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 n...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）.展开更多
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 b...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.展开更多
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 ...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.展开更多
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 ...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.展开更多
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 ...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.展开更多
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 p...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.展开更多
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 exp...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.展开更多
The N70°DASA graben is a closed-rift that seems to be the deepest part of the Tim MersoïBasin,which is located in the northwestern part of Niger in West Africa.It contains more than 805 m of Paleozoic-Mesozo...The N70°DASA graben is a closed-rift that seems to be the deepest part of the Tim MersoïBasin,which is located in the northwestern part of Niger in West Africa.It contains more than 805 m of Paleozoic-Mesozoic sediments.The tectonic subsidence and uplifting was calculated by using well log data and deducing the variations in sedimentary thicknesses over time.Geological mapping and tectono-sedimentary analysis indicate that the structural evolution of the DASA trough is characterized by two major periods:(1)the first period was marked by an uplift stage ranging from the Carboniferous to the Permian.It was typified by a weak subsidence rate(3.45 m/Ma on average),under a transpressive tectonic regime,with a decrease in the thickness of the sedimentary series along the axial zone of the trough,and an increase of the thickness towards the border areas;(2)the second period was characterized by a higher subsidence rate(4.11 m/Ma on average)related to a change in the tectonic regime.It was marked by a rifting stage preserved over a long period,subjected to an extensive tectonic regime,from the Triassic to the lower Cretaceous,during which the highest thicknesses of the sedimentary series developed in the axial zone of the graben.The structural and sedimentological features defined the DASA graben as a particular type of syn-sedimentary basin evolving from a transpressive tectonic regime during the Paleozoic to an extensive tectonic regime during the Lower Mesozoic.Thus,the second period marked by an extensional regime would probably be related to the opening of the first stages of the Atlantic Ocean.展开更多
文摘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）.
文摘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.
基金supported by the National Natural Science Foundation of China(No.51803001 and 51503001)the Natural Science Foundation of Anhui Province(No.2008085ME136 and 2008085QE210)+1 种基金the Research Foundation of Education Department of Anhui Province of China(No.KJ2018ZD003,KJ2018A0006 and KJ2019A0015)the Academic and Technology Introduction Project of Anhui University(AU02303203)grant.
文摘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.
文摘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.
文摘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.
文摘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.
文摘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.
基金The authors are grateful to and acknowledge the efforts of the staff of Global Atomic Corporation for their collaboration.The corresponding author is also grateful to Global Atomic Corporation for their technical and material support.Sincere thanks go to the reviewers for their observations and comments.
文摘The N70°DASA graben is a closed-rift that seems to be the deepest part of the Tim MersoïBasin,which is located in the northwestern part of Niger in West Africa.It contains more than 805 m of Paleozoic-Mesozoic sediments.The tectonic subsidence and uplifting was calculated by using well log data and deducing the variations in sedimentary thicknesses over time.Geological mapping and tectono-sedimentary analysis indicate that the structural evolution of the DASA trough is characterized by two major periods:(1)the first period was marked by an uplift stage ranging from the Carboniferous to the Permian.It was typified by a weak subsidence rate(3.45 m/Ma on average),under a transpressive tectonic regime,with a decrease in the thickness of the sedimentary series along the axial zone of the trough,and an increase of the thickness towards the border areas;(2)the second period was characterized by a higher subsidence rate(4.11 m/Ma on average)related to a change in the tectonic regime.It was marked by a rifting stage preserved over a long period,subjected to an extensive tectonic regime,from the Triassic to the lower Cretaceous,during which the highest thicknesses of the sedimentary series developed in the axial zone of the graben.The structural and sedimentological features defined the DASA graben as a particular type of syn-sedimentary basin evolving from a transpressive tectonic regime during the Paleozoic to an extensive tectonic regime during the Lower Mesozoic.Thus,the second period marked by an extensional regime would probably be related to the opening of the first stages of the Atlantic Ocean.
