1例舒尼替尼致肾脏血栓性微血管病变及肾病综合征报道

舒尼替尼是一种口服多靶点酪氨酸激酶抑制剂,具有抗肿瘤、抗血管增生的作用。该药对肾脏的损伤多表现为非肾病范围蛋白尿,导致肾病综合征相对少见,国内尚无舒尼替尼引起肾脏血栓性微血管病变报道。本文报道1例胃间质瘤术后接受舒尼替尼治疗患者,出现肾病综合征伴肾功能减退,肾活检证实为血栓性微血管病变,同时结合相关文献,对舒尼替尼所致肾脏损伤的临床表现、发病机制及治疗方法进行讨论,以提高对此类药物肾脏损伤的认识与重视。     

舒尼替尼治疗伊马替尼耐药晚期胃肠间质瘤的药物经济学评价

目的:比较舒尼替尼和大剂量伊马替尼用于既往伊马替尼治疗耐药的晚期胃肠间质瘤患者的二线治疗的成本-效果。方法:基于Ⅲ期临床试验的研究数据,结合我国相关药物和不良反应治疗成本,利用TreeAge软件建立Markov模型,对两种用药方案进行成本-效果分析。结果:进口药组大剂量伊马替尼和舒尼替尼方案的成本-效果比分别为45 806.19元/质量调整生存月(QALM)和20 330.79元/QALM,计算得到增量成本-效果比超出意愿支付阈值,舒尼替尼为优势药物。国产药组大剂量伊马替尼和舒尼替尼方案的成本-效果比分别为5 855.50元/QALM和15 101.70元/QALM,伊马替尼为优势药物。敏感性分析的结果与成本-效果分析一致。结论:对于伊马替尼耐药的晚期胃肠间质瘤患者,进口药组舒尼替尼治疗比大剂量伊马替尼治疗具有更好的经济性,但在国产药组中大剂量伊马替尼比舒尼替尼治疗具有经济学优势。     

多靶点抗肿瘤药物舒尼替尼研究进展

舒尼替尼是目前已知的作用靶点最多的靶向抗肿瘤药物之一,具有广谱的抗肿瘤活性。2006年1月美国食品药品管理局（FDA）批准舒尼替尼用于治疗转移性肾细胞癌和不能耐受或伊马替尼治疗失败的转移性胃肠道间质瘤,2008年5月在我国上市。本文就舒尼替尼的作用机理和临床研究进展作一综述。     

舒尼替尼对胃肠道间质瘤患者二线治疗的临床观察

目的 探讨二线药物舒尼替尼治疗胃肠道间质瘤(GIST)的疗效及安全性.方法 回顾性分析经病理组织和免疫组化确诊的GIST患者32例,所有的患者均用二线药物舒尼替尼治疗,37.5 mg·d-1口服,连续给药服用.观察评估舒尼替尼的不良反应及患者的生存时间.结果 舒尼替尼治疗GIST的不良反应轻微,且均可控制.32例患者接受舒尼替尼治疗的时间为3~72个月,中位治疗时间为24个月.获得完全缓解(CR)1例,部分缓解(PR)7例,稳定期(SD)16例,进展(PD)8例,有效率25.0%,疾病控制率75.0%.32例患者中,中位随访时间为96周,中位无进展生存期(PFS)为55周,中位总生存时间(OS)为96周.结论 舒尼替尼治疗伊马替尼耐药进展的GIST疗效可靠,不良反应轻微,安全可控.     

苹果酸舒尼替尼脂质体药物含量及包封率的测定

目的:建立苹果酸舒尼替尼脂质体含量及包封率的测定方法。方法:采用可见分光光度法测定苹果酸舒尼替尼的含量。阳离子交换树脂法分离游离药物,分光光度法测定脂质体中苹果酸舒尼替尼的包封率。结果:苹果酸舒尼替尼在430 nm处有最大吸收,4.0～15.0μg.mL-1范围内线性关系良好(r=0.9998,n=7);苹果酸舒尼替尼脂质体的平均包封率为91.89%。结论:所用方法简便、准确,可用于苹果酸舒尼替尼脂质体的含量及包封率测定。     

舒尼替尼致甲状腺功能减退的研究进展

舒尼替尼是一种口服多靶点受体酪氨酸激酶抑制剂,用于治疗转移性肾细胞癌和伊马替尼治疗失败或不耐受的转移性胃肠道间质瘤.舒尼替尼致甲状腺功能减退的发生率较高,症状不典型,包括乏力、心悸、畏寒、嗜睡等,易与肿瘤相关症状及舒尼替尼的其他常见不良反应混淆.舒尼替尼致甲状腺功能减退可能与破坏甲状腺腺体、抑制甲状腺过氧化物酶和损伤血管有关.服用舒尼替尼的患者需定期监测甲状腺功能,必要时给予甲状腺激素替代治疗.     

探讨舒尼替尼治疗转移性肾癌的预后因素

目的探究转移性肾癌采用舒尼替尼治疗的临床效果以及影响患者预后的相关因素。方法选取我院54例转移性肾癌患者的临床资料进行回顾性分析,所有患者均采用舒尼替尼治疗,观察治疗后患者生存情况,并采用单因素分析法研究与患者预后相关的主要影响因素。结果本组患者总体生存期为2.5~66.4个月,平均生存期为(22.5±14.8)个月,患者1年存活率为72.2%,2年存活率为63.0%,3年存活率为57.4%。影响患者预后的主要因素有ECOG(体力状况)评分、临床症状、骨转移、舒尼替尼1M-RDI(首月相对剂量密度)等,其中存在临床症状患者生存期短于无症状者(P<0.05),发生骨转移患者生存期短于无骨转移者(P<0.05),舒尼替尼1M-RDI<50%患者生存期短于舒尼替尼1M-RDI≥50%者(P<0.05),各项数据比较均存在明显统计学差异。结论采用舒尼替尼治疗转移性肾癌,影响患者预后的因素较多,临床使用靶向药物时需考虑患者实际病情和首日用药剂量等多方面因素,以提高患者生存率和治疗效果。     

转移性肾癌一线治疗药物舒尼替尼、索拉非尼和培唑帕尼的药物经济学评价文献研究

目的:评估转移性肾癌一线治疗药物舒尼替尼、索拉非尼和培唑帕尼的经济性,为医保目录调整、临床用药决策提供参考依据。方法:以"转移性肾癌""舒尼替尼""索拉非尼""培唑帕尼""成本-效果""成本-效用""成本-效益""经济性分析"等为中文检索词,以"Metastatic renal cell carcinoma""m RCC""Sunitinib""Sorafenib""Pazopanib""Cost-effectiveness""Cost-utility""Cost-benefit""Economic analysis"等为英文检索词,在PubMed、Web of Science、the Cochrane Library、中国知网、万方数据库及维普网等数据库中检索2006年1月1日-2019年7月15日公开发表的相关文献,按照纳入排除标准筛选文献。使用卫生经济学评价报告标准共识(CHEERS)量表对纳入文献进行质量评价,提取相关数据后定性比较舒尼替尼、索拉非尼、培唑帕尼治疗转移性肾癌的有效性和经济性。结果:纳入文献10篇,7篇文献的总符合率均在75.00%以上。其中,对比舒尼替尼与索拉非尼方案的4篇文献研究中,3篇文献研究指出舒尼替尼为绝对优势方案,1篇文献研究指出索拉非尼更有经济性;对比舒尼替尼与培唑帕尼方案的6篇文献研究中,4篇文献研究指出培唑帕尼为绝对优势方案,2篇文献研究指出舒尼替尼更有经济性。结论:大多数情况下,培唑帕尼治疗转移性肾癌的有效性和经济性强于舒尼替尼和索拉非尼,但真实世界数据的研究显示舒尼替尼更有经济性。     

多靶点酪氨酸激酶抑制药舒尼替尼

舒尼替尼是一种小分子多靶点酪氨酸激酶抑制药。通过抑制多个受体酪氨酸激酶(RTKs)磷酸化表现出抗肿瘤和抗血管形成活性。相对于更高选择性的激酶抑制剂,它的多靶点协作既具有可以接受的毒性,又大大提高了抗癌活性。2006年1月舒尼替尼获得美国FDA批准用于治疗晚期肾细胞癌(RCC)和服用伊马替尼后疾病出现进展或不耐受伊马替尼的胃肠道间质肿瘤(GIST)。     

临床药师对1例服用分子靶向药物舒尼替尼的肿瘤患者的药学监护

目的：通过临床药师对患者的药学监护,保障肿瘤患者使用药物的安全有效。方法：临床药师通过熟练掌握新药舒尼替尼的药理作用、不良反应以及应采取的防范措施,对1例服用舒尼替尼的患者进行药学监护。结果：临床药师对舒尼替尼所致高血压的降压药物选择、胃肠道不良反应的处理及药物选择、皮肤毒性反应的治疗方法、心血管毒性的监测及防范措施以及血液系统毒性等方面与临床医生共同制定方案,患者最终顺利完成本周期治疗。结论：临床药师通过对患者的药学监护,与临床医生协作,可以协助临床避免不良事件的发生。     

缺氧激活前药TH-302联合舒尼替尼抑制肾细胞癌体外增殖及裸鼠成瘤能力

目的：研究缺氧激活前药TH-302联合舒尼替尼抑制肾细胞癌（786-O细胞）体外增殖及裸鼠成瘤能力,深入探讨其分子机制。方法：采用四甲基偶氮唑蓝（MTT）比色法检测在缺氧条件下TH-302联合舒尼替尼对人肾癌786-O细胞增殖抑制率;建立786-O细胞裸鼠皮下移植瘤模型,通过免疫组化及qPCR法检测TH-302联合抑制裸鼠肿瘤生长的效果及作用机制。结果：在缺氧条件下,TH-302联合在抑制786-O细胞增殖作用中发挥协同作用;联合组可显著抑制肿瘤体积的生长,差异有统计学意义（P<0.05）。与TH-302组相比,TH-302联合舒尼替尼显著降低异种移植瘤中的缺氧区域,深入研究发现,与TH-302组相比,TH-302联合舒尼替尼组显著抑制肿瘤组织中HIF-1α,HIF-2α的表达。结论：TH-302联合舒尼替尼抑制肾癌细胞恶性增殖,减少肿瘤组织的缺氧区域,其作用机制可能与HIF-1α,HIF-2α的表达量变化有关。     

Model-based assessment of pharmacokinetic changes of sunitinib,tacrolimus, and everolimus in a patient with metastatic renal cell carcinoma after renal transplantation

The safety of the coadministration of sunitinib with tacrolimus and everolimus with regard to therapeutic drug monitoring has not been demonstrated. Here, we report a patient who showed high sunitinib concentrations, in addition to pharmacokinetic changes in tacrolimus and everolimus after sunitinib therapy. A living-donor renal transplant patient treated with tacrolimus and everolimus was diagnosed with pulmonary and pleural metastases of renal cell carcinoma. The patient received sunitinib therapy (37.5 mg/day, 2 weeks on and 1 week off). This patient exhibited a high total sunitinib concentration (sunitinib, 105.8 ng/mL; N-desethyl sunitinib, 27.9 ng/mL) on day 10 postinitiation and experienced grade 3 diarrhea. The observed sunitinib concentrations were a little higher than those reported in the 421C>A polymorphism of the ATP-binding cassette subfamily G member 2 gene carrier. The observed concentrations of both tacrolimus and everolimus gradually decreased compared with the Bayesian-predicted values after the onset of sunitinib therapy, and the doses of tacrolimus and everolimus were increased. Careful therapeutic drug monitoring of sunitinib, tacrolimus, and everolimus concentrations is necessary during combination therapy, especially after episodes of diarrhea.     

Comparing the efficacy of sunitinib with sorafenib in xenograft models of human hepatocellular carcinoma: mechanistic explanation

Hepatocellular carcinoma (HCC) is the fifth most common and third deadliest malignancy. Sorafenib has demonstrated 44% survival advantage over placebo and has emerged as a standard of care in advanced HCC. The therapeutic effects of sorafenib are however transient and hence additional treatment options are warranted. In this study, we aimed to compare the efficacy of sunitinib relative to sorafenib, two potent inhibitors of protein tyrosine kinases involved in tumor growth, metastasis, or angiogenesis. We reported that sorafenib and sunitinib suppressed tumor growth, angiogenesis, cell proliferation, and induced apoptosis in both orthotopic and ectopic models of HCC. However, the antitumor effect of 50 mg/kg sorafenib was greater than that of 40 mg/kg sunitinib. Sorafenib inhibited p-eIF4E Ser209, p-p38 Thr180/Tyr182 and reduced survivin expression. This was not seen with sunitinib. In addition, the antitumor and apoptotic effects of sorafenib, which are associated with upregulation of fast migrating Bim and ASK1 and downregulation of survivin, were greater than that of sunitinib. These observations explained in part the apparent superior anti-tumor activity of sorafenib compared to sunitinib. In conclusion, sunitinib demonstrated an inferior anti-tumor activity compared to sorafenib in ectopic and orthotopic models of human HCC. It remains to be seen whether such observations would be recapitulated in humans.     

舒尼替尼对EGFR TKI抵抗的A549细胞株增殖抑制作用及机制研究

目的探讨舒尼替尼(sunitinib)体外对表皮生长因子受体酪氨酸激酶抑制剂(EGFR TKI)耐药的非小细胞肺癌A549细胞的生长抑制作用及其机制。方法 MTT法检测sunitinib对A549细胞的生长抑制作用;荧光显微镜观察sunitinib诱导的细胞凋亡;流式细胞术检测sunitinib作用后细胞周期变化;Western blot检测sunitinib作用后Bcl-2蛋白水平的变化。结果在0.4～12.8μmol.L-1浓度范围内,sunitinib抑制A549细胞增殖,且具有浓度和时间依赖性,24、48、72 h的半数抑制浓度(IC50)分别为(7.34±0.76)、(5.54±0.62)、(3.68±0.53)μmol.L-1。荧光显微镜观察发现sunitinib能够诱导细胞出现核固缩、体积缩小等凋亡形态学改变。细胞周期显示sunitinib将A549细胞阻滞于G0/G1期。Western blot显示sunitinib能够降低Bcl-2蛋白的表达水平,且随着sunitinib浓度的升高,Bcl-2蛋白的表达水平逐渐降低。结论 sunitinib能够抑制EGFR TKI抵抗的A549细胞生长,并具有浓度和时间依赖性,其抗肿瘤的机制可能与诱导细胞周期阻滞和下调Bcl-2的表达有关。     

HPLC测定人血浆中舒尼替尼浓度及其血浆蛋白结合率

目的采用HPLC测定人血浆中舒尼替尼浓度,并结合平衡透析法和超滤法测定舒尼替尼血浆蛋白结合率。方法采用WatersXBridgeTM C18色谱柱(4.6 mm×250mm,5μm),流动相为甲醇-0.02mol·L^-1磷酸二氢钠(70∶30),流速1.0 mL·min^-1,检测波长310 nm。结果舒尼替尼在0.0575~34.5μg·mL^-1内线性关系良好,定量下限为0.0575μg·mL^-1;舒尼替尼在低、中、高3个浓度下平衡透析法测得的血浆蛋白结合率为(84.1±2.1)%,(81.0±1.8)%,(80.6±1.6)%,超滤法蛋白结合率分别为(80.8±1.7)%,(84.2±2.0)%,(82.6±2.2)%,2种方法结果比较接近。结论本方法简单、快速、灵敏,能满足分析要求。舒尼替尼与人血浆蛋白有较高的结合率,且蛋白结合率与浓度无关。     

The effects of topical everolimus and sunitinib on corneal neovascularization

Purpose: To evaluate the effects of topical everolimus and sunitinib on corneal neovascularization (CNV).

Methods: CNV was induced by application of silver nitrate to the cornea for all groups. Rats were divided into four groups of 10 rats each, and two corneas were obtained from each rat. Group I received 1?mg/ml everolimus, Group II received 0.5?mg/ml sunitinib, Group IV received no treatment (control group) and Group IV received 1% Dimethylsulfoxide (DMSO). All treatments were administrated twice daily for 2 weeks. The right corneas were used for extracellular signal-regulated kinase 1/2 (ERK 1/2) protein analysis by western blot analysis and the left corneas were used for ERK 1/2 and vascular endothelial growth factor-receptor (VEGFR-2) gene expression analysis by quantitative real-time PCR.

Results: VEGFR-2 mRNA expression levels (ΔCt, median, min-max) were reduced in the everolimus 1.0 (0.25–1.81) and sunitinib 1.06 (0.24–2.68) treated groups compared with the control 4.74 (1.02–14.74) and DMSO groups 7.41 (0.72–13.10). The expression of ERK 1/2 protein and mRNA levels were reduced in everolimus group compared with the control group (p?<?0.05). These differences were not seen between the sunitinib and control groups.

Conclus?on: Topical administration of both everolimus and sunitinib reduced VEGFR-2 levels and inhibited CNV. In additon, everolimus reduced ERK 1/2 levels and seems to be more effective than sunitinib on CNV.     

Sunitinib in combination with clarithromycin or azithromycin – is there a risk of interaction or not?

BackgroundMacrolides are the most widely prescribed antibiotics. Clarithromycin is a well-known inhibitor of cytochrome P450 CYP3A4 and causes numerous drug interactions that are not found for azithromycin. CYP3A4 is involved in the metabolism of the new oral multikinase inhibitor sunitinib and its active N-desethyl metabolite (SU012662). This study investigated the effects of oral single dose of clarithromycin or azithromycin on the pharmacokinetics of sunitinib.MethodsRabbits were subjected to one of three study drug groups: sunitinib + clarithromycin (n = 6), sunitinib + azithromycin (n = 6), or sunitinib (n = 6). The rabbits were treated with sunitinib in the oral dose of 25 mg. Plasma concentrations of sunitinib were measured with validated HPLC method with UV detection.ResultsComparison of the sunitinib C_max for the sunitinib + clarithromycin group with that of the sunitinib group gave a ratio of 94.4% [90% confidence interval (CI) (76.1, 117.1)]; for the sunitinib + azithromycin group, the ratio was 106.2% (90% CI 85.5, 131.7). Comparison of the sunitinib AUC_0-t of the sunitinib + clarithromycin and sunitinib + azithromycin groups with that of the sunitinib group showed ratios of 86.86% (90% CI 69.7, 108.3) and 99.8% (90% CI 80.1, 124.5), respectively.ConclusionsNo significant effect of the coadministration of clarithromycin or azithromycin on the pharmacokinetics of sunitinib in rabbits was found in this study.     

3-取代-5-氟-1-2-二氢-3H-吲哚-2-酮类化合物的合成及抗肿瘤活性

5-溴-1H-吲哚经氰基取代、Vilsmeier-Haack反应、水解、缩合制得3-[(Z)-(5-氟-1,2-二氢-2-氧代-3H-亚吲哚基)甲基]-1H-吲哚-5-甲酸,再和相应的胺类化合物反应制得10个3-取代-5-氟-1,2-二氢-3H-吲哚-2-酮类化合物.以舒尼替尼为阳性对照,用MTT法测试目标化合物对人乳腺上皮细胞HMEC的体外抑制活性,其中1c、1f、1g和1h在浓度为10 μmol/L时,对HMEC的抑制活性优丁舒尼替尼.进一步测试1c和1e对SGC7901、A549、HL-60、SK-BR-3、HCT116肿瘤细胞株的抗增殖活性.结果表明,1c和1e对白血病细胞株HL-60的抗增殖活性优丁舒尼替尼.     

Determination of sunitinib and its active metabolite N-desethylsunitinib in sweat of a patient

Skin reactions are side effects of sunitinib therapy with an adverse impact on quality of life often necessitating dose reductions. For conventional antineoplastic agents, such as doxorubicin, previous studies have indicated a possible relationship between sweat excretion and the development of skin toxicity. However, the determination of sunitinib and its active metabolite in sweat has not yet been reported. A sensitive and accurate method for the determination of sunitinib and its active metabolite N-desethylsunitinib in human sweat was developed using high-performance liquid chromatography coupled to tandem mass spectrometry detection (LC-MS-MS). Sweat samples of a patient treated with sunitinib were collected using Pharmchek? Drugs of Abuse patches to determine cumulative amounts of sunitinib and metabolite. Validation of the LC-MS-MS method was performed over a range from 1.0 to 200 ng/patch with good intra- and interassay accuracies for sunitinib and N-desethylsunitinib. Ranges of 76-119 and 7.9-10.5 ng/patch for cumulative secretion of sunitinib and metabolite, respectively, were found in patient samples. To our knowledge, this is the first method for determination of cumulative secretion of sunitinib and N-desethylsunitinib in human sweat samples. Sunitinib and its metabolite were easily detectable in sweat patches of a patient treated with sunitinib.