印度拉帕替尼

【印度拉帕替尼说明书，怎么吃？】

拉帕替尼（印度）又名拉帕替尼 LAPATINIB TYKERB，拉帕替尼适用于乳腺癌：拉帕替尼用于联合卡培他滨治疗ErbB-2过度表达的,既往接受过包括蒽环类,紫杉醇,曲妥珠单抗(赫赛汀)治疗的晚期或转移性乳腺癌；或与来曲唑联用治疗绝境女性HER2过表达的激素受体阳性乳腺癌。（在使用赫赛汀时疾病急需进展的，适合开始拉帕替尼联合卡培他滨治疗） 的治疗，拉帕替尼用法及注意事项,:【药品特色】 HER2阳性乳腺癌的绝经后女性，联合来曲唑成为一线口服用药方案。 作用机制： 拉帕替尼是小分子4-苯胺基喹唑啉类受体酪氨酸激酶抑制剂，抑制表皮生长因子受体（ErbB1）和人表皮因...

【药品特色】    HER2阳性乳腺癌的绝经后女性，联合来曲唑成为一线口服用药方案。

作用机制：

拉帕替尼是小分子4-苯胺基喹唑啉类受体酪氨酸激酶抑制剂，抑制表皮生长因子受体（ErbB1）和人表皮因子受体2（ErbB2）
 
常见副作用：

乏力、恶心、呕吐、腹泻、便秘、皮肤干燥、脱发、头痛等
  
给药方法:

每天一次，空腹口服（饭前1小时或饭后1小时）。定时定量服药，不建议将一天的剂量分散为多次服用。注：与卡培他滨联用的，卡培他滨应该每天两次，与食物同时服用，或饭后30分钟内服用。
 
注意事项：

在临床试验及上市后调查中发现有部分服药患者出现严重肝损，并且有死亡案例，如果有肝脏疾病，请务必告知医生。
 
参考用法：

1. 有转移的乳腺癌，HER2阳性（经紫杉醇、环蒽类或赫赛汀治疗）：口服， 1250 mg，每天一次（与卡培他滨联用），直至疾病进展或不可接受的副作用。

2. 有转移的乳腺癌，HER2阳性，需要激素疗法：口服， 1500 mg，每天一次（与来曲唑联用），直至疾病进展。

3. HER2阳性乳腺癌，脑转移，一线治疗（FDA未批准为标签的疗法）：口服，1250 mg，每天一次（与卡培他滨联用），直至疾病进展或不可接受的副作用。

4. HER2阳性乳腺癌，用赫赛汀中出现了疾病进展（FDA未批准为标签的疗法）：1000 mg，每天一次（与卡培他滨联用）


USES OF TYKERB TABLET
Breast cancer

TYKERB TABLET SIDE EFFECTS
Common
Nausea
Headache
Back pain
Breathing difficulty
Rash
Joint pain
Pain in extremity
Insomnia (difficulty in sleeping)
Vomiting
Weakness
Abdominal pain
Indigestion
Loss of appetite
Fatigue
Diarrhea
Cough
Mucosal inflammation
Constipation
Hot flashes
Stomatitis (Inflammation of the mouth)
Weight gain
Increased bilirubin in the blood
Liver damage

HOW TO USE TYKERB TABLET
Take this medicine in the dose and duration as advised by your doctor. Swallow it as a whole. Do not chew, crush or break it. Tykerb 250 mg Tablet is to be taken empty stomach.

HOW TYKERB TABLET WORKS
Tykerb 250 mg Tablet is an anti-cancer medication. This works against the HER2 (human epidermal growth factor receptor protein) receptors and EGFRs (epidermal growth factor receptor) which is responsible for the over-proliferation of cells. This is how it inhibits the growth of cancerous cells causing downstream signaling pathways.

TYKERB TABLET RELATED WARNINGS
warnings
Alcohol
Interaction with alcohol is unknown. Please consult your doctor.

warnings
Pregnancy
WEIGH RISKS VS BENEFITS
Tykerb 250 mg Tablet is unsafe to use during pregnancy.
There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk, for example in life-threatening situations. Please consult your doctor.

warnings
Lactation
UNSAFE
Tykerb 250 mg Tablet is unsafe to use during lactation. Data suggests that the drug may cause toxicity to the baby, or the mother is suffering from a condition in which breastfeeding is not advisable.

warnings
Driving
Tykerb 250 mg Tablet may cause side effects which could affect your ability to drive.

warnings
Kidney
Tykerb 250 mg Tablet should be used with caution in patients with severe kidney disease. Dose adjustment of Tykerb 250 mg Tablet may be needed. Please consult your doctor.
Limited information is available on the use of Tykerb 250 mg Tablet in these patients. No dose adjustment is recommended in patients with mild to moderate kidney disease.

warnings
Liver
CAUTION
Tykerb 250 mg Tablet should be used with caution in patients with liver disease. Dose adjustment of Tykerb 250 mg Tablet may be needed. Please consult your doctor.
Limited information is available on the use of this medicine in patients with the severe liver disease.

Lapatinib

生物活性

产品描述	Lapatinib is a dual inhibitor of Lapatinib is a dual ErbB2/EGFR (IC50: 9.2/10.8 nM) inhibitor
靶点活性	C-Raf-1,>10μM c-Src,3.5μM EGFR,10.8nM HER2/ErbB2,367nM
实验溶液	15% Captisol: 30 mg/mL
体外活性	培养HN5 细胞群2周（不加 Lapatinib ）左右后，再加30 μM Lapatinib 短暂处理，细胞生长完全被抑制。浓度>3.3 μM时，抑制率达50%；浓度为0.37 μM时，抑制率达20%。另一种细胞A-431（EGFR过量表达）与HN5反应类似。在抑制 EGFR过量表达的细胞生长方面，Lapatinib与 OSI-774 相似。除ErbB-4外, Lapatinib 对EGFR 和 ErbB-2的选择性比其他测试激酶高300多倍，如c-Src, MEK和ERK。Lapatinib抑制EGFR 和ErbB-2受体自磷酸化的作用存在剂量依赖性，对BT474 和HN5 细胞的IC50 分别为 0.17 和0.08 μM。作用于EGFR-和ErbB-2-过量表达的肿瘤细胞时，Lapatinib的抑制作用比作用于上述纯化酶的效力低10倍左右。Lapatinib 抑制 EGFR- 和ErbB-2过量表达的细胞生长，而EGFR选择性抑制剂OSI-774和 Iressa则会优先抑制 EGFR过量表达的细胞生长。Lapatinib对肿瘤细胞的作用比正常成纤维细胞效果高约100倍。ErbB-2转染后的乳腺上皮细胞HB4a c5.2对 Lapatinib的敏感度比未转染的亲本细胞高40倍左右。
体内活性	实验对象：肿瘤携带小鼠。给药剂量：30和 100 mg/kg ，2次/天，口服。实验结果：以剂量依赖的方式抑制肿瘤生长。100 mg/kg Lapatinib可完全抑制肿瘤生长。按这种剂量处理，在21天内，有<10%肿瘤损失。Lapatinib可有效抑制人类移植瘤BT474 和HN5 的生长。
激酶实验	In vitro kinase assays: The IC50 values for inhibition of enzyme activity are generated by measuring inhibition of phosphorylation of a peptide substrate. The intracellular kinase domains of EGFR and ErbB2 are purified from a baculovirus expression system. EGFR and ErbB2 reactions are performed in 96-well polystyrene round-bottomed plates in a final volume of 45 μL. Reaction mixtures contain 50 mM 4-morpholinepropanesulfonic acid (pH 7.5), 2 mM MnCl2, 10 μM ATP, 1 μCi of [γ33P] ATP/reaction, 50 μM Peptide A [Biotin-(amino hexonoic acid)-EEEEYFELVAKKK-CONH2], 1 mM dithiothreitol, and 1 μL of DMSO containing serial dilutions of Lapatinib beginning at 10 μM. The reaction is initiated by adding the indicated purified type-1 receptor intracellular domain. The amount of enzyme added is 1 pmol/reaction (20 nM). Reactions are terminated after 10 minutes at 23°C by adding 45 μL of 0.5% phosphoric acid in water. The terminated reaction mix (75 μL) is transferred to phosphocellulose filter plates. The plates are filtered and washed three times with 200 μL of 0.5% phosphoric acid. Scintillation cocktail (50 μL) is added to each well, and the assay is quantified by counting in a Packard Topcount. IC50 values are generated from 10-point dose-response curves.
细胞实验	Cells are exposed to various concentrations of Lapatinib for 72 hours. Relative cell number is estimated using methylene blue staining. The absorbance at 620 nm is read in a Spectra microplate reader. Cell death and cell cycle analysis are assessed by propidium iodide staining and antibody detection of incorporated BrdUrd and staining with propidium iodide.(Only for Reference) 细胞系： HFF, MCF-7, T47D, A-431, HN5, BT474, N87, CaLu-3, HB4a, and HB4a c5.2 cells
动物实验	动物模型：CD-1 nude femice implanted s.c. with HN5 cells, and C.B-17 SCID femice implanted s.c. with BT474 cells

化学信息

分子量	581.06
分子式	C29H26ClFN4O4S
CAS	231277-92-2
溶解度	DMSO: 93 mg/mL (160.1 mM) Ethanol: <1 mg/mL Water: <1 mg/mL （ < 1 mg/ml refers to the product slightly soluble or insoluble )
储存条件	store at -80°C
备注	For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.

配制溶液

	1 mg	5 mg	10 mg
1 mM	1.721 ml	8.605 ml	17.21 ml
5 mM	0.344 ml	1.721 ml	3.442 ml
10 mM	0.172 ml	0.86 ml	1.721 ml
50 mM	0.034 ml	0.172 ml	0.344 ml

参考文献
 
1. Rusnak DW, et al. The effects of the novel, reversible epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor, GW2016, on the growth of human normal and tumor-derived cell lines in vitro and in vivo. Mol Cancer Ther. 2001 Dec;1(2):85-94
2. Chefrour M et al. Positive interaction between lapatinib and capecitabine in human breast cancer models: study of molecular determinants. Fundam Clin Pharmacol. 2012 Aug;26(4):530-7.
3. Wainberg ZA, et al. Lapatinib, a dual EGFR and HER2 kinase inhibitor, selectively inhibits HER2-amplified human gastric cancer cells and is synergistic with trastuzumab in vitro and in vivo. Clin Cancer Res. 2010 Mar 1;16(5):1509-19.
4. Eryilmaz U, et al. S100A1 as a Potential Diagnostic Biomarker for Assessing Cardiotoxicity and Implications for the Chemotherapy of Certain Cancers. PLoS One. 2015 Dec 18;10(12):e0145418.