AIM To evaluate the inhibitory effects of deferasirox(DFX) against hepatocellular carcinoma(HCC) through basic and clinical studies.METHODS In the basic study, the effect of DFX was investigated in three hepatoma cell...AIM To evaluate the inhibitory effects of deferasirox(DFX) against hepatocellular carcinoma(HCC) through basic and clinical studies.METHODS In the basic study, the effect of DFX was investigated in three hepatoma cell lines(Hep G2, Hep3 B, and Huh7), as well as in an N-nitrosodiethylamine-induced murine HCC model. In the clinical study, six advanced HCC patients refractory to chemotherapy were enrolled. The initial dose of DFX was 10 mg/kg per day and was increased by 10 mg/kg per day every week, until the maximum dose of 30 mg/kg per day. The duration of a single course of DFX therapy was 28 consecutive days. In the event of dose-limiting toxicity(according to the Common Terminology Criteria for Adverse Events v.4.0), DFX dose was reduced.RESULTS Administration of DFX inhibited the proliferation of hepatoma cell lines and induced the activation of caspase-3 in a dose-dependent manner in vitro. In the murine model, DFX treatment significantly suppressed the development of liver tumors(P < 0.01), and significantly upregulated the mR NA expression levels of hepcidin(P < 0.05), transferrin receptor 1(P < 0.05), and hypoxia inducible factor-1α(P < 0.05) in both tumor and non-tumor tissues, compared with control mice. In the clinical study, anorexia and elevated serum creatinine were observed in four and all six patients, respectively. However, reduction in DFX dose led to decrease in serum creatinine levels in all patients. After the first course of DFX, one patient discontinued the therapy. We assessed the tumor response in the remaining five patients; one patient exhibited stable disease, while four patients exhibited progressive disease. The one-year survival rate of the six patients was 17%.CONCLUSION We demonstrated that DFX inhibited HCC in the basic study, but not in the clinical study due to dose-limiting toxicities.展开更多
We report the case of a 7 years old girl with Juvenile Hemochromatosis, due to homozygous mutation of HJV, which had increased serum iron indices and liver iron overload in the absence of any clinical sign of disease....We report the case of a 7 years old girl with Juvenile Hemochromatosis, due to homozygous mutation of HJV, which had increased serum iron indices and liver iron overload in the absence of any clinical sign of disease. Oral iron chelation with low dose deferasirox showed good efficacy and no side effects. The oral iron chelator deferasirox could be a valid option for removing excess iron in early Juvenile Hemochromatosis.展开更多
BACKGROUND A perforated gastroduodenal ulcer is rarely observed in children.Certain medications have been reported to cause ulcerations.Deferasirox,an iron chelating agent,has been previously reported to be associated...BACKGROUND A perforated gastroduodenal ulcer is rarely observed in children.Certain medications have been reported to cause ulcerations.Deferasirox,an iron chelating agent,has been previously reported to be associated with the development of gastroduodenal ulcers.CASE SUMMARY We report a case of a 3-year-old boy who was diagnosed with beta thalassemia major and treated with deferasirox.He presented to the emergency department with an acute abdomen.A perforated duodenal ulcer was suspected after X-ray imaging and laparoscopic exploration.It was successfully managed with laparoscopic washout and drainage.CONCLUSION Due to the rarity and severity of this case,it is a reminder that prevention and early recognition of gastrointestinal complications in patients receiving deferasirox are crucial.Minimally invasive laparoscopic surgery is both safe and feasible to treat perforated duodenal ulcers in selected patients.展开更多
4-hydrazinobenzoic acid has been highlighted as one of the potential genotoxic impurities (PGIs). A sensitive HPLC method was developed and validated for the determination of 4-hydrazino benzoic acid in Deferasirox Ta...4-hydrazinobenzoic acid has been highlighted as one of the potential genotoxic impurities (PGIs). A sensitive HPLC method was developed and validated for the determination of 4-hydrazino benzoic acid in Deferasirox Tablet. HPLC method on Zorbax SB C18 column (250 × 4.6 mm i.d.), 5 μm, with UV Detector was used. The proposed method was cost effective, specific, linear, accurate, rugged and precise. The calibration curves showed good linearity over the concentration range of 0.5 μg/ml to 1.5 μg/ml with respect to the sample. The correlation coefficient was 0.999. Excellent recoveries of 102% were obtained at the level 0.5 μg/ml.展开更多
Objective:Our study aimed to investigate the ototoxicity associated with the iron chelator deferasirox in patients withβ-thalassemia major,who were receiving regular transfusion therapy,along with evaluating the data...Objective:Our study aimed to investigate the ototoxicity associated with the iron chelator deferasirox in patients withβ-thalassemia major,who were receiving regular transfusion therapy,along with evaluating the data on audiological tests using appropriate statistical tests.Methods:A cross-sectional observational study was conducted on 100 transfusion-dependentβ-thalassemia major patients on oral iron chelating agent-deferasirox.Pure tone audiometry(PTA)and distortion product otoacoustic emissions(DPOAE)was carried out in all patients to assess the auditory side effects of the drug.Data was collected,compiled,and analyzed statistically using appropriate statistical tests.The relationship between ototoxicity and various demographic parameters such as age,sex,hemoglobin(Hb)level,S.ferritin,duration,and dose of chelation therapy was also assessed.Results:Sixteen patients had abnormal DPOAE and the number of patients with pure tone average above 25 dB HL which was taken as hearing deficit on PTA was 13.No statistically significant relationship between hearing loss and age,gender,S.ferritin,duration of therapy,cumulative dose,Hb levels were found.Conclusion:Despite being a lifesaving drug,the advantages of chelating agent-Deferasirox must be weighed against its probable ototoxic effects.We could not find a relationship of ototoxicity with variable parameters(age,gender,Hb level,Ferritin level,duration,and cumulative dose of drug),thus future research is encouraged to form a definitive basis.展开更多
Deferasirox is the first-line drug for iron overload due to thalassemia in adults and pediatric patients. It is classified as a type II compound in the Biopharmaceutics Classification System, and thus the particle siz...Deferasirox is the first-line drug for iron overload due to thalassemia in adults and pediatric patients. It is classified as a type II compound in the Biopharmaceutics Classification System, and thus the particle size of its active pharmaceutical ingredient(API) should be strictly controlled during the manufacturing process. In the present study, laser diffraction was adopted to measure the particle size distribution of deferasirox API. We also developed and validated an accurate and convenient method by investigating important optical parameters and sample dispersing conditions. The relative standard deviation values, namely, d(0.1), d(0.5), d(0.9), and d(4,3), measured via methodology validation and actual sample measurement were < 3%. The dissolution curves of several batches of dispersible tablets prepared using deferasirox with different particle sizes were compared in the four dissolved media to investigate the influence of particle size on drug dissolution in vitro. Results indicated that the particle size distribution of deferasirox API significantly affected the release of its dispersible tablet.展开更多
We reported herein the synthesis and antibacterial activity evaluation of two oxazolidinone-deferasirox conjugates with different linkers that were designed based on the“Trojan horse”strategy.The conjugates could co...We reported herein the synthesis and antibacterial activity evaluation of two oxazolidinone-deferasirox conjugates with different linkers that were designed based on the“Trojan horse”strategy.The conjugates could combine with Fe^(3+)ions as the deferasirox.However,both conjugates were inactive against tested bacteria,including S.aureus,E.coli,A.baumannii,and P.aeruginosa.The results suggested that the synthesized iron chelator deferasirox was not suitable as a siderophore of the bacteria to transport the antibiotic,or the coupling linker of the synthesized conjugates could not be hydrolyzed to release the oxazolidinone in the cytoplasm.Therefore,the design and synthesis of oxazolidinone-deferasirox conjugates need further exploration.展开更多
Accurate evaluation of iron overload is necessary to establish the diagnosis of hemochromatosis and guide chelation treatment in transfusion-dependent anemia. The liver is the primary site for iron storage in patients...Accurate evaluation of iron overload is necessary to establish the diagnosis of hemochromatosis and guide chelation treatment in transfusion-dependent anemia. The liver is the primary site for iron storage in patients with hemochromatosis or transfusion-dependent anemia, therefore, liver iron concentration (LIC) accurately re? ects total body iron stores. In the past 20 years, magnetic resonance imaging (MRI) has emerged as a promising method for measuring LIC in a variety of diseases. We review the potential role of MRI in LIC determination in the most important disorders that are characterized by iron overload, that is, thalassemia major, other hemoglobinopathies, acquired anemia, and hemochromatosis. Most studies have been performed in thalassemia major and MRI is currently a widely accepted method for guiding chelation treatment in these patients. However, the lack of correlation between liver and cardiac iron stores suggests that both organs should be evaluated with MRI, since cardiac disease is the leading cause of death in this population. It is also unclear which MRI method is the most accurate since there are no large studies that have directly compared the different available techniques. The role of MRI in the era of genetic diagnosis of hemochromatosis is also debated, whereas data on the accuracy of the method in other hematological and liver diseases are rather limited. However, MRI is a fast, non-invasive and relatively accurate diagnostic tool for assessing LIC, and its use is expected to increase as the role of iron in the pathogenesis of liver disease becomes clearer.展开更多
基金Supported by Grants-in-Aid for Scientific Research from the Japan Society for the Program of Science,No.23590978 and No.16H05287the Strategic Research Promotion Program from Yamaguchi University
文摘AIM To evaluate the inhibitory effects of deferasirox(DFX) against hepatocellular carcinoma(HCC) through basic and clinical studies.METHODS In the basic study, the effect of DFX was investigated in three hepatoma cell lines(Hep G2, Hep3 B, and Huh7), as well as in an N-nitrosodiethylamine-induced murine HCC model. In the clinical study, six advanced HCC patients refractory to chemotherapy were enrolled. The initial dose of DFX was 10 mg/kg per day and was increased by 10 mg/kg per day every week, until the maximum dose of 30 mg/kg per day. The duration of a single course of DFX therapy was 28 consecutive days. In the event of dose-limiting toxicity(according to the Common Terminology Criteria for Adverse Events v.4.0), DFX dose was reduced.RESULTS Administration of DFX inhibited the proliferation of hepatoma cell lines and induced the activation of caspase-3 in a dose-dependent manner in vitro. In the murine model, DFX treatment significantly suppressed the development of liver tumors(P < 0.01), and significantly upregulated the mR NA expression levels of hepcidin(P < 0.05), transferrin receptor 1(P < 0.05), and hypoxia inducible factor-1α(P < 0.05) in both tumor and non-tumor tissues, compared with control mice. In the clinical study, anorexia and elevated serum creatinine were observed in four and all six patients, respectively. However, reduction in DFX dose led to decrease in serum creatinine levels in all patients. After the first course of DFX, one patient discontinued the therapy. We assessed the tumor response in the remaining five patients; one patient exhibited stable disease, while four patients exhibited progressive disease. The one-year survival rate of the six patients was 17%.CONCLUSION We demonstrated that DFX inhibited HCC in the basic study, but not in the clinical study due to dose-limiting toxicities.
文摘We report the case of a 7 years old girl with Juvenile Hemochromatosis, due to homozygous mutation of HJV, which had increased serum iron indices and liver iron overload in the absence of any clinical sign of disease. Oral iron chelation with low dose deferasirox showed good efficacy and no side effects. The oral iron chelator deferasirox could be a valid option for removing excess iron in early Juvenile Hemochromatosis.
文摘BACKGROUND A perforated gastroduodenal ulcer is rarely observed in children.Certain medications have been reported to cause ulcerations.Deferasirox,an iron chelating agent,has been previously reported to be associated with the development of gastroduodenal ulcers.CASE SUMMARY We report a case of a 3-year-old boy who was diagnosed with beta thalassemia major and treated with deferasirox.He presented to the emergency department with an acute abdomen.A perforated duodenal ulcer was suspected after X-ray imaging and laparoscopic exploration.It was successfully managed with laparoscopic washout and drainage.CONCLUSION Due to the rarity and severity of this case,it is a reminder that prevention and early recognition of gastrointestinal complications in patients receiving deferasirox are crucial.Minimally invasive laparoscopic surgery is both safe and feasible to treat perforated duodenal ulcers in selected patients.
文摘4-hydrazinobenzoic acid has been highlighted as one of the potential genotoxic impurities (PGIs). A sensitive HPLC method was developed and validated for the determination of 4-hydrazino benzoic acid in Deferasirox Tablet. HPLC method on Zorbax SB C18 column (250 × 4.6 mm i.d.), 5 μm, with UV Detector was used. The proposed method was cost effective, specific, linear, accurate, rugged and precise. The calibration curves showed good linearity over the concentration range of 0.5 μg/ml to 1.5 μg/ml with respect to the sample. The correlation coefficient was 0.999. Excellent recoveries of 102% were obtained at the level 0.5 μg/ml.
文摘Objective:Our study aimed to investigate the ototoxicity associated with the iron chelator deferasirox in patients withβ-thalassemia major,who were receiving regular transfusion therapy,along with evaluating the data on audiological tests using appropriate statistical tests.Methods:A cross-sectional observational study was conducted on 100 transfusion-dependentβ-thalassemia major patients on oral iron chelating agent-deferasirox.Pure tone audiometry(PTA)and distortion product otoacoustic emissions(DPOAE)was carried out in all patients to assess the auditory side effects of the drug.Data was collected,compiled,and analyzed statistically using appropriate statistical tests.The relationship between ototoxicity and various demographic parameters such as age,sex,hemoglobin(Hb)level,S.ferritin,duration,and dose of chelation therapy was also assessed.Results:Sixteen patients had abnormal DPOAE and the number of patients with pure tone average above 25 dB HL which was taken as hearing deficit on PTA was 13.No statistically significant relationship between hearing loss and age,gender,S.ferritin,duration of therapy,cumulative dose,Hb levels were found.Conclusion:Despite being a lifesaving drug,the advantages of chelating agent-Deferasirox must be weighed against its probable ototoxic effects.We could not find a relationship of ototoxicity with variable parameters(age,gender,Hb level,Ferritin level,duration,and cumulative dose of drug),thus future research is encouraged to form a definitive basis.
基金CAMS Innovation Fund for Medical Sciences(CIFMS No.2016-I2M-3-010 and CIFMS No.2017-I2M-1-011)。
文摘Deferasirox is the first-line drug for iron overload due to thalassemia in adults and pediatric patients. It is classified as a type II compound in the Biopharmaceutics Classification System, and thus the particle size of its active pharmaceutical ingredient(API) should be strictly controlled during the manufacturing process. In the present study, laser diffraction was adopted to measure the particle size distribution of deferasirox API. We also developed and validated an accurate and convenient method by investigating important optical parameters and sample dispersing conditions. The relative standard deviation values, namely, d(0.1), d(0.5), d(0.9), and d(4,3), measured via methodology validation and actual sample measurement were < 3%. The dissolution curves of several batches of dispersible tablets prepared using deferasirox with different particle sizes were compared in the four dissolved media to investigate the influence of particle size on drug dissolution in vitro. Results indicated that the particle size distribution of deferasirox API significantly affected the release of its dispersible tablet.
基金The CAMS Innovation Fund for Medical Sciences(CIFMS 2021-I2M-1-028).
文摘We reported herein the synthesis and antibacterial activity evaluation of two oxazolidinone-deferasirox conjugates with different linkers that were designed based on the“Trojan horse”strategy.The conjugates could combine with Fe^(3+)ions as the deferasirox.However,both conjugates were inactive against tested bacteria,including S.aureus,E.coli,A.baumannii,and P.aeruginosa.The results suggested that the synthesized iron chelator deferasirox was not suitable as a siderophore of the bacteria to transport the antibiotic,or the coupling linker of the synthesized conjugates could not be hydrolyzed to release the oxazolidinone in the cytoplasm.Therefore,the design and synthesis of oxazolidinone-deferasirox conjugates need further exploration.
文摘Accurate evaluation of iron overload is necessary to establish the diagnosis of hemochromatosis and guide chelation treatment in transfusion-dependent anemia. The liver is the primary site for iron storage in patients with hemochromatosis or transfusion-dependent anemia, therefore, liver iron concentration (LIC) accurately re? ects total body iron stores. In the past 20 years, magnetic resonance imaging (MRI) has emerged as a promising method for measuring LIC in a variety of diseases. We review the potential role of MRI in LIC determination in the most important disorders that are characterized by iron overload, that is, thalassemia major, other hemoglobinopathies, acquired anemia, and hemochromatosis. Most studies have been performed in thalassemia major and MRI is currently a widely accepted method for guiding chelation treatment in these patients. However, the lack of correlation between liver and cardiac iron stores suggests that both organs should be evaluated with MRI, since cardiac disease is the leading cause of death in this population. It is also unclear which MRI method is the most accurate since there are no large studies that have directly compared the different available techniques. The role of MRI in the era of genetic diagnosis of hemochromatosis is also debated, whereas data on the accuracy of the method in other hematological and liver diseases are rather limited. However, MRI is a fast, non-invasive and relatively accurate diagnostic tool for assessing LIC, and its use is expected to increase as the role of iron in the pathogenesis of liver disease becomes clearer.
