达沙替尼(dasatinib)通过上调上皮钙黏蛋白表达抑制SK-Hep-1人肝癌细胞的增殖、分散和迁移

目的研究多靶点激酶抑制剂达沙替尼(dasatinib)对SK-Hep-1人肝癌细胞增殖、黏附和迁移能力的影响及机制。方法先采用dasatinib处理SK-Hep-1、Bel-7402、SNU-423、SNU-387、Huh-7肝癌细胞,噻唑蓝(MTT)法检测dasatinib对肝癌细胞存活和增殖的影响,筛选出对dasatinib敏感的肝癌细胞;培养SK-Hep-1细胞,采用(0.5、1、2)μmol/L dasatinib处理,对照组采用二甲基亚砜(DMSO)处理。采用细胞缓慢聚集实验和分离实验检测dasatinib对SK-Hep-1肝癌细胞间同质黏附力的影响,划痕实验观察dasatinib对肝癌细胞迁移能力的影响;Western blot法检测dasatinib对上皮钙黏蛋白(E-cadherin)表达的影响。结果MTT实验证明dasatinib明显抑制肝癌细胞增殖,且SK-Hep-1细胞对dasatinib最敏感。dasatinib处理促进SK-Hep-1细胞聚集,抑制细胞分散和迁移,上调肝癌细胞E-cadherin表达。结论Dasatinib通过上调E-cadherin表达促进SK-Hep-1肝癌细胞聚集和黏附,抑制细胞增殖、分散和迁移。

A validated UPLC–MS/MS method for simultaneous determination of imatinib, dasatinib and nilotinib in human plasma

A sensitive, rapid, simple and economical ultra-performance liquid chromatography-tandem mass spectrometric method （UPLC-MS/MS） was developed and validated for simultaneous determination of imatinib, dasatinib and nilotinib in human plasma using gliquidone as internal standard （IS）. Liquid-liquid extraction method with ethyl acetate was used for sample pre-treatment. The separation was performed on an Xtimate Phenyl column using isocratic mobile phase consisting of A （aqueous phase： 0.15% formic acid and 0.05% ammonium acetate） and B （organic phase： aeetonitrile） （A：B=40：60, v/v）. The flow rate was 0.25 mL/min and the total run time was 6 min. The multiple reaction monitoring （MRM） transitions, m/z 494.5-394.5 for imatinib, 488.7-401.5 for dasatinib, 530.7-289.5 for nilotinib and 528.5-403.4 for IS, were chosen to achieve high selectivity in the simultaneous analyses. The method exhibited great improvement in sensitivity and good linearity over the concentration range of 2.6-5250.0 ng/mL for imatinib, 2.0-490.0 ng/mL for dasatinib, and 2.4-4700.0 ng/mL for nilotinib. The method showed acceptable results on sensitivity, specificity, recovery, precision, accuracy and stability tests. This UPLC-MS/MS assay was successfully used for human plasma samples analysis and no significant differences were found in imatinib steady-state trough concentrations among the SLC22A5 -1889T 〉 C or SLCOIB3 699G 〉 A genotypes （P 〉 0.05）. This validated method can provide support for clinical therapeutic drug monitoring and pharmacokinetic investigations of these three tyrosine kinase inhibitors （TKIs）.

Efficacy and Safety of Generic Dasatinib as a Second-line Treatment for Patients with Chronic Myeloid Leukemia:a Multicenter Retrospective Study in Hubei Province,China

Dasatinib is a second-generation tyrosine kinase inhibitor (TKI)and it could be used as a second-line treatment for patients with chronic myeloid leukemia (CML).Yinishu,a generic dasatinib made in China,was approved by the China Food and Drug Administration in 2013 and it costs much less than the patented dasatinib SPRYCEL.The present study aimed to examine the efficacy and safety of Yinishu as a second-line treatment for CML by comparing the baseline clinical characteristics,rates of adverse events and efficacy between Yinishu and SPRYCEL groups. The results showed that there were no significant differences in the rates of optimal response between Yinishu and SPRYCEL for patients who started second-line treatment because of treatment failure.For patients who started second-line treatment because of intolerance of first-line treatment, their levels of BCR-ABL1/ABL1 on the international scale (BCR-ABL^IS)was maintained very low throughout the course of Yinishu treatment.Drug-related adverse events occurred with the same frequency in these two groups.It was confirmed that Yinishu was effective and safe as a second- line treatment for CML patients.Yinishu may be more suitable for patients who are economically unable to pay for the patented dasatinib SPRYCEL.

Carrier-free prodrug nanoparticles based on dasatinib and cisplatin for efficient antitumor in vivo

Carrier-free drug self-delivery systems consisting of amphiphilic drug-drug conjugate(ADDC)with well-defined structure and nanoscale features have drawn much attention in tumor drug delivery.Herein,we report a simple and effective strategy to prepare ADDC using derivatives of cisplatin(CP)and dasatinib(DAS),which further selfassembled to form reduction-responsive nanoparticles(CP-DDA NPs).DAS was modified with succinic anhydride and then connected with CP derivative by ester bonds.The size,micromorphology and in vitro drug release of CP-DDA NPs were characterized.The biocompatibility and bioactivity of these carrier-free nanoparticles were then investigated by HepG2 cells and H22-tumor bearing mice.In vitro and in vivo experiments proved that CPDDA NPs had excellent anti-tumor activity and significantly reduced toxicities.This study provides a new strategy to design the carrier-free nanomedicine composed of CP and DAS for synergistic tumor treatment.

Severe hemorrhagic colitis in a patient with chronic myeloid leukemia in the blastic phase after dasatinib use

Dasatinib is a second-line tyrosine kinase inhibitor used in patients with imatinib resistant or intolerant chronic myeloid leukemia (CML) and Philadelphia chromosomepositive acute leukemia. Gastrointestinal bleeding may occur in up to 7% of patients using dasatinib, although, severe dasatinib-related acute colitis had rarely been reported. Here, we present the case of a 36-year-old female who progressed to acute myeloid leukemia after fourteen months of receiving imatinib for CML in the chronic phase and was treated with a dasatinib-containing chemotherapy regimen. On day 34 of treatment, the patient developed moderate abdominal pain and bloody diarrhea with mucous. Analyses of stool specimens were negative for parasites, Clostridium difficile , and other pathogenic bacteria. The cytomegalovirus pp65 antigen was negative in her blood leukocytes. A colonoscopy revealed acute colitis, and a mucosal biopsy showed nonspecific colitis. The patient was treated with broad-spectrum antibiotics, bowel rest and hydration, and dasatinib treatment was stopped. Her bloody diarrhea improved within 72 h. After confirming cytological remission, the patient received initial course of consolidation, and dasatinib treatment was reinstated. However, hemorrhagic colitis recurred. After discontinuing dasatinib, herhemorrhagic colitis drastically improved and did not recur following the administration of nilotinib. The characteristics of our patient suggest that dasatinib treatment can lead to hemorrhagic colitis, which typically resolves after discontinuation of the drug.

Dasatinib-Induced Hepatic Dysfunction

A 53-year-old man with chronic myeloid leukaemia developed significant hepatic dysfunction when treatment was changed from imatinib (because of drug-induced rash) to dasatinib. Liver function tests returned to normal 77 days after cessation of therapy and have remained normal despite recommencement of dasatinib. Although the pathogenesis for the significant hepatic dysfunction is unclear, this case illustrates the reversibility of this event with dose interruption and that dasatinib can be safely recommenced for ongoing treatment.

Clinical Effect of Imatinib,Nilotinib,and Dasatinib on Chronic Myeloid Leukemia in Chronic Phase

The study was conducted to explore the effect of imatinib,nilotinib,and dasatinib in the treatment of chronic myeloid leukemia(CML)patients.Around 66 patients with CML in chronic phase were selected,subsequently the patients were subdivided into 3 groups with 22 patients in each group:Group A were treated with imatinib;Group B were treated with nilotinib;and Group C were treated with dasatinib.The study showed that,at 18 months of treatment,compared with group A,the molecular biology remission rates of group B and group C were significantly higher,p<0.05;at 6 months and 18 months of treatment,compared with group A,the complete cytogenetic remission rates of group B and group C were significantly higher,p<0.05;and compared with group A,the incidences of vomiting,headache and edema in groups B and C were significantly lower,p<0.05.However,no significant different p>0.05 were observed in the complete hematologic remission rates,and the incidences of neutropenia and thrombocytopenia among the three groups.In summary,nilotinib and dasatinib are effective in the treatment of patients with CML in the chronic phase,which is significantly better than imatinib treatment.

Clinical Efficacy of Dasatinib in the Treatment of Chronic Myeloid Leukemia (CML) Patients with Different Clinical Stages

Objective:To study the efficacy of dasatinib treatment in different clinical stages of patients with chronic myeloid leukemia(CML).Methods:A total of 80 patients with chronic myeloid leukemia(CML)were selected for experimental research.According to different clinical stages,they were divided into chronic phase,accelerated phase and blast phase,and all of them were treated with dasatinib.Results:The complete cytogenetic response remission rate,complete hematologic remission rate,and major molecular biological remission rate in the chronic phase were significantly higher.Besides,the overall survival time and relapse-free survival time in the chronic phase were significantly longer,and the mortality during the follow-up period in the chronic phase was also significantly higher.Furthermore,the incidence of hematological adverse reactions of gradesⅢtoⅣin the chronic phase was significantly lower compared with the corresponding data of patients in the accelerated phase and blast phase with P<0.05.Conclusion:Different clinical stages of CML patients have different curative effects of dasatinib,which can effectively treat patients in chronic stage.

Repurpose dasatinib and quercetin:Targeting senescent cells ameliorates postmenopausal osteoporosis and rejuvenates bone regeneration

Clinical therapies developed for estrogen-deficiency-driven postmenopausal osteoporosis(PMO)and related diseases,such as bone degeneration,show multiple adverse effects nowadays.Targeting senescent cells(SnCs)and the consequent senescence-associated secretory phenotype(SASP)with a combination of dasatinib and quercetin(DQ)is a recently developed novel therapy for multiple age-related diseases.Herein,we found that estrogen deficiency induced-bone loss was attributed to a pro-inflammatory microenvironment with SASP secretions and accelerated SnC accumulation,especially senescent mesenchymal stem cells(MSCs)characterized by exhaustion and dysfunction in middle aged rats.Systematically targeting SnCs with DQ strikingly ameliorated PMO and restored MSC function.Local administration of DQ and bone morphogenetic protein 2(BMP2)in combination promoted osteogenic differentiation of MSCs and rejuvenated osteoporotic bone regeneration.Our results repurposed DQ as an attractive therapy for treating PMO and related diseases.

Src酪氨酸激酶抑制剂dasatinib对人食管鳞癌细胞KYSE180生长及凋亡的影响

目的:探讨Src酪氨酸激酶抑制剂dasatinib对人食管鳞癌细胞生长和凋亡的影响及其相关机制。方法:采用蛋白质印迹法检测食管鳞癌细胞株KYSE180、EC109、KYSE30和人永生化食管上皮细胞株SHEE中总Src和磷酸化Src激酶的表达。用不同剂量的Src酪氨酸激酶抑制剂dasatinib作用KYSE180细胞后,分别采用MTT法、FCM法、蛋白质印迹法和裸鼠皮下移植瘤实验观察dasatinib对KYSE180细胞Src激酶的抑制作用,以及对细胞增殖、细胞周期、细胞凋亡和裸鼠皮下移植瘤的影响。结果:KYSE180、EC109和KYSE30细胞中Src激酶显著活化,而在SHEE细胞中未见活化Src激酶。Dasatinib可显著抑制KYSE180细胞增殖,阻碍细胞G1/S期转换,促进细胞凋亡,并上调caspase3、cytochrome C和Bax等凋亡相关蛋白的表达。另外,dasatinib可显著抑制裸鼠皮下KYSE180细胞移植瘤的生长。结论:Dasatinib可通过抑制食管鳞癌细胞增殖、促进细胞凋亡以及影响细胞周期等机制,抑制食管鳞癌细胞皮下移植瘤的生长,因此其可望成为治疗食管鳞癌的一个有效药物。

达沙替尼基于PI3K/AKT信号通路调节乳腺癌细胞生物学行为

目的:基于PI3K/AKT信号通路探讨达沙替尼(dasatinib,DAS)对乳腺癌MCF-7细胞生物学行为的影响。方法:分别使用噻唑蓝(methyl thiazolyl tetrazolium,MTT)法、Transwell法、流式细胞术和Western blotting法检测DAS不同浓度(0、2、6、10μmol/L)作用下MCF-7细胞增殖、侵袭和迁移、细胞凋亡以及PI3K/AKT信号通路相关蛋白表达情况。同时设置对照组(溶媒对照)、DAS组(DAS 10μmol/L)、PI3K抑制剂组(LY29400220μmol/L)、联合组(DAS 10μmol/L+LY29400220μmol/L),比较各组细胞增殖、侵袭和迁移、细胞凋亡以及PI3K/AKT信号通路相关蛋白表达情况。结果:随着DAS作用浓度的升高,MCF-7细胞增殖抑制率和细胞凋亡率升高(P<0.05),侵袭细胞数、迁移细胞数和PI3K、p-PI3K、p-AKT蛋白表达降低(P<0.05)。与对照组相比,DAS组、PI3K抑制剂组、联合组MCF-7细胞增殖抑制率和细胞凋亡率升高(P<0.05),PI3K、p-PI3K、p-AKT蛋白表达降低。与PI3K抑制剂组、DAS组相比,联合组MCF-7细胞增殖抑制率和细胞凋亡率升高,PI3K、p-PI3K、p-AKT蛋白表达降低(P<0.05)。结论:DAS能抑制乳腺癌MCF-7细胞增殖、侵袭和迁移能力,诱导细胞凋亡,其机制可能与调控PI3K/AKT信号通路有关。

达沙替尼体外抑制慢性淋巴细胞白血病增殖及BTKC481S功能

目的探讨达沙替尼(BMS-354825)体外对慢性淋巴细胞白血病(chronic lymphocytic leukemia,CLL)细胞系增殖及野生型/耐药突变型布鲁顿激酶(BTK)活化及功能的影响。方法观察不同浓度的达沙替尼对CLL细胞系的增殖抑制作用。采用不同浓度的达沙替尼及伊布替尼处理外源性表达野生型BTK及常见突变子BTKC481S、BTKT474F及BTKT474I/C481S的细胞系,Western blot检测BTK及其下游靶点PLCγ2的磷酸化水平。结果达沙替尼能显著抑制CLL细胞系MEC-1及JVM3细胞的增殖,且呈剂量依赖性,IC50分别为3.54μmol/L及0.65μmol/L;0.5μmol/L的伊布替尼及0.2μmol/L的达沙替尼可抑制野生型BTK及PLCγ2的磷酸化活化。当BCR信号激活后,BTKC481S、BTKT474F及BTKT474I/C481S均可功能性激活并磷酸化活化下游PLCγ2,这些突变子均对生理浓度的伊布替尼耐药。0.5μmol/L的达沙替尼体外可抑制BTKC481S活化并进而抑制PLCγ2活化,但不能抑制BTKT474F及BTKT474I/C481S的活化,提示沙替尼体可克服BTKC481S导致的耐药而对“守门员”位点突变无效。结论达沙替尼可抑制野生型BTK及BTKC481S激酶活化及功能并抑制CLL细胞增殖,有望解决BTKC481S引发的伊布替尼耐药。

达沙替尼致重度肺动脉高压1例并文献分析

目的探讨达沙替尼导致重度肺动脉高压的临床特征、诊断、转归及治疗。方法通过分析1例慢性髓性白血病(Chronic myeloid leukemia,CML)患者应用达沙替尼治疗后出现重度肺动脉高压的临床特点、治疗经过,并检索近10年国内外有关数据库(截至2022年12月31日)进行文献汇总分析。结果1例CML患者使用进口达沙替尼片(100 mg/d),24个月后BCR/ABL融合基因转阴,后更改为国产达沙替尼治疗36个月后,无明显诱因下出现胸闷,爬楼2层以上、快走时伴有胸痛。超声心动图显示右心增大,重度肺动脉高压伴重度三尖瓣反流,左室舒张功能减退,肺动脉收缩压(PASP)114 mmHg,心包积液;胸部CT提示两肺多发实性结节灶,两侧胸腔积液。考虑重度肺动脉高压及胸腔积液与达沙替尼有关,停用达沙替尼,给予安立生坦5 mg qd,利尿、平喘治疗2 d后,PASP降至66 mmHg,2个月后随访PASP降至53 mmHg。近10年内,报道的达沙替尼致肺动脉高压案例国内有6例,国外24例,服用达沙替尼至出现肺动脉高压的中位时间分别为41.5个月和40个月,临床表现为不同程度的胸闷、气喘、呼吸困难、胸腔积液等,除停药外,93.75%的患者使用靶向药物治疗后好转或恢复正常。结论达沙替尼导致肺动脉高压是少见的、严重的但可逆转的不良反应,若使用达沙替尼出现肺动脉高压,应立即停药且终身禁用。故达沙替尼治疗期间应监测肺动脉压。

达沙替尼联合化疗治疗儿童费城染色体阳性急性淋巴细胞白血病的循证药学评价

目的全面评价达沙替尼在儿童费城染色体阳性(Ph^(+))急性淋巴细胞白血病(ALL)中的应用情况,为临床合理应用提供循证证据。方法检索Daily Med、EMC药品信息数据库及药品说明书,收集达沙替尼的最新版说明书并比较不同厂家说明书内容的差异性;检索美国国立综合癌症网络(NCCN)、美国国家癌症研究所(NCI)、医脉通、UpToDate等网站,收集达沙替尼治疗儿童Ph^(+)ALL的诊疗指南/规范并对推荐的治疗方案进行归纳总结;计算机检索PubMed、Embase、Cochrane Library、Clinical Trials.gov、CNKI、Sino-Med、VIP和万方数据库,检索时限为2000年1月1日至2023年3月31日,收集达沙替尼治疗儿童Ph^(+)ALL的临床试验研究并进行meta分析。结果共获得4个厂家的21条药品标签信息,不同厂家说明书承载内容各异,达沙替尼原研说明书信息最规范、全面,国产达沙替尼说明书未记载治疗儿童Ph^(+)ALL的适应证;收集到儿童ALL诊疗指南/规范3篇,其中2篇推荐达沙替尼联合化疗可一线治疗Ph^(+)ALL;检索到达沙替尼治疗儿童Ph^(+)ALL的研究文献186篇,经逐层筛选,最终4篇文献289例Ph^(+)ALL患儿纳入单臂meta分析。结论达沙替尼联合化疗治疗儿童Ph^(+)ALL在国内属于超说明书用药,该联合治疗方案是否能带来临床获益,仍需大规模的真实世界数据和更长的随访时间来确证。

尼洛替尼与达沙替尼二线治疗慢性髓性白血病的成本效用分析

目的评估费城染色体阳性慢性髓性白血病慢性期(Ph+CML-CP)患者中对伊马替尼耐药或不耐受的二线尼洛替尼与达沙替尼的成本效果。方法建立状态转移马尔可夫(Markov)模型进行成本效用分析,模型包括4种健康状态:慢性期(CP),加速期(AP),急变期(BP)和死亡。尼洛替尼与达沙替尼治疗的无进展生存率,疾病进展发生率,总生存率等有关临床参数来源于既往发表的研究和专家意见,健康状态效用值来源于文献。通过Treeage软件以增量成本效果比(ICER)作为评价指标,对尼洛替尼和达沙替尼2个方案的总产出和总成本进行评价,并通过单变量、概率敏感性分析评估模型稳定性。结果与选用达沙替尼治疗相比,选用尼洛替尼治疗的ICER为182487.71元·QALY^(-1),低于3倍2021年全国人均GDP。敏感性分析显示主要的影响参数有贴现率,达沙替尼价格和尼洛替尼价格,模型结果稳定。结论选用尼洛替尼相对达沙替尼用于对伊马替尼耐药或不耐受的Ph+CML-CP患者治疗具有成本效用优势。

Superiority of allogeneic hematopoietic stem cell transplantation to nilotinib and dasatinib for adult patients with chronic myelogenous leukemia in the accelerated phase

In the tyrosine kinase inhibitor （TKI） era, imatinib is the first-line therapy for patients with chronic myeloid leukemia （CML） in chronic or accelerated phase. Although second-generation TKIs （TKI2）, including dasatinib and nilotinib, are appropriate treatment regimens for patients with disease that progressed to accelerated phase following imatinib therapy, allogeneic hematopoietic stem cell transplantation （allo-HSCT） is the only curative therapy. This study retrospectively analyzed the efficacy of TKI2 and HSCT for treatment of CML in accelerated phase. Ninety-three patients with CML registered in the Chinese CML alliance database from February 2001 to February 2014 were enrolled and divided into the TKI2 （n = 33） and allo-HSCT （n = 60） groups. In the TKI2 group, 26 and 7 patients received nilotinib and dasatinib, respectively, as initial TKI2 and 11 patients transferred to the alternative TKI2 after failure to one TKI2. In the allo-HSCT group, 22 （36.7%）, 35 （58.3%）, and 3 （10%） patients underwent aHo-HSCT from an HLA-matched sibling donor, HLA mismatched/haploidentical donor, and unrelated donor, respectively. All patients in the HSCT group were engrafted. Overall, 69.7%, 48.5%, and 45.5% of patients presented hematological, cytogenetic, and major molecular responses, respectively, to at least one of TKI2. All 60 patients （100%） achieved CHR and cytogenetic response in the HSCT group. Patients in the TKI2 group exhibited lower 5-year overall survival rate （42.9% vs. 86.4%, P = 0.002）, 5-year event-free survival rate （14.3% vs. 76.1%, P 〈 0.001）, and 5-year progression-free survival （28.6% vs. 78.1%, P 〈 0.001） than those in the alIo-HSCT group. Multivariate analysis showed that male sex and TKI2 therapy were predictors of poor overall survival, whereas hemoglobin 〈 100 g/L and TKI2 therapy were predictors of poor event-free survival and progression-free survival. These results indicated that allo-HSCT may be superior to nilotinib and dasatinib for adult patients with CML in accelerated phase.

Four-year follow-up of patients with imatinib-resistant or intolerant chronic myeloid leukemia receiving dasatinib:efficacy and safety

Dasatinib is a highly effective second-generation tyrosine kinase inhibitor used to treat chronic myeloid leukemia (CML).In 2007,a pivotal phase-2 study of dasatinib as second-line treatment was initiated in 140 Chinese CML patients.This report from the 4-year follow-up revealed that 73% of 59 patients in chronic phase (CML-CP) and 32% of 25 patients in accelerated phase (CML-AP) remained under treatment.The initial dosage of dasatinib for CML-CP and CML-AP patients were 100 mg once daily and 70 mg twice daily (total=140 mg/ day),respectively.The cumulative major cytogenetic response (MCyR) rate among patients with CML-CP was 66.1%(versus 50.8% at 18 months),and the median time to MCyR was 12.7 weeks.All CML-CP patients who achieved MCyR after a 4-year follow-up also achieved a complete cytogenetic response.The cumulative complete hematological response (CHR) rate among patients with CML-AP was 64%(16/25),with three CML-AP patients achieving CHR between 18 months and 4 years of follow-up;the median time to CHR was 16.4 weeks.The adverse event (AE) profile of dasatinib at 4 years was similar to that at 6 and 18 months.The most frequently reported AEs (any grade) included pleural effusion,headache,and myelosuppression.These long-term follow-up data continue to support dasatinib as a second-line treatment for Chinese patients with CML.

HPLC法测定达沙替尼片的降解杂质

目的:建立高效液相色谱法定量分析达沙替尼片中的4个主要降解杂质。方法:采用YMC Pack Pro C_(18)(150 mm×4.6 mm, 3μm)色谱柱,以0.05 mol/L醋酸铵溶液(pH值5.25±0.05)-乙腈-甲醇(体积比90∶5∶5)为流动相A,0.05 mol/L醋酸铵溶液(pH值5.25±0.05)-乙腈-甲醇(体积比10∶85∶5)为流动相B,进行线性梯度洗脱;流速为每分钟1.2 mL;检测波长为320 nm;柱温为35℃;进样量10μL。经验证4个降解杂质检测限分别为28.82,15.29,15.06,15.15 ng/mL;定量限为57.63,30.58,30.12,30.31 ng/mL。分别在约30~600 ng/mL数量级范围内,与各自峰响应值呈显著线性关系,相关系数r均≥0.999,精密度试验和重复性试验良好,4个降解杂质的平均回收率(n=9)分别为95.7%,109.2%,83.8%,88.4%,RSD(n=9)分别为4.71%,1.86%,1.64%,1.90%。结论:该方法专属性强、灵敏度高、准确度可靠,可用于达沙替尼片中4个主要降解杂质的定量分析,为达沙替尼片的质量控制评估提供依据。

Pharmacokinetics of generic dasatinib in the management of chronic myeloid leukemia in the chronic phase

Objective To evaluate the pharmacokinetics and bioequivalence of generic dasatinib in patients with chronic myeloid leukemia in the choronie phase(CML-CP).Methods Using randomized,parallel,overlapping,self-

Dasatinib抑制PDGFR／Bcr—AbI信号通路抗肝星状细胞介导肝纤维化的机制

越来越多的研究表明肝星状细胞（HSC）的活化是肝纤维化发生的核心环节.当肝脏受到炎症等慢性损伤刺激时，多种细胞因子可以激活HSC，促进其分化为肌成纤维母细胞（MFB）并开始表达α-平滑肌肌动蛋白（α-SMA），合成细胞外基质，启动肝纤维化；此外，活化的HSC还大量分泌转化生长因子（TGF）β1和血小板源性生长因子（PDGF）等细胞因子，进一步促进肝纤维化的进展。