神经毒性
神经毒性物质诱发疾病的发病机制及治疗策略
神经毒性物质诱发疾病的发病机制及治疗策略神经毒性物质是指那些能够直接或间接影响神经系统功能的化学物质，这类物质的存在不仅给人类生命造成了危害，还极具挑战和研究意义。
目前，神经毒性物质的种类非常多，比如重金属、农药、工业化学品等。
这些物质在环境、工作和生活中广泛存在，会导致多种神经系统疾病。
本篇文章旨在探讨神经毒性物质诱发疾病的发病机制及治疗策略。
一、神经毒性物质引发神经系统疾病的发病机制1. 神经元细胞死亡神经毒性物质会导致神经元细胞死亡，这是引发神经系统疾病的主要机制之一。
神经元细胞死亡直接影响了神经元数量和功能，导致神经功能丧失。
神经毒性物质通过多种途径诱导神经元细胞死亡，例如：氧化应激、线粒体损伤、细胞凋亡、炎症反应等。
2. 炎症反应神经毒性物质不仅可以诱发细胞凋亡，还会导致神经系统炎症反应。
神经系统炎症反应可以导致神经元间的信号传递障碍，严重时会引发神经系统疾病。
炎症反应与神经系统疾病之间的关系比较复杂，不同疾病的发生对炎症反应的程度也有所不同。
3. 神经递质的改变神经毒性物质还会直接或者间接地改变神经递质的释放和代谢，从而影响神经信号传递。
当神经递质失衡时，就会导致神经系统功能异常。
例如，大量乙醇会抑制谷氨酸的释放，致使谷氨酸去甲基化酶活性升高，导致脑内甲基谷氨酸增加，发生神经系统疾病。
二、神经毒性物质引发神经系统疾病的治疗策略1. 抗氧化剂治疗神经毒性物质可以通过氧化应激途径引发神经元细胞死亡，而抗氧化剂是通过减少ROS（活性氧）的生成，增加天然抗氧化剂的活性等方式来延缓氧化过程，从而保护神经元。
目前，抗氧化剂包括维生素C、E、硒等，可以通过口服或注射等方式来治疗神经系统疾病。
其中，维生素C和维生素E是两种重要的抗氧化剂，能够减轻脑损伤和神经元细胞死亡。
2. 抗炎剂治疗神经系统炎症反应是神经毒性物质引起神经系统疾病的重要机制，抗炎剂能够减轻神经系统炎症反应，改善神经系统疾病症状。
目前，常用的抗炎剂主要包括非甾体抗炎药、糖皮质激素、免疫抑制剂等。
局麻药对外周神经毒性有哪些
局麻药对外周神经毒性有哪些【术语与解答】①神经系统分为中枢神经和周围神经两大部分，而周围神经则由脑神经和脊神经组成，当局麻药与周围神经接触的剂量过大、浓度过高，则可引起对神经组织的结构及功能相对递增的病理性改变;②临床上无论选择硬脊膜外隙脊神经干阻滞(简称脊神经干阻滞或硬膜外阻滞)，还是采用蛛网膜下腔脊神经根阻滞(简称脊神经根阻滞或腰麻)，或应用外周神经干(丛)阻滞(如颈神经丛或臂神经丛阻滞等)，均有可能引发相关并发症或异常症状，这主要由局麻药本身的周围神经毒性作用所致。
【麻醉与实践】临床实践发现局麻药周围神经毒性主要包括以下几方面:1. 脑神经毒性①脑神经是与脑直接相连的周围神经，除嗅神经和视神经外(第Ⅰ、Ⅱ对脑神经)，其他十对脑神经(Ⅲ～Ⅻ)均由脑干的不同部位发出，它们主要分布和支配头颈-颌面部(迷走神经还分布和支配胸、腹腔脏器) ;②脑神经的特点较脊神经复杂，其病理状态下表现出的临床异常症状也各有差异;③延髓在枕骨大孔处与脊髓连接，一旦局麻药经椎管内途径进入颅内，首先透过血-脑屏障与起源于延髓的脑神经接触(由下而上舌下神经、副神经、迷走神经、舌咽神经、前庭蜗神经)，其次与发自脑桥的脑神经接触，故临床上脊神经干阻滞(全称硬脊膜外隙脊神经干阻滞)期间局麻药中毒常表现为口舌麻木或口金属味、眩晕耳鸣等脑神经异常症状;④由于椎管内静脉(也称硬脊膜外隙静脉丛)与颅内静脉均无静脉瓣，而且硬脊膜外隙静脉与颅内的基底静脉、枕窦、乙状窦、舌下神经管静脉丛，以及横窦在枕骨大孔处相连接，并互相交通，如选择脊神经干阻滞的手术患者仰卧位非重力作用下其椎管内静脉血液回流至椎外静脉往往较缓慢，一旦不慎将局麻药误注入硬脊膜外隙静脉或该静脉丛吸收过多(如硬脊膜外隙导管误入静脉丛或损伤该静脉血管壁)，吸收后的局麻药液则可逆流或弥散直接进入颅内基底静脉等，并随局麻药的脂溶性不同而透过血-脑屏障的速度也稍有快慢。
此外，发自脑干的脑神经根部对局麻药最为敏感，当两者一旦接触，可立即出现相关的脑神经毒性症状，如口舌麻木或口金属味(舌咽神经、面神经和三叉神经毒性)、发声困难或声音嘶哑(迷走神经毒性)、眩晕耳鸣或眼球震颤(前庭蜗神经毒性)、斜视或复视(外展神经毒性)，甚至视物模糊(视神经毒性)等;⑤一般而言，硬脊膜外隙脊神经干阻滞所引起的脑神经局麻药中毒，首先与局麻药接触的枕骨大孔界面以上延髓区域的脑神经先出现毒性反应，其次出现脑桥与中脑区域的脑神经毒性反应，然后则为高级中枢神经中毒症状。
神经毒素
谢谢观看
由于塔崩在军事上特殊用途，研究人员开始深入地研究塔崩的结构。在塔崩基本结构的基础上，相继合成了 一系列神经性毒剂，最具代表性的四个神经性毒剂是塔崩、沙林、梭曼和维埃克斯（VX）。这类毒剂对乙酰胆碱 酯酶（Acetylcholinesterase, AChE）活性有强烈的抑制作用，使乙酰胆碱在体内蓄积，从而引起中枢和外周 胆碱能神经功能严重紊乱。因其毒性强、作用快，能通过皮肤、呼吸道、黏膜、消化道及眼等吸收引起全身中毒， 加之性质稳定、生产容易、使用性能良好，因此成为外军装备的主要化学战剂。
基本信息
基本信息
常可引起神经毒素（如蛇毒）和突触前神经毒素。也有作用于神经轴突（如石房蛤毒素），中枢神经系统的 （如某些蕈毒素）。
主要是指作用于离子通道的毒素。
钠通道受体毒素是一类重要的神经毒素之一，因其作用于钠通道的不同位点而产生不同的毒理作用。主要包 括：
（1）钠通道阻滞剂，包括河豚毒素（tetrodotoxin, TTX）、麻痹性贝毒（paralytic shell fish poisoning toxins, PSP）等。
神经毒素
免疫学名词
01 基本信息
03 结构与分类 05 锰及其毒性
目录
02 历史 04 神经毒性 06 丙烯酰胺毒性
基本信息
神经毒素是指对神经组织有破坏性的有毒物质。如AF64A、6一羟多巴胺和海人酸等。AF64A能选择性地破坏 胆碱能神经元。6一羟多巴胺能选择性地破坏多巴胺、去甲肾上腺素和肾上腺素神经元，易被儿茶酚胺神经元摄取， 一般注入脑内约5天～7天，就可使神经元变性，但不能破坏5一羟色胺神经元。海人酸对神经组织的破坏具有高 度选择性，能破坏神经元的胞体而不损伤神经纤维。由于对神经组织具有选择性的破坏作用，常被用来制备高级 心理功能障碍的动物模型。
神经毒性药物的作用机制和风险评估
神经毒性药物的作用机制和风险评估概述神经毒性药物是一类对人体中枢神经系统产生不良影响的药物。
这些药物可能对神经细胞结构和功能造成损害，从而引起一系列不可逆或可逆的神经系统疾病。
了解这些药物的作用机制和风险评估方法对于保护人类健康至关重要。
作用机制1. 突触传递干扰：一些神经毒性药物通过抑制或增强突触传递过程来干扰神经信号的传递。
例如，某些抗焦虑药如苯二氮䓬类可以增强γ-氨基丁酸（GABA）能突触传递，导致中枢抑制效应；而某些兴奋剂如阿黄碱则可以干扰儿茶酚胺类递质在突触间隙中的转运过程。
2. 蛋白质与酶活性干扰：其他神经毒性药物通过与特定蛋白质相互作用，改变其结构或功能来影响神经细胞正常活动。
例如，某些抗生素如多黏菌素B会与细菌的蛋白质合成机制结合，从而抑制细菌生长和增殖。
3. 氧化应激：一些神经毒性药物通过诱发氧化应激反应来引起神经损伤。
氧化应激是指在代谢过程中产生大量自由基或减少抗氧化防御系统时，导致氧化物对细胞膜、DNA和蛋白质等分子的破坏。
这进一步导致细胞死亡或功能障碍，最终影响神经系统的正常功能。
风险评估1. 动物实验：采用动物模型是评估神经毒性药物作用机制和风险的重要方法之一。
在实验室中，科学家们可以通过给小鼠、大鼠或其他动物注射目标药物，并观察其对行为、神经传导以及大脑组织等方面的影响来评估药物的毒性。
这可以揭示药物的作用途径和潜在危害。
2. 细胞实验：在细胞水平上进行实验也是评估神经毒性药物风险的重要方法。
科学家们可以使用神经元细胞株或其他特定细胞类型，将其暴露于确定浓度和时间内药物，之后评估细胞存活、代谢、DNA损伤等指标。
这有助于预测药物对神经系统的潜在危害。
3. 临床观察：通过监测人类使用特定药物后的不良反应报告来评估潜在的神经毒性风险是另一种常用的方法。
临床观察能够反映真实生活环境下药物的效果和副作用，但缺点是容易受到其他因素干扰，结果具有一定主观性。
预防与治疗1. 个体职业防护：对于那些接触潜在神经毒性药物的工作者，必须采取适当的个人防护措施以降低暴露风险。
神经毒性原文
n engl j med 350;23june 3, 2004 The new england journal of medicine2343Oxaliplatin, Fluorouracil, and Leucovorin as Adjuvant Treatment for Colon CancerThierry André, M.D., Corrado Boni, M.D., Lamia Mounedji-Boudiaf, M.D., Matilde Navarro, M.D., Josep Tabernero, M.D., Tamas Hickish, M.D., Clare Topham, M.D., Marta Zaninelli, M.D., Philip Clingan, M.D.,John Bridgewater, M.D., Isabelle Tabah-Fisch, M.D.,and Aimery de Gramont, M.D., for the Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatmentof Colon Cancer (MOSAIC) InvestigatorsF rom Hôpital Tenon, Paris (T.A.);GERCOR Oncology Multidisciplinary Group, Paris (T.A., A.G.); Arcispedale San-ta Maria Nuova, Reggio Emilia, Italy (C.B.); Sanofi-Synthelabo, Paris (L.M.-B.,I.T.-F.); Hospital Duran i Reynals, l’Hospi-talet de Llobregat, Llobregat, Spain (M.N.);Vall d’Hebron University Hospital, Barcelo-na, Spain (J.T.); Dorset Cancer Centre,Royal Bournemouth and Poole Hospitals,Bournemouth, United Kingdom (T .H.); Roy-al Surrey County Hospital, Guildford, Sur-rey, United Kingdom (C.T.); Ospedale Bor-gotrento, Verona, Italy (M.Z.); Southern Medical Day Care Centre, Wollongong, Aus-tralia (P.C.); North Middlesex Hospital,London (J.B.); and Hôpital Saint-Antoine,Paris (A.G.). Address reprint requests to Dr. de Gramont at Hôpital Saint Antoine,184 rue du Faubourg Saint Antoine, Paris 75012, France, or at aimery.de-gramont@sat.ap-hop-paris.fr.N Engl J Med 2004;350:2343-51.Copyright © 2004 Massachusetts Medical Society.backgroundThe standard adjuvant treatment of colon cancer is fluorouracil plus leucovorin (FL).Oxaliplatin improves the efficacy of this combination in patients with metastatic colo-rectal cancer. We evaluated the efficacy of treatment with FL plus oxaliplatin in the postoperative adjuvant setting.methodsWe randomly assigned 2246 patients who had undergone curative resection for stage II or III colon cancer to receive FL alone or with oxaliplatin for six months. The primary end point was disease-free survival.resultsA total of 1123 patients were randomly assigned to each group. After a median follow-up of 37.9 months, 237 patients in the group given FL plus oxaliplatin had had a can-cer-related event, as compared with 293 patients in the FL group (21.1 percent vs. 26.1percent; hazard ratio for recurrence, 0.77; P=0.002). The rate of disease-free survival at three years was 78.2 percent (95 percent confidence interval, 75.6 to 80.7) in the group given FL plus oxaliplatin and 72.9 percent (95 percent confidence interval, 70.2 to 75.7)in the FL group (P=0.002 by the stratified log-rank test). In the group given FL plus ox-aliplatin, the incidence of febrile neutropenia was 1.8 percent, the incidence of gastro-intestinal adverse effects was low, and the incidence of grade 3 sensory neuropathy was 12.4 percent during treatment, decreasing to 1.1 percent at one year of follow-up. Six patients in each group died during treatment (death rate, 0.5 percent).conclusionsAdding oxaliplatin to a regimen of fluorouracil and leucovorin improves the adjuvanttreatment of colon cancer.The new england journal of medicine2344olorectal cancer is the secondleading cause of death from cancer inWestern countries1; 40 to 50 percent of pa-tients who undergo potentially curative surgeryalone ultimately relapse and die of metastatic dis-ease.2 The most important prognostic indicator ofsurvival in early colon cancer is the stage of the tu-mor (T, according to the tumor–node–metastasis[TNM] classification), determined by the depth ofpenetration through the bowel wall, and the num-ber of involved lymph nodes.3The demonstration that postoperative adjuvanttreatment with fluorouracil and levamisole reducedthe mortality rate by 33 percent among patientswith stage III colon cancer4 prompted several trials,which established six months of treatment withfluorouracil plus leucovorin (FL) as the standard ad-juvant chemotherapy for stage III colon cancer.5-11Oxaliplatin is a third-generation platinum deriva-tive, which, when combined with fluorouracil andleucovorin, is among the most effective chemo-therapies for metastatic colorectal cancer.12-15 Todetermine whether oxaliplatin can also benefit pa-tients with disease in an earlier stage, we conduct-ed an international phase 3 clinical trial in patientswith stage II or III colon cancer — the MulticenterI nternational Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of ColonPatients were eligible if they had undergone com-plete resection of histologically proven stage II (T3or T4,N0,M0) or stage III (any T,N1 or N2,M0) co-lon cancer, as defined by the presence of the inferi-or pole of the tumor above the peritoneal reflection— that is, at least 15 cm from the anal margin.Treatment had to be started within seven weeks af-ter surgery. Other eligibility criteria included an ageof 18 to 75 years; a Karnofsky performance-statusscore of at least 60; a carcinoembryonic antigenlevel of less than 10 ng per milliliter; the absence ofprior chemotherapy, immunotherapy, or radio-therapy; and adequate blood counts and liver andkidney function. Written informed consent was re-quired from all patients, and the study was ap-proved by the ethics committees of the participat-ing centers.treatmentEligible patients were randomly assigned to receiveFL alone or with oxaliplatin. In the FL group, eachcycle comprised a 2-hour infusion of 200 mg of leu-covorin per square meter of body-surface area fol-lowed by a bolus of 400 mg of fluorouracil persquare meter and then a 22-hour infusion of 600mg of fluorouracil per square meter given on 2 con-secutive days every 14 days, for 12 cycles. I n thegroup given FL plus oxaliplatin, the same FL regi-men was used, plus a two-hour infusion of 85 mgof oxaliplatin (Eloxatin, Sanofi-Synthelabo) persquare meter on day 1, given simultaneously withleucovorin, with the use of a Y infusion device. Theuse of disposable pumps (LV5 infusors, BaxterHealthcare) allowed outpatients to receive a contin-uous infusion of fluorouracil.Adverse effects were graded according to theCommon Toxicity Criteria of the National CancerInstitute, version 1. According to these criteria, ascore of 1 indicates mild adverse effects, a score of2 moderate adverse effects, a score of3 severe ad-verse effects, and a score of 4 life-threatening ad-verse effects. Dose reductions were based on theworst adverse effects observed during the previouscycle. The dose of oxaliplatin was to be reduced to75 mg per square meter in the event of persistent(at least 14 days) paresthesias, temporary painfulparesthesias, or functional impairment. Oxalipla-tin was discontinued in cases of persistent painfulparesthesias or functional impairment. Togetherwith reductions in the dose of oxaliplatin, the bolusdose of fluorouracil was reduced to 300 mg persquare meter and the infusion to 500 mg persquare meter in the event of grade 3 or 4 neutrope-nia or thrombocytopenia (or both), diarrhea, sto-matitis, or other drug-related adverse effects ofgrade 3. Only the dose of fluorouracil was sched-uled to be reduced in the event of skin-related ad-verse effects of grade 3 or 4. Treatment was delayedby up to three weeks until the patient recoveredfrom various adverse effects, the neutrophil countexceeded 1500 per cubic millimeter, and the plate-let count exceeded 100,000 per cubic millimeter.Chemotherapy was stopped in the event of cardiacor neurocerebellar adverse effects or grade 3 or 4 al-lergic reactions.follow-upPatients were assessed before randomization, ev-ery two weeks during treatment, and then every six cn engl j med 350; june 3, 2004n engl j med 350;23june 3, 2004oxaliplatin, fluorouracil, and leucovorin for colon cancer2345months for five years. The baseline assessment involved a medical history taking, physical exami-nation, biologic tests, measurement of the carcino-embryonic antigen level, chest radiography, and abdominal ultrasonography or computed tomog-raphy. Patients were monitored for adverse effects throughout the treatment period and until 28 days after the last cycle of chemotherapy, unless treat-ment-related adverse effects required additional follow-up.The diagnosis of recurrence was made on the basis of imaging and, if necessary, cytologic analysis or biopsy. An elevated carcinoembryonic antigen level as a solitary finding was not accepted as evi-dence of relapse. Neurologic adverse effects were to be reported at each visit during follow-up and were assessed with the use of the neurosensory section of the Common Toxicity Criteria of the National Cancer Institute, version 1.statistical analysis Randomization was performed centrally, and the minimization method was used to balance treat-ment allocation according to the TNM stage (T2 orT3 vs. T4 and N0, N1, or N2), the presence or ab-sence of bowel obstruction or tumor perforation,and the medical center. The sample size of 2200patients was calculated under the assumptions of a three-year disease-free survival rate of 73 percent in the control group and 79 percent in the group giv-en FL plus oxaliplatin, with a ratio of stage II dis-ease to stage III disease of 0.4:0.6, an enrollment period and a follow-up period of three years, a de-crease in the risk of relapse after three years, a sta-tistical power of 90 percent, and an alpha value of 0.05 and two-sided P values derived with the use of the log-rank test. The primary efficacy variable was disease-free survival, defined as the time from ran-domization to relapse or death, whichever occurred first. Second colorectal cancers were considered relapses, whereas noncolorectal tumors were dis-regarded in the analyses.The primary statistical analysis of efficacy was the comparison, after three years of follow-up, of disease-free survival between groups according to the intention-to-treat principle, with the use of a two-sided log-rank test stratified according to base-line disease stage. Hazard ratios and 95 percent con-fidence intervals were calculated with the use of the Cox proportional-hazards model. Survival curves were drawn according to Kaplan–Meier methods.To assess the consistency of the effect of treat-ment on disease-free survival across prognostic subgroups, we calculated hazard ratios and 95 per-cent confidence limits for subgroups defined ac-cording to the following variables: sex, age, disease stage (II vs. III), baseline serum carcinoembryon-ic antigen level, number of involved lymph nodes (≤4 vs. >4), T classification (T4 vs. T1, T2, or T3),degree of cellular differentiation (well vs. poorly differentiated), and the presence or absence of per-foration, obstruction, and venous invasion.The cutoff date of the analysis was April 22,2003. The duration of follow-up was defined as the number of months from randomization to the cut-off date.Secondary end points were safety, including long-term adverse effects, and overall survival, mea-sured from the time of randomization to death from any cause. With a median follow-up of three years,it is too early to compare the two treatment groups statistically in terms of survival, and only descrip-tive analyses of overall survival are presented. Safe-ty analyses included patients who had received at least one cycle of treatment. organization of the trialThe concept underlying this study was developed by Dr. de Gramont, and the investigation was de-signed by the investigators and Sanofi-Synthelabo.Data were collected, managed, and analyzed by the sponsor. The article was written by the investiga-tors, on the basis of data and statistical analyses provided by Sanofi-Synthelabo.A data and safety monitoring board of indepen-dent experts reviewed safety data every six months during the treatment period to provide the sponsor with independent advice on the progress of the study and on safety. No interim analysis wasBetween October 1998 and January 2001, 2246 pa-tients were enrolled at 146 centers in 20 countries:1123 patients were randomly assigned to receive FL plus oxaliplatin and 1123 to receive FL without oxaliplatin. Of these patients, 1108 received at least one cycle of FL plus oxaliplatin and 1111 received at least one cycle of FL. The patients’ characteristics were well matched in the two groups (Table 1). In both groups, 60 percent of the patients had stage III disease and 40 percent had stage II disease. Then engl j med 350;23june 3 , 2004The new england journal of medicine2346n engl j med 350;23june 3, 2004 oxaliplatin, fluorouracil, and leucovorin for colon cancer2347(Table 3). Of the 137 patients (12.4 percent) who had grade 3 peripheral neuropathy during treat-ment, grade 3 symptoms were still present in 8 pa-tients at the six-month follow-up visit and in 5 pa-tients at the one-year visit. In 12 patients, grade 3peripheral neurosensory symptoms appeared after the end of treatment, and 6 of these patients had persistent grade 3 symptoms after one year. In total,11 of 1018 patients (1.1 percent) who were assessed one year after the end of treatment continued to have grade 3 peripheral neurosensory symptoms.This number dropped to five (0.5 percent) after 18months (Table 3).Twelve patients — six in each group (0.5 per-cent) — died within 1 month after the end of treat-ment; these included three deaths in each group during the first 60 days of treatment. In the group given FL plus oxaliplatin, four patients died of in-fection or sepsis (two with neutropenia) and two of intracranial hemorrhage. In the FL group, one pa-tient each died of sepsis, Stevens–Johnson syn-drome in the context of severe diarrhea and flucon-azole treatment, and anoxic cerebral infarction;one patient committed suicide; and two died sud-denly from cardiac causes.follow-upThere was good compliance with follow-up visits.The mean time between visits was 5.97 months in the group given FL plus oxaliplatin and 5.98 months in the FL group. The median interval was 6.01months in both groups.*Fisher’s exact test was used to calculate P values. NA denotes not applicable.†There are only three grades of paresthesia in version 1 of the Common Toxicity Criteria of the National Cancer Institute.‡This category included the hand–foot syndrome.§There are only two grades of alopecia in version 1 of the Common Toxicity Criteria of the National Cancer Institute. The incidence of grade 2 alopecia was 5.0 percent in each group.*Only patients who actually received treatment were included in the analysis. A grade of 0 indicates no change or no symptoms, a grade of 1 mild paresthe-sia and loss of deep tendon reflexes, a grade of 2 mild or moderate objective sensory loss and moderate paresthesia, and a grade of 3 severe objective sen- sory loss or paresthesias that interfere with function.n engl j med 350;23june 3 , 2004The new england journal of medicine2348 disease-free survivalAt the time of analysis (median follow-up, 37.9months), 237 patients in the group given FL plus oxaliplatin (21.1 percent) had relapsed or died, as compared with 293 (26.1 percent) in the FL group.The hazard ratio for recurrence in the group given FL plus oxaliplatin, as compared with the FL group,was 0.77 (P=0.002), corresponding to a 23 percent reduction in the risk of relapse. The probability of disease-free survival at three years was 78.2 percent (95 percent confidence interval, 75.6 to 80.7 per-A Cox-model analysis showed that the reduced risk of recurrence with FL plus oxaliplatin was sim-ilar in patients with stage II and those with stage III disease (P=0.77). Calculation of hazard ratios and 95 percent confidence intervals (Fig. 3) showed *FL denotes fluorouracil and leucovorin, and CI confidence interval.†P=0.002 by the stratified log-rank test for the comparison between groups.‡The same patient could have been counted in more than one relapse category if several types of relapses were reported at the same follow-up visit.n engl j med 350;23june 3, 2004oxaliplatin, fluorouracil, and leucovorin for colon cancer2349which found that this approach was superior (with respect to all efficacy variables, including overall survival) to the combination of irinotecan, fluoro-uracil (given as a bolus), and leucovorin. 15 Our trial was designed to test the efficacy of adjuvant treat-ment with the regimen of FL plus oxaliplatin. We chose disease-free survival as the primary end point of the study because, like others, 16 we believe that the absence of relapse is the best indicator of efficacy, since it relates directly to the effect of the treatment under investigation. By allowing early appraisal of the results, the use of three-year dis-ease-free survival as the primary end point for adju-vant trials of patients with colon cancer should per-mit rapid evaluation of new treatments. Whether disease-free survival should be a primary end point is still under discussion, but a recent analysis of several studies supports the appropriateness of the use of three-year disease-free survival as a good predictor of five-year overall survival in trials of ad-juvant treatment of colon cancer. 17Disease-free survival in the FL group in our study falls within the highest range reported in most studies of adjuvant treatment of colon cancer with FL. 6-8,18,19 The improvement in disease-free survival among patients who were treated with FL plus oxaliplatin corresponds to a relative reduction in the risk of recurrence of 23 percent. Since most relapses after curative surgery occur within the first three years, we consider our results in this respect to be complete.Although it is agreed that patients with stage III disease benefit from adjuvant treatment, whether all patients with stage I I disease should receive such treatment remains debatable. This controver-sy was sustained for years by the contradictory con-clusions of two large groups of investigators. The National Surgical Adjuvant Breast and Bowel Project concluded that the relative benefits of treat-ment were largely the same for stage II and stage III tumors, 20 whereas the International Multicen-tre Pooled Analysis of B2 Colon Cancer Trials (IMPACT B2) failed to demonstrate a statistically significant benefit for stage II tumors. 21A recent meta-analysis from the Mayo Clinic, 22 which evaluated individual data on 3300 patients who were enrolled in five randomized trials, in-cluding those analyzed in IMPACT B2, concluded that patients with stage I I disease could benefit from adjuvant chemotherapy, but to a lesser extent than patients with stage III tumors. Indeed, the ab-solute benefit among patients with stage II disease is only half as great as that among patients with stage III disease, and twice as many patients with stage II tumors are required in such studies in or-der to detect a difference.The new england journal of medicine2350A test for interaction is an appropriate statisticalapproach to the question of whether the benefit ofadjuvant treatment differs between stage I I andstage III colorectal cancer.23 In our study, this testshowed no significant interaction between the stageof disease and the treatment, indicating that FLplus oxaliplatin benefited both stage II and stageI I I colorectal cancer. From a clinical standpoint,stage I I colon cancer occurs in a heterogeneous,node-negative population in which clinical and bi-ologic prognostic factors other than the status oflymph-node involvement need to be taken into ac-count. Tools are being developed to help physi-cians assess the risk–benefit ratio of adjuvant che-motherapies for individual patients.22n engl j med 350; june 3, 2004n engl j med 350;23june 3, 2004 oxaliplatin, fluorouracil, and leucovorin for colon cancer2351tal cancer is approximately 20 months, 13-15,28 we expect that the effect of oxaliplatin on survival will become apparent within the next 2 years.Supported by Sanofi-Synthelabo.Dr. Boni reports having received consulting fees from Sanofi-Synthelabo and Lilly; Dr. Tabernero consulting and lecture fees from Sanofi-Synthelabo; and Dr. Hickish consulting and lecture fees from Sanofi-Synthelabo, Aventis, and Roche. Dr. Topham reports having equity ownership in Sanofi-Synthelabo and having received lecture fees from Sanofi-Synthelabo and consulting fees from Roche and Baxter. Dr. Bridgewater reports having received consulting fees from Novartis Consumer Health; Dr. Clingan consulting fees from Sanofi-Synthelabo and Roche Australia; and Dr. de Gramont consulting and lecture fees from Sanofi-Synthelabo and Baxter. Dr. Mounedji-Boudiaf and Dr. Tabah-Fisch are employed by Sanofi-Synthelabo.We are indebted to all those who have contributed to the conduct and analysis of the MOSAIC trial, including the 146 investigators from France, the United Kingdom, Spain, Italy, Belgium, Greece,Hungary, the Netherlands, Portugal, Germany, Sweden, Austria, Po-land, Denmark, Norway, Australia, Israel, Cyprus, Singapore, and Switzerland who enrolled patients in the study; to the members of the data and safety monitoring board, especially Marc Buyse (statis-tician); to the dedicated teams from Sanofi-Synthelabo, including Christelle Lorenzato and Robert Bigelow (statistical department)and Jeanne Marceau-Suissa, Nathalie Lebail, and Noelle Muller (clinical development); and to Daniel Sargent (Mayo Clinic) for thediscussion of the results.1. GLOBOCAN 2000: cancer incidence,mortality and prevalence worldwide, version 1.0. IARC CancerBase no. 5. Lyon, France:IARC Press, 2001.2. Obrand DI, Gordon PH. Incidence and patterns of recurrence following curative resection for colorectal carcinoma. Dis Colon Rectum 1997;40:15-24.3. Colon and rectum. I n: American Joint Committee on Cancer. AJCC cancer staging manual. 5th ed. Philadelphia: Lippincott–Raven, 1997:83-90.4. Moertel CG, Fleming TR, Macdonald JS,et al. Levamisole and fluorouracil as adju-vant therapy of resected colon carcinoma.N Engl J Med 1990;322:352-8.5. Wolmark N, Rockette H, Fisher B, et al.The benefit of leucovorin-modulated fluo-rouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project protocol C-03. J Clin Oncol 1993;11:1879-87.6. International Multicentre Pooled Analy-sis of Colon Cancer Trials (IMPACT) Investi-gators. Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. Lancet 1995;345:939-44.7. O’Connell MJ, Mailliard JA, Kahn MJ, et al. Controlled trial of fluorouracil and low-dose leucovorin given for 6 months as post-operative adjuvant therapy for colon cancer.J Clin Oncol 1997;15:246-50.8. Wolmark N, Rockette H, Mamounas E,et al. Clinical trial to assess the relative effi-cacy of fluorouracil and leucovorin, fluoro-uracil and levamisole, and fluorouracil, leu-covorin, and levamisole in patients with Dukes’ B and C carcinoma of the colon:results from National Surgical Adjuvant Breast and Bowel Project C-04. J Clin Oncol 1999;17:3553-9.9. O’Connell MJ, Laurie JA, Kahn M, et al.Prospectively randomized trial of postoper-ative adjuvant chemotherapy in patients with high-risk colon cancer. J Clin Oncol 1998;16:295-300.10. Haller DG, Catalano PJ, Macdonald JS,Mayer RJ. Fluorouracil (FU), leucovorin (LV)and levamisole (LEV) adjuvant therapy for colon cancer: five-year final report of INT-0089. Prog Proc Am Soc Clin Oncol 1998;17:256a.11. Zaniboni A. Adjuvant chemotherapy in colorectal cancer with high-dose leucovorin and fluorouracil: impact on disease-free sur-vival and overall survival. J Clin Oncol 1997;15:2432-41.12. Andre T, Bensmaine MA, Louvet C, et al.Multicenter phase II study of bimonthly high-dose leucovorin fluorouracil infusion, and oxaliplatin for metastatic colorectal cancer resistant to the same leucovorin and fluoro-uracil regimen. J Clin Oncol 1999;17:3560-8. 13. Giacchetti S, Perpoint B, Zidani R, et al.Phase I multicenter randomized trial of oxaliplatin added to chronomodulated fluo-rouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 2000;18:136-47.14. de Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or with-out oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000;18:2938-47.15. Goldberg RM, Sargent DJ, Morton RF,et al. A randomized controlled trial of fluo-rouracil plus leucovorin, irinotecan and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004;22:23-30.16. Elfenbein GJ. Stem-cell transplantation for high-risk breast cancer. N Engl J Med 2003;349:80-2.17. Sargent D, Wieand S, Goldberg R, et al.3 Year DFS vs. 5 year OS as an endpoint for adjuvant colon cancer studies: data from randomized trials. Rockville, Md.: Food and Drug Administration, November 2003.(Accessed May 10, 2004, at /cder/drug/cancer_endpoints/Sargent/index.htm.)18. Andre T, Colin P, Louvet C, et al. Semi-monthly versus monthly regimen of fluoro-uracil and leucovorin administered for 24 or 36 weeks as adjuvant therapy in stage II and I I I colon cancer: results of a randomized trial. J Clin Oncol 2003;21:2896-903.19. Francini G, Petrioli R, Lorenzini L, et al.Folinic acid and 5-fluorouracil as adjuvant chemotherapy in colon cancer. Gastroenter-ology 1994;106:899-906.20. Mamounas E, Wieand S, Wolmark N, et al. Comparative efficacy of adjuvant chemo-therapy in patients with Dukes’ B versus Dukes’ C colon cancer: results from four National Surgical Adjuvant Breast and Bowel Project adjuvant studies (C-01, C-02, C-03,and C-04). J Clin Oncol 1999;17:1349-55. 21. International Multicentre Pooled Analy-sis of B2 Colon Cancer Trials (IMPACT B2)nvestigators. Efficacy of adjuvant fluoro-uracil and folinic acid in B2 colon cancer.J Clin Oncol 1999;17:1356-63.22. Gill S, Loprinzi CL, Sargent DJ, et ing a pooled analysis to improve the understanding of adjuvant therapy (AT)benefit for colon cancer (CC). Prog Proc Am Soc Clin Oncol 2003;22:253a.23. Buyse M, Piedbois P. Should Dukes’ B patients receive adjuvant therapy? A statisti-cal perspective. Semin Oncol 2001;28:Suppl 1:20-4.24. de Gramont A, Bosset JF, Milan C, et al.Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluoro-uracil bolus plus continuous infusion for advanced colorectal cancer: a French inter-group study. J Clin Oncol 1997;15:808-15. 25. Extra JM, Espie M, Calvo F, Ferme C,Mignot L, Marty M. Phase I study of oxali-platin in patients with advanced cancer. Can-cer Chemother Pharmacol 1990;25:299-303. 26. Rothenberg ML, Meropol NJ, Poplin EA, Van Cutsem E, Wadler S. Mortality asso-ciated with irinotecan plus bolus fluoroura-cil/leucovorin: summary findings of an inde-pendent panel. J Clin Oncol 2001;19:3801-7. 27. Wolmark N, Bryant J, Smith R, et al.Adjuvant 5-fluorouracil and leucovorin with or without interferon alfa-2a in colon carci-noma: National Surgical Adjuvant Breast and Bowel Project protocol C-05. J Natl Can-cer Inst 1998;90:1810-6.28. Tournigand C, André T, Achille E, et al.FOLF R followed by FOLFOX 6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004;22:229-37.Copyright © 2004 Massachusetts Medical Society.。
毒性物质神经毒性测试方法研究
毒性物质神经毒性测试方法研究毒性物质是指会对人体生命系统造成伤害的物质，如化学毒剂、药物、农药等。
当这些毒性物质进入人体内部后，会对神经系统造成巨大的伤害，导致神经细胞损伤、失调，进而引起不同程度的中毒症状和健康问题。
为了减少毒性物质对人类健康的危害，科研人员开发了各种测试方法，通过测试来检测毒性物质的危害程度。
不同的毒性物质会对不同的组织和器官产生不同的毒性作用，而神经系统是最容易受到影响的目标系统，因此神经毒性测试方法对于对不同的毒性物质的毒性进行评估具有重要意义。
1. 细胞毒性测试法细胞毒性测试法是一种比较常见的方法，基于这种测试方法，科研人员可以通过检测毒性物质对于人体细胞的毒性程度来评估其危害程度。
具体的操作过程是：首先，将毒性物质加入培养基中，并培养人体细胞，然后检测毒性物质对细胞的影响。
不同的检测结果会得到不同的评估值，反映出毒性物质对细胞的毒性水平。
虽然细胞毒性测试法有效，但是它只能评估到毒性物质对细胞造成的影响，而对于毒性物质对神经细胞的影响还需要其他的测试方法进行评估。
2. 离体神经系统测试法离体神经系统测试法是一种对于神经毒性进行评估的方法，它主要基于研究毒性物质对于神经细胞的直接影响。
这种方法通过单独的神经组织或者细胞培养来评估毒性物质对于神经细胞的影响，对于分析毒性物质对于神经细胞通讯机制的影响非常有用。
具体的操作过程是：将大脑闪电切片或者神经细胞培养在封闭的环境中，将毒性物质加入组织中，暴露一段时间后检测其毒性水平。
这种方法可以提供毒性物质对神经系统影响的更加相信的证据。
3. 动物毒性测试法动物毒性测试法是一种对于毒性进行评估的方法，它通过给实验动物（如小鼠、大鼠、猴子等）注射不同剂量的毒性物质，评估其对体内的系统的影响。
这种方法成本高，时间长，但是其结果比其他测试方法更加生物相似，更能够模拟人体的实际情况，是比较常用的毒性测试方法之一。
总结起来，毒性物质神经毒性测试方法的发展历程非常漫长，针对不同的毒性物质可以选择不同的实验方法进行毒性评估。
哪些药品可致神经毒性？
哪些药品可致神经毒性？神经毒性即由用药所引起的神经系统功能障碍，包括周围神经、自主神经、颅脑神经、视神经、听神经等损伤，并出现一系列神经毒性症状。
（1）抗菌药物青霉素类特别是青霉素G的用药剂量过大或静注速度过快时，可对大脑皮层直接产生刺激，出现肌痉挛、惊厥、癫痫、昏迷等严重反应，称为“青霉素脑病”，一般于用药后24～72小时内出现。
青霉素用至惊厥量（脑脊液中的青霉素浓度超过8ug/ml），可因大脑皮层兴奋性增高而致癫痫发作。
鞘内注射青霉素G或链霉素的剂量过大时，可引起脑膜刺激征或神经根的刺激症状；鞘内注射多黏菌素B、杆菌肽、两性霉素B时也可对脑膜及神经根产生直接刺激作用；大剂量应用氨苄西林后，也可引起大脑损害。
另外，第8对脑神经损害为氨基糖苷类抗生素的主要不良反应；双氢链霉素、卡那霉素、新霉素和阿米卡星能引起耳蜗损害为主；而链霉素、妥布霉素及庆大霉素则以前庭功能损害为主，或二者兼有之。
（2）抗结核药异烟肼用后偶见有步态不稳或针刺麻木感、手足疼痛；大剂量可致周围神经炎和中枢神经系统紊乱、四肢感觉异常、精神病、昏迷、抽搐和视神经炎。
（3）抗疟药氯喹服后可见有激动不安、精神失常、人格改变、抑郁等；大剂量可致耳鸣或神经性耳聋，常在应用几周后出现，多为不可逆的耳聋。
（4）抗肿瘤药长春碱类药可抑制神经轴突的微管功能，尤其是长春新碱；长春碱类的周围神经损害常见最初表现为腱反射减弱、肢端感觉异常，分别从跟腱反射减弱和指尖感觉异常开始，甚至出现下肢无力、垂足、下肢轻瘫；部分患者用药时出现肌痛，数日后自行消退；颅神经损害可有眼肌麻痹、面瘫；自主神经损害表现为便秘、排尿困难，甚至发展为麻痹性肠梗阻、尿潴留。
顺铂可引起耳毒性，60mg/m2可引起耳鸣、高频听力下降、听力异常、视神经炎、暂时性失明、周围神经感觉异常、腱反射消失等。
阿糖胞苷静脉注射及鞘内注射均能产生神经毒性，常见小脑功能失调，伴有头痛、精神症状、记忆减退、嗜睡。
神经毒性药物应用对患者的影响及预防措施
神经毒性药物应用对患者的影响及预防措施神经毒性药物是指能够影响神经系统的一类药物，常用于治疗中枢神经系统疾病。
然而，使用神经毒性药物也会产生一系列的副作用和风险。
因此，在使用该类药物时，应该进行必要的预防措施，以防止对患者造成的不必要的损害。
神经毒性药物的影响神经毒性药物对患者的影响，可以分为两类：短期的和长期的影响。
短期的影响是指使用神经毒性药物后，患者在使用期间或者短时间内出现的不适反应。
这些不适反应主要包括头痛、恶心、呕吐、疲劳等一些较为常见的症状。
此外，患者可能会出现一些精神方面的反应，比如失眠、焦虑、抑郁等。
有时，患者还会出现神经系统的反应，如手脚麻木、震颤等。
长期的影响是指在使用神经毒性药物过程中，患者可能会出现一些长期的影响。
这些影响可能会持续数月或数年，包括神经系统的损伤、智力水平的下降、高血压等。
这些不良影响对患者的身体健康和心理健康均会产生负面影响。
预防措施为了避免上述风险，医生在给患者开具神经毒性药物时，应该采取必要的预防措施。
首先，医生应该对患者进行详细的评估，了解其病史和身体情况，确定是否适合使用该类药物。
此外，医生还要尽量使用剂量较小的药物，并在使用过程中监测患者的反应，以及时进行调整。
其次，医生应从多个角度考虑患者的身体状况，如年龄、肝功能等等，并进行必要的调整。
例如，肝功能不良的患者应该使用剂量较小的药物；年龄较大的患者在使用过程中需要特别注意药物的副作用等。
此外，患者在服用神经毒性药物的同时，应该注意自我保护，避免不必要的损伤。
患者应尽量避免剧烈运动，如跑步、跳跃等，避免不必要的外伤。
此外，还应避免使用酒精等药物，以免造成药物的相互作用，增加副作用。
总之，神经毒性药物的影响和风险，需要我们认真对待，并采取必要的预防措施。
结语神经毒性药物的影响和风险是不可忽视的。
医生在使用该类药物时，应该做好详细的评估和调整，并注意监测患者的反应，及时进行调整。
患者在服用神经毒性药物的同时，也应该注意自我保护，避免不必要的损伤。
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化疗--神经毒性
一．长春碱类
1．长春碱类抑制神经轴突的微管功能，产生神经毒性，尤其是长春新碱，神经毒性是它的限制性毒性。
2．长春碱类的神经毒性表现为周围神经、颅神经、自主神经损害。
3．周围神经损害：最常见最初的表现是腱反射减弱/消失和肢端感觉异常，分别从跟腱反射减弱及指尖感觉异常开始。
甚至出现下肢无力、垂足、下肢轻瘫。
部分患者用药时出现肌肉疼痛，数天后自行消退。
4．颅神经损害：可有眼肌麻痹、面瘫。
5．自主神经损害：表现为便秘、排尿困难，甚至发展为麻痹性肠梗阻、尿潴留。
[治疗原则]
目前暂无有效的治疗方法，停药后数周或数月，神经症状逐渐改善。
[注意事项]
严格按照常规剂量用药，如出现严重的神经毒性，应考虑减量或改用其他替代药物。
二．顺铂
1．顺铂引起的神经毒性与重金属中毒引起的神经损害相似，可能与无机铂在神经的累积有关，并且是不可逆的；
2．顺铂可引起耳毒性，60mg/m2顺铂可引起耳鸣（10%）、高频听力下降（6%）、听力敏感图异常（25%）；
3．顺铂亦引起视神经炎、暂时性失明、周围神经感觉异常、腱反射消失等。
[治疗原则]
停药后数月神经症状可能恢复，细胞保护剂Amifostine对预防顺铂的神经毒性有一定的帮助。
[注意事项]
应避免顺铂每疗程单一剂量过高及累积量过高（600mg/m2）。
三．阿糖胞苷
1．阿糖胞苷可用于静脉注射及鞘内注射，均能产生神经毒性，并可在用药后数天内急性产生。
2．常见的神经毒性是小脑功能失调，伴有头痛、精神症状、记忆减退、嗜睡；周围神经损害较少见。
3．鞘内注射可产生上行性脊髓病。
4．严重的神经毒性可能引起昏迷甚至死亡。
[治疗原则]
目前尚无有效的治疗，停药后数天症状会改善，但严重的神经损害可能是不可逆的。
[注意事项]
有以下危险因素时慎用阿糖胞苷：
（1）年龄>50岁；
（2）阿糖胞苷剂量>1g/m2（神经毒性发生率15%~37%）；
（3）曾反复阿糖胞苷治疗；
（4）肾功能不良。
四．异环磷酰胺
1．高剂量异环磷酰胺引起神经毒性的发生率约30%。
2．神经症状表现为：幻觉、幻听、多梦、精神错乱、人格改变、焦虑、烦躁、小脑及颅神经功能紊乱、轻度偏瘫、癫痫发作、昏迷、偶尔引起死亡。
3．神经症状在开始用异环磷酰胺46小时可出现，停药后数天恢复。
4．异环磷酰胺引起的神经毒性可能与异环磷酰胺的代谢产物氯乙醛有关。
[治疗原则]
停药、静脉用地西泮及亚甲蓝。
[注意事项]
有以下危险因素时慎用异环磷酰胺：
（1）低蛋白血症；
（2）肾功能不良；
（3）曾用过顺铂（隐性肾功能不良）；
（4）中枢神经系统肿瘤；
（5）年龄（儿童易受影响）。
五．氟脲嘧啶
1．任何常规剂量的氟脲嘧啶均可引起神经毒性，通常急性发作，发生率为5%，二氢嘧啶脱氢酶缺乏者更易发生。
2．最常见的神经毒性为小脑功能紊乱，包括：辨距不良、共济失调、语言混乱、眼球震颤、眩晕。
亦有精神错乱及大脑认知缺失。
[治疗原则]
停药后神经症状可恢复。
[注意事项]
用高剂量氟脲嘧啶后更常出现小脑功能紊乱。
六．氨甲喋呤
1．氨甲喋呤引起的神经毒性表现为：脑膜刺激征短暂性下肢轻瘫和脑病。
2．氨甲喋呤鞘内给药可引起脑膜刺激征：头痛、恶心、呕吐、嗜睡、颈项强直等；亚急性症状：下肢轻瘫、颅神经麻痹和小脑症状等；反复鞘内给药偶尔会发生进行性、坏死性脑白质病，表现为记忆力下降、痴呆、癫痫发作。
3．氨甲喋呤静脉给药亦会引起脑病，同时加颅脑放疗或氨甲喋呤大剂量给药更易发生，症状与鞘内给药相似。
[治疗原则]
治疗包括注意加强水化、四氢叶酸救援等[见第八节(二)]。
[注意事项]
同时放疗、脑脊液找到肿瘤细胞、药物累积是脑病发生的危险因素。
七．紫杉醇类
1．紫杉醇类影响神经微管引起神经病变。
2．紫杉醇类引起的周围神经病变与顺铂、长春碱类引起的相似，表现为手、脚、口周感觉异常或烧灼样痛、振动感觉消失、腱反射消失、直立性低血压。
[治疗原则]
神经病变可在首剂后数天或数疗程后发生，停药一段时间后症状可恢复。
[注意事项]
周围神经病变是剂量依赖性的，紫杉醇>175mg/m2，神经毒性的发生率高。
累积剂量亦增加神经毒性的发生，Docetaxel累积量400 mg/m2可产生严重神经症状。