拉帕替尼lapatinib一种新的EGFR靶向治疗药物.doc

拉帕替尼（lapatinib）一种新的EGFR靶向治疗药物 简介：拉帕替尼（lapatinib）一种新的EGFR靶向治疗药物乳腺癌晚期新药 Tykerb,是葛兰素史克公司研制的。 临床试验显示,对于那些已对罗氏的赫赛汀(Herceptin)产生耐药性的HER2型乳癌患者,这种新药有很好的临床效果。乳腺癌晚期新药 Tykerb,是葛兰素史克公司研制的。 临床试验显示,对于那些已对罗氏的赫赛汀(Herceptin)产生耐药性的HER2型乳癌患者,这种新药有很好的临床效果。拉帕替尼（lapatinib）是一种口服的小分子表皮生长因子（EGFR:ErbB-1，ErbB-2）酪氨酸激酶抑制剂。在体外试验中，对Her-2过表达乳腺癌细胞系的生长抑制作用明显。在Her-2过表达的进展期乳腺癌的期临床试验中，拉帕替尼（lapatinib）也具有较高的有效率，且与赫赛汀（曲妥珠单抗）无交叉耐药。因为其结构为小分子，与赫赛汀（曲妥珠单抗）不同，能够透过血脑屏障，对于乳腺癌脑转移有一定的治疗作用。Spector报告了拉帕替尼（lapatinib）单药（1500mg/d）在难治性炎性乳腺癌（曾用过蒽环类药物或复发）中的期临床结果。病人分为两组A组（ErbB-2过表达）和B组（ErbB-1表达，ErbB-2不表达）。A组使用拉帕替尼（lapatinib）的部分缓解率达62%，B组仅为8.3%。毒性反应主要表现为/级皮肤和胃肠道反应。这表明，拉帕替尼（lapatinib）疗效与HER-2过表达有密切关系。该药由葛兰素史克公司研制，是一种新型的靶向抗癌药物。所谓靶向治疗药物，是指将某些受体、基因或关键蛋白作为靶点，进而有的放矢地杀灭相关肿瘤细胞的药物。该药和另外一种乳腺癌治疗药物希罗达一起使用，可以有效控制晚期的转移性HER2阳性乳腺癌。两种药物联合用药疗法适用于那些之前服用过其他药物但治疗无效后乳腺癌转移的患者。拉帕替尼是一种激酶抑制剂，它的独特之处在于可以通过多种途径发挥作用，乳腺癌癌细胞不能接收到生长所需的信号。拉帕替尼说明书：/oblog31/images/tykerb.pdfGlaxoSmithKline Pharmacologic class: Antineoplastic (tyrosine kinase inhibitor) Active ingredient: Lapatinib 250mg; tabs.Indication: In combination with capecitabine, for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab. Pharmacology: Overexpression of epidermal growth factor receptor (EGFR) and human epidermal receptor type 2 (HER2) has been reported in a variety of tumors. Lapatinib works by inhibiting the tyrosine kinase components of the EGFR and HER2 receptors. Clinical trials: Lapatinib was evaluated in combination with capecitabine in the treatment of breast cancer in a randomized, Phase 3 trial that enrolled 399 patients. The patients had HER2 overexpressing locally-advanced or metastatic breast cancer that had progressed following prior treatment with anthracyclines, taxanes, and trastuzumab. Capecitabine was given on Days 1?4 on a 21-day cycle, and lapatinib was given once daily continuously. The endpoint was time to progression (time from randomization to tumor progression or death due to breast cancer). An interim analysis revealed that, according to an independent assessment, the median time to progression in the group given lapatinib + capecitabine was 27.1 weeks compared to 18.6 weeks for capecitabine only. The response rate was 23.7% for the lapatinib + capecitabine group compared to 13.9% for the capecitabine-only group. Data results from investigator assessment was significant as well. Adults: Take 1 hour before or 1 hour after a meal. Take once daily on Days 1?1 continuously with capecitabine (see literature for capecitabine dose) in a repeating 21 day cycle. 1250mg (5 tablets). Severe hepatic dysfunction (Child-Pugh Class C): 750mg (no clinical data for this dose adjustment). After recovery from left ventricular ejection fraction (LVEF) decrease: 1g. Concomitant potent CYP3A4 inhibitors: 500mg (no clinical data for this dose adjustment). Concomitant potent CYP3A4 inducers: may titrate up to 4500mg (no clinical data for this dose adjustment). Discontinue if Grade 2 NCI CTC toxicity occurs; may restart at 1250mg if toxicity improves to grade 1; if recurs, may restart at 1g.Children: Not recommended. Contraindications: Renal disease or dysfunction. Metabolic acidosis, ketoacidosis. Concomitant intravascular iodinated contrast agents (suspend during and for 48 hours after use). Type 1 diabetes. Precautions: Discontinue if Grade 2 decrease in LVEF occurs, or if LVEF falls below institution lower limit of normal; may restart after at least 2 weeks at reduced dose if asymptomatic and LVEF recovers. Conditions that impair left ventricular function, or risk factors for QT prolongation (eg, hypokalemia, hypomagnesemia, congenital long QT syndrome, concomitant antiarrhythmics, cumulative high dose anthracyclines); correct electrolyte disturbances before starting. Severe hepatic impairment. Pretreat for diarrhea with antimotility drugs. Monitor ECG. Pregnancy (Cat.D). Nursing mothers: not recommended. Interactions: Avoid potent CYP3A4 inhibitors (eg, ketoconazole), grapefruit; reduce dose if unavoidable. Avoid potent CYP3A4 inducers (eg, carbamazepine); slowly titrate dose up if unavoidable. May affect drugs that are affected by p-glycoprotein, CYP2C8. Adverse reactions: Diarrhea (may be severe), nausea, vomiting, hand/foot syndrome, rash, fatigue; decreased LVEF, QT prolongation.As of Microsoft Internet Explorer 4.0, you can applmultimedia-style effects to your Web pages using visual filters and transitions. You can apply visual filters and transitions to standard HTML controls, such as text containers, images, and other windowless objects. Transitions are time-varying filters that create a transition from one visual state to another. By combining filters and transitions with basic scripting, you can create visually engaging and interactive documents.Internet Explorer 5.5 and later supports a rich variety of optimized filters. Click the following button to see a demonstration of many of these filters and how to usetheProcedural surfaces are colored surfaces that display between the content of an object and the objects background. Procedural surfaces define each pixels RGB color and alpha values dynamically. Only the procedure used to compute the surface is stored in memory. The content of an object with a procedural surface applied is not affected by the procedural surface.警告：此类已序列化的对象将不再与以后的 Swing 版本兼容。当前的序列化支持适合在运行相同 Swing 版本的应用程序之间短期存储或 RMI。从 1.4 版开始，已在 java.beans 包中加入对所有 JavaBeansTM 的长期存储支持。请参见 XMLEncoder。引用类型和原始类型的行为完全不同，并且它们具有不同的语义。引用类型和原始类型具有不同的特征和用法，它们包括：大小和速度问题，这种类型以哪种类型的数据结构存储，当引用类型和原始类型用作某个类的实例数据时所指定的缺省值。对象引用实例变量的缺省值为 null，而原始类型实例变量的缺省值与它们的类型有关。当JAVA程序违反了JAVA的语义规则时，JAVA虚拟机就会将发生的错误表示为一个异常。违反语义规则包括2种情况。一种是JAVA类库内置的语义检查。例如数组下标越界,会引发IndexOutOfBoundsException;访问null的对象时会引发NullPointerException。另一种情况就是JAVA允许程序员扩展这种语义检查，程序员可以创建自己的异常，并自由选择在何时用throw关键字引发异常。所有的异常都是java.lang.Thowable的子类。这里我们采用的是Java语言，Java，是由Sun Microsystems公司于1995年5月推出的Java程序设计语言和Java平台的总称。用Java实现的HotJava浏览器（支持Java applet）显示了Java的魅力：跨平台、动态的Web、Internet计算。从此，Java被广泛接受并推动了Web的迅速发展，常用的浏览器现在均支持Java applet。Java是一种简单的，面向对象的，分布式的，解释型的，健壮安全的，结构中立的，可移植的，性能优异、多线程的动态语言。当1995年SUN推出Java语言之后，全世界的目光都被这个神奇的语言所吸引。那么Java到底有何神奇之处呢？Java语言其实最早诞生于1991年，起初被称为OAK语言，是SUN公司为一些消费性电子产品而设计的一个通用环境。他们最初的目的只是为了开发一种独立于平台的软件技术，而且在网络出现之前，OAK可以说是默默无闻，甚至差点夭折。但是，网络的出现改变了OAK的命运。在Java出现以前，Internet上的信息内容都是一些乏味死板的HTML文档。这对于那些迷恋于WEB浏览的人们来说简直不可容忍。他们迫切希望能在WEB中看到一些交互式的内容，开发人员也极希望能够在WEB上创建一类无需考虑软硬件平台就可以执行的应用程序，当然这些程序还要有极大的安全保障。对于用户的这种要求，传统的编程语言显得无能为力。SUN的工程师敏锐地