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印度威罗菲尼

资料发布时间:2018-10-30 14:50:00 最后更新时间:2020-08-13 10:11:16

【药品简介】 威罗菲尼,是一种激酶抑制剂。通过抑制BRAF(丝氨酸-苏氨酸激酶),阻止缺乏细胞因子的细胞增殖,从而起到抗肿瘤效应。

【适应症状】 威罗菲尼,威罗菲尼是一种激酶抑制剂,威罗菲尼适用于有不可切除或转移黑色素瘤,且用FDA-批准的检验检测BRAFV600E突变患者的治疗。

【 药品别名 】 威罗菲尼 Vemurafenib

印度威罗菲尼(威罗菲尼 Vemurafenib)价格,正品图片,治疗黑色素瘤药物, 购买威罗菲尼请到印度药房官方网站进行购买 【印度药房大全目录】

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【印度威罗菲尼说明书,怎么吃?】

【威罗菲尼用法用量】
 
1)推荐剂量:威罗菲尼960 mg,口服bid。
 
2)接近12小时间隔给予有或无进餐。
 
3)应用一杯水完整吞服。
 
4)不应咀嚼威罗菲尼或压碎。
 
5)若出现不良药物反应可能需要减低威罗菲尼剂量,中断或终止威罗菲尼治疗。
 
  
【不良反应】
 
威罗菲尼最常见不良反应(≥ 30%)是关节痛,皮疹,脱发,疲乏,光敏反应,恶心,瘙痒和皮肤乳头状瘤。
 
 威罗菲尼
 
【威罗菲尼注意事项】
 
1)24%患者中发生皮肤鳞状细胞癌(cuSCC):治疗开始前和当用治疗时每2个月进行皮肤学评价。
 
2)治疗期间和再次开始治疗时曾报道严重超敏反应,包括过敏反应。经受严重超敏反应患者中终止威罗菲尼。
 
3)曾报道严重皮肤学反应,包括Stevens-Johnson综合征和中毒性表皮坏死溶解。经受威罗菲尼严重皮肤学反应患者中终止威罗菲尼治疗。
 
4)曾报道QT延长。如QT超过500 ms,短暂中断,校正电解质异常,和控制对QT延长风险因子。
 
5)可能发生肝实验室异常。治疗开始前和治疗期间每月,或当临床指示时监视肝酶和胆红素。
 
6)曾报道光敏性:服用威罗菲尼时建议患者避免暴露阳光。
 
7)威罗菲尼曾报道严重眼科反应,包括葡萄膜炎,虹膜炎和视网膜静脉阻塞。对眼科反应常规监视患者。

8)威罗菲尼曾报道新原发性恶性黑色素瘤。切除处理,无需剂量调整。如上所述,进行皮肤学监视。
 
9)妊娠:可能致胎儿危害;对胎儿潜在风险.
 
10)为了选择适于威罗菲尼治疗患者,用一种FDA-批准的检验BRAF突变。尚未在有野生型BRAF黑色素瘤患者中研究威罗菲尼的疗效和安全性。
 

产品描述

Vemurafenib (PLX4032) is a novel and potent B-Raf (V600E) inhibitor (IC50: 31 nM).

靶点活性

ACK1,19 nM (cell free)

BLK,547nM

B-Raf,100nM

B-Raf (V600E),31 nM (cell free)

BRK,213nM

C-Raf,48nM

CSK,2.339μM

FGR,63nM

FRK (PTK5),1.884μM

Lck,183nM

Lyn B,599nM

MAP4K5 (KHS1),51nM

MNK2,1.717μM

NEK11,317nM

Src,2.389μM

SRMS,18 nM (cell free)

WNK3,877nM

Yes1,604nM

c-Raf-1,48 nM (cell free)

实验溶液

30% PEG400+0.5% Tween80+5% propylene glycol: 5 mg/mL

体外活性

Vemurafenib (PLX4032, RG7204) displays similar potency for B-RAFV600E (31nM) and c-RAF-1 (48nM) and selectivity against many other kinases, including wild type B-RAF (100nM) [1]. In 17 melanoma cell lines, RG7204 was a potent inhibitor of proliferation in those expressing BRAFV600E but not BRAFWT. RG7204 also potently inhibited proliferation of melanoma cell lines expressing other codons 600 BRAF mutations (V600D, V600K, and V600R) [2]. Melanoma cells were more sensitive to PLX4032 than CRC cells. The inhibition of EGFR does not significantly affect the proliferation of EGFR in WiDr cells. In contrast, suppression of EGFR in combination with PLX4032 caused a marked inhibition of proliferation in WiDr cells [3].

体内活性

In BRAFV600E-mutant xenograft, PLX4032 (6 or 8 mg/kg) demonstrated dose-dependent inhibition of tumor growth, with higher exposures resulting in tumor regression [1]. In mice bearing Colo829 tumor xenografts, RG7204 at 100 mg/kg bid for 21 days showed greatly improved antitumor activity at the end of the study on day 38 after the tumor cell implant. There was complete tumor regression in all 10 mice treated with RG7204 by the end of the study [2]. In the dose-escalation cohort, among the 16 patients with melanoma whose tumors carried the V600E BRAF mutation and who were receiving 240 mg or more of PLX4032 twice daily, 10 had a partial response and 1 had a complete response [4].

激酶实验

Expression and purification of B-RAF, structure determination, and protein kinase activity measurements were carried out as previously described. To obtain co-crystals of B-RAFV600E with PLX4032, the protein solution was initially mixed with the compound dissolved in DMSO at a final compound concentration of 1 mM. This complex was co-crystallized by a sitting drop vapor diffusion experiment in which equal volumes of complex (at 10 mg/ml concentration) and reservoir solution (100mM BisTris at pH 6.0, 12.5% 2,5-hexanediol, and 12% PEG3350) were mixed and allowed to equilibrate against the reservoir at 4°C. The crystal was soaked in cryosolvent, followed by flash-freezing in liquid nitrogen. The data were collected at Beamline ALS831 with the wavelength of 1.11?. The Ramachandran plot from the refined structure shows that 94%, 5.6% and 0.4% residues are in the most favored, additional allowed and generously allowed regions, respectively. A summary of the crystallography statistics is included in Supplementary Table 3. COLO205 tumor xenograft studies (Molecular Imaging Research, Ann Arbor, MI) were carried out as previously described either using a conventional formulation (5%DMSO, 1% methylcellulose) or using the MBP formulation [1].

细胞实验

Cellular proliferation was evaluated by MTT assay. Briefly, cells were plated in 96-well microtiter plates at a density of 1,000 to 5,000 cells per well in a volume of 180 μL. For the assay, RG7204 was prepared at 10 times the final assay concentration in media containing 1% DMSO. Twenty-four hours after cell plating, 20 μL of the appropriate dilution were added to plates in duplicate. The plates were assayed for proliferation 6 days after the cells were plated according to the procedure originally described by Mosmann [2].

细胞系: MALME-3M, Colo829, Colo38, A375, SK-MEL28, and A2058 cells

动物实验

All animal procedures were approved by the Ethical Commission of the Institute for Cancer Research and Treatment and by the Italian Ministry of Health. WiDr cells were injected subcutaneously into the right posterior flanks of 7-week-old immunodeficient NODSCID female mice (6 mice per group). Tumour formation was monitored twice a week, and tumour volume based on caliper measurements was calculated by the modified ellipsoidal formula: tumour volume = 1/2 length × width. When tumours reached a volume of approximately 200–250 mm^3, mice were randomly assigned to treatment with vehicle or drug(s) [3].

动物模型:Mice (athymic nude) xenograft models of LOX, Colo829, and A375 cells

化学信息

分子量

489.92

分子式

C23H18ClF2N3O3S

CAS

918504-65-1

溶解度

DMSO: 90 mg/mL (183.7 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 2.041 ml 10.206 ml 20.411 ml
5 mM 0.408 ml 2.041 ml 4.082 ml
10 mM 0.204 ml 1.021 ml 2.041 ml
50 mM 0.041 ml 0.204 ml 0.408 ml

参考文献

 
1. Bollag G, et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature, 2010, 467(7315), 596-599.
2. Yang H, et al. RG7204 (PLX4032), a selective BRAFV600E inhibitor, displays potent antitumor activity in preclinical melanoma models. Cancer Res, 2010, 70(13), 5518-5527.
3. Prahallad A, et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature, 2012, 483(7387), 100-103.
4. Flaherty KT, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010 Aug 26;363(9):809-19.
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