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International Journal of Ophthalmology(English edition) 2018年第12期11卷 1909-1915页

作者： Sabiha Gungor Kobat Fatma Ulku Celiker Adile Ferda Dagli Kader Kasar Department of Ophthalmology Elazig Health Sciences University Department of Ophthalmology School of Medicine Firat University Department of Pathology School of Medicine Firat University Department of Ophthalmology Ordu State Hospital

AIM: To compare the effects of bevacizumab and pazopanib with corticosteroids on wound healing after trabeculectomy. METHODS: In the study, 35 New Zealand white rabbits were randomly divided into five groups. Apart from the first group, limbus-based trabeculectomy was performed for the eyes of rabbits. No postoperative treatment was administered for group Ⅰ. Topically administered saline, prednisolone acetate(1%), bevacizumab 5 mg/mL, pazopanib 5 mg/mL for group Ⅱ, Ⅲ, Ⅳ and Ⅴ respectively were applied for groups 6 h daily for 28 d. On day 28 of the experiment, eyes were enucleated and histologically and immunohistochemically ***: The fibroblast counts of groups Ⅳ and Ⅴ were determined to be lower than those of groups Ⅱ and Ⅲ(P0.05). The immunohistochemical staining intensity of fibroblast growth factor β(FGF-β) and vascular endothelial growth factor(VEGF) was determined to be lower in groups Ⅳ and Ⅴ than in groups Ⅱ and Ⅲ(P0.05). The platelet derived growth factor β(PDGF-β) intensity was lower in group Ⅴ than in groups Ⅱ, Ⅲ and Ⅳ(P0.05). CONCLUSION: Bevacizumab and pazopanib might be good alternatives of corticosteroid treatment on delaying wound healing in glaucoma surgery.

关键词： trabeculectomy wound healing corticosteroid bevacizumab pazopanib

pazopanib Induced Hand-Foot Syndrome in a Patient Previously Treated with Sunitinib: A Possible Cumulative Skin Toxicity?

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Pharmacology & Pharmacy 2016年第8期7卷 354-357页

作者： Emanuele Cozzani Sanja Javor Stefano Ottoboni Aurora Parodi Department of Endocrinological and Metabolic Sciences Section of Dermatology University of Genoa Genoa Italy Department of Chirurgic and Diagnostic Sciences (DISC) University of Genoa Genoa Italy

Hand-foot syndrome (HFS), also known as palmar-plantar erythrodysesthesia, is a skin toxicity that could be observed during target therapies such as with tyrosine-kinase inhibitors (TKI). It usually develops within the first 2 - 4 weeks of drug administration. We present a case of HFS induced by pazopanib after 2 months of treatment, in patients previously treated with Sunitinib, suggesting a possible cumulative toxicity of two drugs. The clinical and therapeutic management of skin adverse reactions during TKI therapy usually requires 25% dose reduction and adequate local treatment. It is important for the clinicians to recognize clinical signs and symptoms of such skin toxicities. Attention should be paid especially when two or more drugs from the same class are used in combined treatment.

关键词： Hand-Foot Syndrome pazopanib Sunitinib Tyrosine-Kinase Inhibitors Cumulative Toxicity 1.

Posterior Reversible Encephalopathy Syndrome Induced by pazopanib in a Patient with Soft-Tissue Sarcoma: A Case Report

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Case Reports in Clinical Medicine 2019年第5期8卷 127-133页

作者： Chien-Ting Wu Chieh-Tsung Yen Hsiu-Lan Cheng Chi-Hui Lee Department of Pharmacy Dalin Tzu Chi Hospital Buddhist Tzu Chi Medical Foundation Taiwan

Posterior reversible encephalopathy syndrome (PRES), a rare disease is characterized by multiple neurological complications. It has been reported to be associated with the use of angiogenesis inhibitors such as sorafenib, sunitinib, pazopanib, regorafenib, and lenvatinib. We reported a case of 76-year-old woman with history of stage III hepatocellular carcinoma (HCC), who developed adverse drug reactions related to pazopanib induced PRES. pazopanib, an angiogenesis inhibitor which inhibits the vascular endothelial growth factor (VEGF) pathway may lead to vascular endothelial damage, and these pathophysiological changes may lead to vascular leaks and brain edema. Medical staff must be aware of the possible association between angiogenesis inhibitors and the development of PRES. In patients with retroperitoneal soft-tissue sarcoma undergoing treatment with pazopanib, regular monitoring of their blood pressure and following-up brain magnetic resonance imaging (MRI) should be encouraged.

关键词： Posterior Reversible Encephalopathy Syndrome pazopanib Hepatocellular Carcinoma Vascular Endothelial Growth Factor Magnetic Resonance Imaging

Molecular Markers of Kidney Cancer Progression, Association with Efficiency of pazopanib Therapy

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Journal of Biomedical Science and Engineering 2015年第11期8卷 756-766页

作者： Liudmila V. Spirina Evgeny A. Usynin Irina V. Kondakova Zahar A. Yurmazov Elena M. Slonimskaya Tomsk Cancer Research Institute Siberian State Medical University Tomsk Russia Tomsk Cancer Research Institute Tomsk Russia

Purpose: The aim of the study is to reveal associations between NF-κB, HIF-1alpha, VEGF expres-sions, proteasome and calpain activities with tumor progression in patients with kidney cancers and to find molecular parameters, associated with the effective pazopanib therapy. 93 patients with clear cell kidney cancers are included in investigation. 26 patients with disseminated kidney cancer have the pazopanib therapy. Methods: Transcription factors, VEGF, VEGFR2 and p-m-TOR expression are measured by ELISA kits. Proteasome and calpain activity are determined using specific fluorogenic substrate. Results: It is found the increase of NF-κB, HIF-1 expression in cancer tissues followed the hematogenic metastasis development. Coefficient NF-κB р65/р50 and VEGF expression are increased in cancer tissues with single metastasis and are decreased in cancer tissues with multiple ones. It is observed in the low proteasome activity in metastatic cancer tissues. The partial cancer regression is revealed in 29.6% of patients treated with pazopanib, cancer stabilization—in 61.5% of patients and cancer progression—in 11.5% of patients. The increased level of transcription factors NF-κB, HIF-1, growth factor VEGF and high proteasome activity in cancer tissues before targeted therapy are associated with the effective treatment. It is obtained the significant decrease of investigated markers after pazopanib application in metastatic kidney cancer patients. Conclusion: Coefficient NF-κB р65/р50, VEGF expression and proteases activities are the potential prognostic molecular markers of hematogenic metastasis development in kidney cancers. NF-κB, HIF-1 and VEGF levels can be considered as additional molecular markers predicting the effective pazopanib therapy.

关键词： Kidney Cancer NF-κB HIF-1 VEGF VEGFR2 m-TOR Proteasome Calpain pazopanib

First-line pazopanib in patients with advanced non-clear cell renal carcinoma:An Italian case series

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World Journal of Clinical Oncology 2021年第11期12卷 1037-1046页

作者： Sebastiano Buti Melissa Bersanelli Francesco Massari Ugo De Giorgi Orazio Caffo Gaetano Aurilio Umberto Basso Giacomo Carteni Claudia Caserta Luca Galli Francesco Boccardo Giuseppe Procopio Gaetano Facchini Giuseppe Fornarini Alfredo Berruti Elena Fea Emanuele Naglieri Fausto Petrelli Roberto Iacovelli Camillo Porta Alessandra Mosca Medical Oncology Unit University Hospital of ParmaParma 43126Italy Medicine and Surgery Department University of ParmaParma 43126Italy Division of Oncology Policlinico Sant’Orsola-Malpighi HospitalBologna 40138Italy Department of Oncology IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori(I.R.S.T.)Meldola 47014Italy Department of Medical Oncology Santa Chiara HospitalTrento 38122Italy Department of Medical Oncology Division of Urogenital and Head and Neck TumoursEuropean Institute of Oncology IRCCSMilan 20141Italy Medical Oncology Unit 3 Istituto Oncologico Veneto IOV IRCCSCastelfranco VenetoPadova 31033Italy Division of Oncology Azienda Ospedaliera di Rilievo Nazionale A.CardarelliNapoli 80131Italy Medical Oncology Unit Azienda Ospedaliera S.MariaTerni 05100Italy Oncology Unit 2 University Hospital of PisaPisa 56126Italy Academic Unit of Medical Oncology IRCCS San Martino Polyclinic HospitalGenova 16132Italy Medical Oncology Genitourinary Section Fondazione IRCCS Istituto Nazionale Dei TumoriMilan 20133Italy Departmental Unit of Clinical and Experimental Uro-Andrologic Oncology Istituto Nazionale Tumori IRCCS Fondazione G.PascaleNapoli 80131Italy Medical Oncology Unit Istituto di Ricovero e Cura a Carattere Scientifico(IRCCS)Ospedale Policlinico San MartinoGenova 16132Italy University of Brescia ASST-Spedali CiviliBresciaBrescia 25123Italy Medical Oncology Unit S Croce and Carle Teaching HospitalCuneo 12100Italy Division of Medical Oncology Istituto Tumori G Paolo IIIRCCSBari 70124Italy Medical Oncology Unit ASST Bergamo OvestTreviglioBergamo 24047Italy Medical Oncology Unit Fondazione Policlinico Universitario Agostino Gemelli IRCCSRome 00161Italy Division of Oncology AOU Consorziale Policlinico di BariBari 70124Italy Department of Biomedical Sciences and Human Oncology University of Bari"A.Moro"Bari 70124Italy Multidisciplinary Outpatient Oncology Clinic Candiolo Cancer InstituteFPO-IRCCSCandioloTurin 10060Italy

BACKGROUND Non-clear cell(ncc)metastatic renal-cell carcinoma(RCC)has dismal results with standard systemic therapies and a generally worse prognosis when compared to its clear-cell *** systemic combination therapies have emerged for metastatic RCC(mRCC),but the pivotal phase III trials excluded patients with nccRCC,which constitute about 30%of metastatic RCC *** To provide a piece of real-life evidence on the use of pazopanib in this patient *** The present study is a multicenter retrospective observational analysis aiming to assess the activity,efficacy,and safety of pazopanib as first-line therapy for advanced nccRCC patients treated in a real-life *** Overall,48 patients were *** the median follow-up of 40.6 mo,the objective response rate was 27.1%,the disease control rate was 83.3%,and the median progression-free survival and overall survival were 12.3(95%confidence interval[CI]:3.6-20.9)and 27.7(95%CI:18.2-37.1)mo,*** 3 adverse events occurred in 20%of patients,and no grade 4 or 5 toxicities were *** pazopanib should be considered as a good first-line option for metastatic RCC with variant histology.

关键词： pazopanib Non-clear cell Kidney cancer Renal-cell carcinoma Variant histology Tyrosine kinase inhibitors

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pazopanib中间体的合成工艺研究

科技视界 2012年第27期 11-11,74页

作者：刘媛媛谢文燕中国药科大学制药有限公司江苏南京210009

pazopanib是葛兰素史克公司研制的一种口服小分子多靶点受体酪氨酸激酶抑制剂的抗肿瘤药[1],选择性抑制VEG-FR-1,2,3,PDGFR-α,PDGFR-β,c-Kit。目前,pazopanib已进入Ⅲ期临床研究。但是目前合成pazopanib以3-甲基-6-硝基-1H-吲唑(化合... 详细信息

pazopanib是葛兰素史克公司研制的一种口服小分子多靶点受体酪氨酸激酶抑制剂的抗肿瘤药[1],选择性抑制VEG-FR-1,2,3,PDGFR-α,PDGFR-β,c-Kit。目前,pazopanib已进入Ⅲ期临床研究。但是目前合成pazopanib以3-甲基-6-硝基-1H-吲唑(化合物4)为原料合成,不易购买且成本较高,中间处理过程也比较复杂,通过比较与优化,为其中间体设计了一条方便高效的合成路线。2-乙基苯胺经混酸硝化,亚硝酸叔丁酯成环生成3-甲基-6-硝基-1H-吲唑,再经硫酸二甲酯甲基化制得2,3-二甲基-6-硝基-2H-吲唑。探索了不同条件对合成中间体的产率的影响,找出合适的反应条件,使之更适于工业生产。最终产物的结构由核磁共振谱、元素分析等波谱进行了表征和确认。

关键词： pazopanib 多靶点受体酪氨酸激酶抑制剂抗肿瘤药合成

pazopanib治疗复发或转移肾癌临床疗效与皮肤毒性反应

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中国药物应用与监测 2008年第3期5卷 7-8,11页

作者：祖强洪宝发符伟军杨素霞解放军总医院北京100853

目的:调查分析pazopanib相关的皮肤不良反应,指导临床安全用药。方法:按照美国国家癌症研究所-常见毒性反应标准(NCI-CTC)3.0版对药物不良反应进行评价和分级,对我科参与的pazopanib治疗局部复发或转移性肾透明细胞癌的全球性临床试验... 详细信息

目的:调查分析pazopanib相关的皮肤不良反应,指导临床安全用药。方法:按照美国国家癌症研究所-常见毒性反应标准(NCI-CTC)3.0版对药物不良反应进行评价和分级,对我科参与的pazopanib治疗局部复发或转移性肾透明细胞癌的全球性临床试验的13例患者的药物相关性皮肤不良反应结果进行观察分析。结果:作为新型的分子靶向抗肿瘤药物,pazopanib的皮肤不良反应较多见,以皮肤和毛发脱色、手足皮炎最常见。结论:pazopanib的皮肤不良反应较常见,但程度轻、易耐受;其中,手足反应的程度可能与疗效有一定关系。

关键词：分子靶向药物不良反应手足反应 pazopanib

pazopanib血药浓度个体差异与细胞色素P4503A4基因多态性的关系初探

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中国临床药理学与治疗学 2020年第12期25卷 1376-1380页

作者：吴茂锋刘畅戴慧晖麦长凤黄丹丽缪经纬刘丽忠方翼广州医科大学附属第六医院/清远市人民医院药物Ⅰ期临床研究室广东清远511518 北京大学人民医院药剂科北京100044

目的:分析健康受试者口服pazopanib片后体内药代动力学(PK)规律,初步探讨pazopanib片PK个体差异的遗传学机制。方法:14例健康男性受试者分别在给药当天单次口服pazopanib片(200 mg)后,采集基线至96 h血液样本,用LC-MS/MS法测定服药后各... 详细信息

目的:分析健康受试者口服pazopanib片后体内药代动力学(PK)规律,初步探讨pazopanib片PK个体差异的遗传学机制。方法:14例健康男性受试者分别在给药当天单次口服pazopanib片(200 mg)后,采集基线至96 h血液样本,用LC-MS/MS法测定服药后各时间点血药浓度,用WinNonlin 6.3软件计算药代动力学相关参数,采用SNapShot法测定细胞色素P4503A4(CYP3A4)基因多态性。结果:Cmax变化范围(7361.65-26081.00)ng/mL,平均值±标准差(15410.72±6366.21)ng/mL;tmax变化范围(1.50-4.00)h、平均值±标准差(2.50±0.83)h;AUC0-t变化范围(228013.55-775231.63)ng·mL-1·h,平均值±标准差(516279.90±175688.41)ng·mL-1·h。个体间Cmax、AUC相差达3倍以上,tmax可相差2倍以上;14例受试者CYP3A4(RS35599367)位点皆为野生型。结论:pazopanib片在中国健康男性志愿者中个体差异较大,未观察到CYP3A4(rs35599367)位点单核苷酸多态性,pazopanib个体间PK差异可能与其他药物代谢相关基因多态性有关。

关键词： pazopanib 细胞色素P4503A4 基因多态性

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口服抗肿瘤药pazopanib

药学进展 2010年第1期34卷 42-43页

作者：范鸣

新血管的生成对于体积为2～3 mm3的实体瘤生长是必需的,其主要调节因子为血管内皮生长因子(VEGF),因此,干预VEGF及其受体(VEGFR)信号系统以调节肿瘤血管生成,已成为人们的研究热点.VEGF与受体结合后,致其同源或异源二聚化,从而引起受体... 详细信息

新血管的生成对于体积为2～3 mm3的实体瘤生长是必需的,其主要调节因子为血管内皮生长因子(VEGF),因此,干预VEGF及其受体(VEGFR)信号系统以调节肿瘤血管生成,已成为人们的研究热点.VEGF与受体结合后,致其同源或异源二聚化,从而引起受体胞内激酶区域自身磷酸化,激活信号系统的级联反应.近年来,作为很有希望的抗血管生成药物,靶向VEGFR的小分子酪氨酸激酶抑制剂的研发取得了长足进展,已有30多个用于治疗癌症的VEGFR抑制剂正处开发阶段.

关键词： pazopanib 抗血管生成抗肿瘤 VEGF抑制剂

抗肿瘤药pazopanib可延缓卵巢癌复发

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药学进展 2013年第6期37卷 I0002-I0002,F0003页

葛兰素史克（GSK）公司于近期在美国临床肿瘤学会（AmericanSocietyofClinicalOncolo）年会上公布了一项Ⅲ期临床研究结果，称其研发的抗肿瘤药pazopanib（商品名：Votfient@）用作晚期上皮性卵巢癌患者经一线化疗后的维持治疗手段，达... 详细信息

葛兰素史克（GSK）公司于近期在美国临床肿瘤学会（AmericanSocietyofClinicalOncolo）年会上公布了一项Ⅲ期临床研究结果，称其研发的抗肿瘤药pazopanib（商品名：Votfient@）用作晚期上皮性卵巢癌患者经一线化疗后的维持治疗手段，达到了主要考察指标，即与安慰剂组相比，pazopanib组受试者的无进展生存期（PFS）显著延长。

关键词： pazopanib 卵巢癌维持治疗无进展生存期