COOH
H H
HH
NH2CC
HO
HO
HO
HO
C C NH2
H
HH
HO
HO
C C
H
HH
CH2 O
HO
OH
H
H
C
HO
CH2 O COOH
COOH
L-Tyrosine
L-Dopa
Dopamine
HVA
NE
MHPG
DH
AADC
TH
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肝代谢 脱羧成多巴胺 DA 难通过 BBB ,进中枢 1% 同时用多巴脱羧酶抑制剂,减少外周 DA 生成 L-dopa + 卡比多巴 复方卡比多巴(信尼麦) L-dopa + 苄丝肼 多巴丝肼(美多巴) 2-4 年后逐渐失去作用
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Side effects:
1, cardiovascular system: orthostatic (体位性) hypertension
2, nervous system:
symptoms occurred after short term use
symptoms occurred after long term (>1 year) use
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金刚烷胺( amantadine)
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amantadine (金刚烷胺)
facilitation of DA release
inhibition of DA reuptake
direct DA receptor agonistic property
weak acetylcholine antagonistic action
used for mild PD
effective only for 1-2 years
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bromocriptine (溴隐亭)
central D2 agonist
inhibition of prolactin (催乳素) and growth hormone secretion
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生长激素
促甲状腺素
促肾上腺皮质激素
促性腺激素
催乳素
黑色细胞刺激素
垂体前叶分泌的激素
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bromocriptineused for
PD as an adjunctive
prolactinemia (高催乳素血症) acromegaly (肢端肥大症) delactation (回乳)
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苯海索 trihexyphenidyl
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trihexyphenidyl
selective central cholinergic antagonist
used for
mild PD
intolerable to levo-dopa
no response to levo-dopa
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Anti-dementia drugs
治疗老年性痴呆药物
Dementia
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1994 年 11 月 5日,美国前总统里根向公众宣布: “我最近被告知我是美国将患阿尔茨海默病的人中的一员。目前,我感觉良好。我打算在上帝赐予我的有生之年,一如既往地做我的事情。我还将和我的爱妻南希及全家一起在生命的旅途上行进。我打算多享受些野外生活的乐趣并与我的朋友和支持者们保持联系。”
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二年后 不认识熟人 六年后 不认识妻子;不知自己曾为总统 说话、做事困难 十年后 2004,died
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这是一种什么病?
为什么美国总统也治不好?
我们有多大机率得这种疾病?
病因、发病机制?
有什么预防、治疗的办法?
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What is the disease?
1906 年 德国巴伐利亚精神科医生
Alois Alzheimer描述了一名 50多岁女性
病人的临床病理学综合征,由此得名。
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Senile plaque - Silverstaining
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DR. ALOIS ALZHEIMER (1864-1915)
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9 月 21 日 世界老年痴呆日
2005主题:行动改变未来 2006主题 : 阿尔茨海默病 100周年——关注痴呆,刻不容缓!
全世界约有痴呆患者 2400 万
2040 年 , 约 8000 万
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我们有多大机会得病?
>60岁 3%
>70岁 4.5~ 6%
>85岁 >20%
中国 600 万人 确诊后平均寿命 5~ 15 年
每年治疗及护理费用: 2万元
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痴呆原因:
变性疾病:阿尔茨海默病、帕金森病、老年性舞蹈病、肝豆状核变性
血管性疾病:多梗塞性痴呆、皮质下白质脑病
损伤:拳击家痴呆、脑外伤后、脑缺氧后、蛛网膜下腔出血、一氧化碳中毒
感染:脑炎、脑膜炎后、克 -雅病、艾滋病
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中毒:酒精依赖性痴呆
肿瘤:脑瘤、慢性硬膜下血肿
代谢性疾病:维生素 B12 、叶酸缺乏、甲状腺功能低下
其他:正常颅压脑积水、癫痫、多种全身性疾病等
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60多种痴呆中:
50% 阿尔茨海默病(研究原型)
30% 血管性痴呆
20% 其他类型的痴呆
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阿尔茨海默病成为研究重点
1~ 2 年隐性发病
95%散发性( sporadic)
<5%家族性( familial )
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主要症状
进行性记忆损害
认知功能障碍
行为改变:妄想、偏执、社会恰当性丧失
进行性语言功能降低
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早期的发现:
与学习记忆有关的胆碱能神经元显著损伤
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cholinesterase inhibitors
donepesil (多奈哌齐)
huperzine A (石杉碱甲)
galantamine( 加兰他敏 )
rivastigmine( 卡巴拉汀 )
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tacrine 他克林 not used because of hepatic toxicity
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Evaluation:
40 ~ 50 % effective
therapeutic effect lasts about only several months ~ 1.5 years
many peripheral adverse drug reactions
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previously, DA agonist
now, non-competitive NMDA antagonist→inhibit the prolonged influx of Ca2+ ions→inhibit the over-excitation of neurons caused by Aβ, one of the etiologic factors of AD lower affinity than glutamate→preserves the physiological function of the receptor
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1982 as an anti-Parkinson’s disease drug, but had little effect
2002 Europe approved as anti-dementia drug
Used for moderate-severe AD
美国纽约大学医学院精神病科 Reisberg:
美金刚 (memantine) 对中~重度阿尔茨海默病 (AD) 有显著长期疗效
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阿尔茨海默病的病理特征•细胞外 •神经炎性斑块 (neuritic plaques)•主要成分 :β-淀粉样蛋白 (-amyloid , A)
细胞内 神经纤维缠结 (neurofibrillary tangles)主要成分 : 蛋白高磷酸化使该蛋白与微管解离,形成聚集
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β-淀粉样蛋白产生增加
聚集成块
对神经元产生毒性
发展成 AD
形成寡聚体,损伤神经元
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病 理 特 征:
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Potential targets for the treatment of AD:
inhibitors of β,γ secretase
inhibition of Aβ production
inhibition of Aβaggression into oligomers
increase of Aβ degragation
…
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第十六章 中枢兴奋药(不作要求)
建议阅读一遍
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建议的阅读材料 :
1, Selkoe DJ. Defining molecular targets to prevent Alzheimer disease. Arch Neurol. 2005; 62(2):192-5
2, 尹玲玲, 朱兴族 . 帕金森病的发病机制及其药物治疗研究进展。国外医学-药学分册 2006 ; 33 ( 2 ): 93-96