醫聲論壇

bruinhilde 寫:太好了
正好是選前
全部統統都納入給付最好
以後睡覺不爽造成腰痛
健保也給付獨立統床墊最好

lionelchiu 寫:http://tw.news.yahoo.com/%E9%86%AB%E5%B ... 00248.html

十四個月?

Repeated, large-scale studies show that it is usually necessary to treat between 25 and 100 patients to prevent a single death during the next two to four years.[21] [22]

抗癌新藥：Lapatinib

台北榮民總醫院 內科部 血液腫瘤科王緯書醫師 | 2010 元月 22

日前所公佈2006年台灣十大癌症死亡原因之中，乳癌佔女性十大死因之第四位，且在癌症發生率中更超越子宮頸癌而躍居第一位。部份乳癌患者癌細胞之表皮生長因子受體（epidermal growth factor receptor；EGFR）的表現會出現增加的情形，導致其酪胺酸激酶（tyrosine kinase）出現活化，而這些激酶的活化則會導致乳癌的復發。研究指出有第二型人類表皮生長因子受體(human epidermal growth factor receptor type 2；HER2)過量表現之乳癌患者，其疾病惡化及死亡的危險性比沒有HER2過量表現者高。因此先前醫界利用單株抗體藥物，來對抗位於乳癌細胞膜上的HER2(或稱ErbB2)，獲得卓越的療效。Herceptin(trastuzumab)是利用基因重組技術製得的擬人化單株抗體，可結合至HER2蛋白質之細胞外部份，用於治療癌細胞上有HER2過度表現之轉移性乳癌病患。然而仍有部分病患的癌細胞對Herceptin具有抗藥性，或在使用Herceptin一段時間後產生抗藥性。所幸，最近發現一種小分子酪胺酸激酶抑制劑Lapatinib(Tykerb®)具有抑制HER2活化的效果，可用來治療對Herceptin具有抗藥性的乳癌。

HER2是一種跨膜醣蛋白，也是細胞膜上的一種生長素接受體。它的胞內結構具有酪胺酸激酶的活性，因此它可以接受胞外配子(ligands)的刺激而加速細胞的生長與分裂。如果HER2基因因為某種原因不斷擴大表現，所產生的HER2蛋白就會在出現過量的情形。我們可以經過免疫化學染色方法，以及螢光原位雜交(fluorescence in-situ hybridization; FISH)等方法來檢查HER2是否出現過量表現的情形。HER2過量表現，會增強癌細胞繁殖以及抗凋亡的能力。若乳癌病患的癌細胞呈現過量表現的HER2，其預後明顯較差。已知有20-25% 的乳癌病人的乳癌細胞有HER2的過度表現，這些病人對荷爾蒙治療藥物Tamoxifen具有抗藥性，且預後不良。

Lapatinib(Tykerb®)為口服之小分子酪胺酸激酶抑制劑，可同時抑制HER2(ErbB2)及EGFR(ErbB1)之酪胺酸激酶活性，阻斷受體之磷酸化反應，因而阻斷下游訊息傳遞之進行。與Herceptin不同的是，Lapatinib並不是抗體，因此於實驗室中發現Lapatinib並不會與Herceptin產生交叉抗藥性之情形。Lapatinib對酪胺酸激酶之雙重抑制作用(亦即同時抑制ErbB1及ErbB2)，有別於只抑制ErbB2之細胞外部份的單株抗體Herceptin。由於單一酪胺酸激酶抑制劑可能無法有效地抑制由ErbB1及ErbB2所組成之異二聚體(heterodimer)，而Lapatinib則可同時抑制ErbB1及ErbB2，因此這種雙重酪胺酸激酶抑制劑可能比單一酪胺酸激酶抑制藥物更具療效。由於其臨床療效，美國食品暨藥物管理局於2007年3月已核准Lapatinib上市，與capecitabine併用，用於治療HER2過度表現且曾使用小紅莓、紫杉醇類及Herceptin治療無效之進展性或轉移性乳癌。

在一項第二期臨床試驗中，78位HER2過度表現，且曾接受過Herpeptin治療仍病情惡化之轉移型乳癌病患，投與Lapatinib，整體反應率為22%；在另一項試驗中，針對曾接受過小紅莓、紫杉醇類及capecitabine治療後仍呈現惡化之轉移型乳癌病患，投與Lapatinib，整體反應率為14%。進一步分析顯示，轉移型乳癌病患若呈現雌性素接受體(ER)陰性、黃體激素接受體(PR)陰性及ErbB2過度表現，則可能對Lapatinib有反應。

根據2007年發表於新英格蘭醫學雜誌的一項第三期臨床試驗指出，Lapatinib與capecitabine合併使用，比單獨使用capecitabine，可明顯延長HER2陽性轉移型乳癌病患疾病惡化時間，對HER2陽性且曾接受過Herceptin治療後仍呈現惡化之乳癌病患提供更有效的治療。該研究包括324位HER2陽性，且曾接受過小紅莓、紫杉醇類及Herceptin治療後仍呈現惡化之局部進展性或轉移型乳癌病患，隨機分成Lapatinib＋capecitabine合併療法組(163位；每日投與1250 mg Lapatinib，第1-14天每日投與2000 mg/m2 capecitabine，以3週為一個治療週期)及單獨使用capecitabine組(161位；第1-14天每日投與2500 mg/m2 capecitabine，以3週為一個治療週期)，評估到惡化時間(time to progression; TTP)、整體反應率(overall response rate)、無惡化存活期(progression-free survival; PFS)及整體存活期(overall survival)。結果發現，合併療法組及單獨使用capecitabine組的整體反應率分別為22%及14%(p=0.09)，到惡化時間分別為8.4月及4.4月(p<0.001)，無惡化存活期分別為8.4月及4.1月(p<0.001)，而且使用Lapatinib之患者發生三級以上的副作用的機率並未明顯增加。顯示Lapatinib合併使用capecitabine比單獨使用capecitabine可明顯延長乳癌病患疾病惡化時間，這種治療組合對於各種化療失敗的晚期乳癌病患可說是一項福音。

Lapatinib常見的副作用大多屬於一、二級，而較嚴重的三、四級副作用則極為罕見。最常見的三、四級副作用為腹瀉及手足症候群。由於Lapatinib多用於使用小紅莓及Herceptin治療失敗的乳癌病患，因此心臟方面之安全性也極受重視。研究發現，Lapatinib造成左心室收縮功能(LVEF)降低之發生率極低(約1%)，且目前並無其他研究資料顯示Lapatinib具明顯之心臟毒性，因此整體而言，Lapatinib在使用安全性無虞。

Lapatinib（Tykerb®）可同時抑制HER2及EGFR酪胺酸激酶之活性，且不會與Herceptin產生交叉抗藥性。併用capecitabine於治療過度表現HER2之進展性或轉移性乳癌，Lapatinib可有效地延長乳癌病患癌症惡化的時間，為晚期HER2陽性乳癌患者帶來治療的新契機。目前仍有許多相關的臨床試驗正在進行，我們拭目以待！

Lapatinib (INN), used in the form of lapatinib ditosylate, (USAN) (Tykerb/Tyverb, GSK) is an orally active drug for breast cancer and other solid tumours.[1] It is a dual tyrosine kinase inhibitor which interrupts the HER2 growth receptor pathway.[2] It is used in combination therapy for HER2-positive breast cancer. It is used for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 (ErbB2).[3]

Contents [hide]
1 Status
2 Mode of action
2.1 Biochemistry
2.2 Clinical application
2.2.1 Breast cancer
3 Adverse effects
4 References
5 External links

[edit] StatusOn March 13, 2007, the U.S. Food and Drug Administration (FDA) approved lapatinib in combination therapy for breast cancer patients already using capecitabine (Xeloda, Roche).[2][3] In January 2010, Tykerb received accelerated approval for the treatment of postmenopausal women with hormone receptor positive metastatic breast cancer that overexpresses the HER2 receptor and for whom hormonal therapy is indicated.[3]

Pharmaceutical company GlaxoSmithKline (GSK) markets the drug under the propriety names Tykerb (mostly US) and Tyverb (mostly Europe).[4] The drug currently has approval for sale and clinical use in the US,[2][4] Australia,[2] Bahrain,[2] Israel, Kuwait,[2] Venezuela,[2] Brazil,[5] New Zealand,[5][6] South Korea,[5] Switzerland,[4] Japan, the European Union, India and Pakistan.[4]

The drug lapatinib ditosylate is classified as S/NM (a synthetic compound showing competitive inhibition of the natural product) that is naturally derived or inspired substrate (Gordon M. Cragg, Paul G. Grothaus, and David J. Newman, Impact of Natural Products on Developing New Anti-Cancer Agents, Chem. Rev. 2009, 109, 3012–3043)

[edit] Mode of action[edit] BiochemistryLapatinib inhibits the tyrosine kinase activity associated with two oncogenes, EGFR (epidermal growth factor receptor) and HER2/neu (Human EGFR type 2).[7] Over expression of HER2/neu can be responsible for certain types of high-risk breast cancers in women.[2] Like Sorafenib, lapatinib is a protein kinase inhibitor shown to decrease tumor-causing breast cancer stem cells. [8] Lapatinib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFR/HER2 protein kinase domain, preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinase#Signal transduction).[9]

[edit] Clinical application[edit] Breast cancerLapatinib is used as a treatment for women's breast cancer in treatment naive, ER+/EGFR+/HER2+ breast cancer patients (now often called "triple positive") and in patients who have HER2-positive advanced breast cancer that has progressed after previous treatment with other chemotherapeutic agents, such as anthracycline, taxane-derived drugs, or trastuzumab (Herceptin, Genentech).

A 2006 GSK-supported randomized clinical trial on female breast cancer previously being treated with those agents (anthracycline, a taxane and trastuzumab) demonstrated that administrating lapatinib in combination with capecitabine delayed the time of further cancer growth compared to regime that use capecitabine alone. The study also reported that risk of disease progression was reduced by 51%, and that the combination therapy was not associated with increases in toxic side effects.[10] The outcome of this study resulted in a somewhat complex and rather specific initial indication for lapatinib—use only in combination with capecitabine for HER2-positive breast cancer in women whose cancer have progressed following previous chemotherapy with anthracycline, taxanes and trastuzumab.

[edit] Adverse effectsLike many small molecule tyrosine kinase inhibitors, lapatinib is regarded as well tolerated. The most common side effects reported are diarrhea, fatigue, nausea and rashes.[2][11] In ongoing studies the drug have shown to provoke toxic hepatitis, the toxicity is reversible when the treatment is stopped.[citation needed]

a469822 寫:如果無效衛生署許可證就不應該發給藥商,健保局是否不承認衛生署的許可證?