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1、抗中枢退行性疾病药抗中枢退行性疾病药1抗帕金森病药nPARKINSONISM (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 rel
2、ate 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. Parkinsons disease is generally progress
3、ive, leading to increasing disability unless effective treatment is provided.2nThe 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 successfu
4、l 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 idiopa
5、thic parkinsonism, dopaminergic neurons in the substantia nigra that normally inhibit the output of -aminobutyric acid (GABA)ergic cells in the corpus striatum are lost.3Schematic representation of the sequence of neurons involved in parkinsonism. Top: Dopaminergic neurons (color) originating in the
6、 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). 45 Fate of orally administered levodopa and the effect of carbidopa, es
7、timated 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
8、to peripheral tissues and an increase in the fraction of the dose that reaches the brain.6一、左旋多巴及其增效剂一、左旋多巴及其增效剂 1. 1.左旋多巴（左旋多巴（L-dopa)L-dopa) 药理作用与机制药理作用与机制 左旋多巴可使左旋多巴可使 80% PD 病人症状明显改善。病人症状明显改善。其中其中20%的病人可恢复到正常运动状态。起病初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
9、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。改善，生活质量明显提高。7特点特点 奏效慢，用药奏效慢，用药2 3周后才出现体征的改善，周后才出现体征的改善， 16个月后获得最大疗效。个月后获得最大疗效。 对轻症及年轻患者疗效好，对重症及年老患对轻症及年轻患者疗效好，对重症及年老患 者疗效差。者疗效差。机制机制 L-dopa属属DA的前体药，本身无药理活性，的前体药，本身无药理活性，脑内转化为脑内转化为DA，补
10、充了纹状体中，补充了纹状体中DA的不足，提的不足，提高中枢高中枢DA神经功能，抑制胆碱能神经功能，产神经功能，抑制胆碱能神经功能，产生抗震颤麻痹的作用。生抗震颤麻痹的作用。8 体内过程体内过程 口口服服后后主主要要在在小小肠肠经经主主动动转转运运系系统统而而迅迅速速吸吸收收。进进入入中中枢枢量量不不到到1%，99%在在外外周周经经脱脱羧羧换换化化为为DA是是引引起起不不良良反反应应的的主主要要原原因因。因因此此，提提出出与与外外周周多多巴巴脱脱羧羧酶酶抑抑制制剂剂合合用用达达到到增增效效，减少不良反应，还可减少左旋多巴的用量。减少不良反应，还可减少左旋多巴的用量。 9临床应用临床应用 1. 1
11、. 帕帕金金森森病病治治疗疗 广广泛泛用用于于各各种种类类型型PD病病人人，运运动动障障碍碍症症状状不不明明显显者者一一般般不不用用。对对抗抗精精神神病病药药物物所所致致锥锥体体外外系系症症状状无无效效。病病人人长长期期用用药药效效果果有有较较大个体差异。服药大个体差异。服药6年后，约半数病人失效。年后，约半数病人失效。 2 2肝肝昏昏迷迷辅辅助助治治疗疗 肝肝昏昏迷迷病病人人，由由于于肝肝功功能能障障碍碍，血血中中苯苯乙乙胺胺、酪酪胺胺升升高高，在在神神经经细细胞胞内内经经-羟羟化化酶酶作作用用生生成成苯苯乙乙醇醇胺胺和和 章章胺胺（伪伪递递质质）妨妨碍碍正正常常神神经经功功能能。用用左左旋
12、旋多多巴巴后后，转转化化为为NA恢恢复复正正常神经功能，病人逐渐转为清醒。常神经功能，病人逐渐转为清醒。鱼10不良反应不良反应 大多是由于左旋多巴在体内生成大多是由于左旋多巴在体内生成DA所致。所致。1 1胃肠道反应胃肠道反应 厌食、恶心、呕吐、腹部不适。是由于厌食、恶心、呕吐、腹部不适。是由于DA兴奋延脑催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。轻。2 2心心血血管管反反应应 部部分分病病人人出出现现体体位位性性低低血血压压反反应应，表表现现头头晕晕，偶偶见见晕晕厥。少数病人心律失常厥。少数病人心律失常
13、(DA兴奋心脏兴奋心脏1受体受体) 。3 3不不自自主主异异常常运运动动 如如咬咬牙牙、吐吐舌舌、点点头头、做做怪怪相相及及舞舞蹈蹈样样动动作作，发发生生率率约约4080%，多多在在长长期期用用药药后后出出现现，主主要要是是由由于于DA补补充充过过度度，须须减减量量。少少数数病病人人长长期期用用药药后后，可可出出现现“开开关关现现象象”，表表现现为为突突然然多多动动不不安安(开开)，转转为为全全身身产产生生强强直直不不动动(关关)，二二者者交交替替出出现现，机机制制尚无完满解释。尚无完满解释。4 4精神障碍精神障碍 与与DA过度兴奋中脑一边缘系统过度兴奋中脑一边缘系统DA受体有关。受体有关。1
14、12.2.外周多巴脱羧酶抑制剂外周多巴脱羧酶抑制剂卡卡 比比 多多 巴巴 （ Carbidopa） 、 苄苄 丝丝 肼肼（benserazide） 外周多巴脱羧酶抑制剂，不易通过血脑屏障。外周多巴脱羧酶抑制剂，不易通过血脑屏障。单独应用对单独应用对PD无治疗作用，主要与左旋多巴按一无治疗作用，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，可增加血和脑内血和脑内L-dopa达达3 4倍。倍。信尼麦（信尼麦（sinemet, 心宁美）心宁美）左左旋旋多多巴巴 : 卡卡比比多多巴巴=10 : 1（100mg : 10mg）复方苄丝肼（美多巴，复方
15、苄丝肼（美多巴，Madopar）左旋多巴左旋多巴 : 苄丝肼苄丝肼=4 1（100mg 25mg）12联合用药主要优点联合用药主要优点 1、提高左旋多巴疗效（增效）、提高左旋多巴疗效（增效） 2、减少外周副作用（减毒）、减少外周副作用（减毒） 3、减少左旋多巴用量（、减少左旋多巴用量（70 80%）133. COMT抑制剂抑制剂 L-dopa代谢有两条途径：代谢有两条途径： L-dopa DA 3-OMD（3-O-甲基甲基多巴）多巴）而而3-OMD又可与又可与L-dopa竞争转运载体而影响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）的吸收和进入脑组织（生物利用度降低）-c
16、o2COMT14 硝替卡朋（硝替卡朋（硝替卡朋（硝替卡朋（nitecaponenitecapone） 托托托托 卡卡卡卡 朋（朋（朋（朋（tocaponetocapone） 安托卡朋（安托卡朋（安托卡朋（安托卡朋（entocaponeentocapone） 可增加纹状体中可增加纹状体中L-dopa和和DA。当与卡比多巴。当与卡比多巴合用时，只抑制外周合用时，只抑制外周COMT，增加，增加L-dopa生物利生物利用度，而不影响脑内用度，而不影响脑内COMT（不易通过血脑屏障）。（不易通过血脑屏障）。15抗老年性痴呆药 Downsized Target A tiny protein called
17、ADDL could be the key to Alzheimers Scientific American 2004 16 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
18、 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 Alzheimers disease and possibly even reversing th
19、e early symptoms. 17 The discovery of ADDLs explains glaring anomalies in the conventional thinking about Alzheimers, 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 tha
20、t virtually every older person carries some amyloid plaque, but only a few develop Alzheimers. Conversely, those with Alzheimers 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 microtub
21、ules 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. 18 In 1994 Caleb E. Finch, a neurogerontologist at the University of Southern California, attempted to create
22、 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 Alzheimers. The clusterin did not trigger the formation of amyloid plaques, but the resulting solution profoundly disrupted the ability of th
23、e neurons to transmit signals. 19 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.
24、 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 amyl
25、oid 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.) 20 Klein developed an antibody that revealed how ADDLs attach to dendrites in th
26、e 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 Alzheimers, whereas brains from normal patients were virtually free of ADDLs. What is more,
27、they discovered that neurons of mice functioned normally once the ADDLs were removed. The obvious solution to treat Alzheimers disease, in Kraffts opinion, is to remove the ADDLs or prevent them from forming. Attempts to eradicate amyloid plaques are misguided, he believes, and any attempt to interv
28、ene after neurons have started to die comes too late to do much good. Its pretty clear to me that were wasting about 90 percent of the Alzheimers research budget on things that are worthless, he says. 21 While crafting their theory, Krafft, Klein and Finch acquired patent rights to ADDLs and formed
29、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
30、 the right to develop an antibody against Alzheimers 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 Alzheimers, as well as diagnostic tests that would reveal early signs of the disease. 22
