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 机制 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。 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（nitecapone） 托 卡 朋（tocapone） 安托卡朋（entocapone） 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 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.