AIM: To evaluate cladribine [2-chlorodeoxyadenosine (2-CdA)] therapy in refractory celiac disease (RCD) Ⅱ. METHODS: An open-label cohort-study of RCD Ⅱ patients treated with 2-CdA was performed between 2000 and 2010...AIM: To evaluate cladribine [2-chlorodeoxyadenosine (2-CdA)] therapy in refractory celiac disease (RCD) Ⅱ. METHODS: An open-label cohort-study of RCD Ⅱ patients treated with 2-CdA was performed between 2000 and 2010. Survival rate, enteropathy associated T-cell lymphoma (EATL) occurrence, clinical course, and histological and immunological response rates were evaluated. RESULTS: Overall, 32 patients were included with a median follow-up of 31 mo. Eighteen patients responded well to 2-CdA. Patients responsive to 2-CdA had a statistically significant increased survival compared to those who were unresponsive. The overall 3- and 5-year survival was 83% in the responder and 63% and 22% in the non-responder group, respectively. The overall 2-year clinical, histological and immunological response rates were 81%, 47% and 41%, respectively. Progression into EATL was reported in 16%, all of these patients died. CONCLUSION: Treatment of RCD Ⅱ with 2-CdA holds promise, showing excellent clinical and histological response rates, and probably less frequent transition into EATL.展开更多
Objective:To evaluate the neuroprotective effect of cryptotanshinone against cladribine-induced cognitive impairment in rats.Methods:Rats were administered with cladribine(1 mg/kg,p.o.)and cryptotanshinone(10 and 20 m...Objective:To evaluate the neuroprotective effect of cryptotanshinone against cladribine-induced cognitive impairment in rats.Methods:Rats were administered with cladribine(1 mg/kg,p.o.)and cryptotanshinone(10 and 20 mg/kg,i.p.)for four weeks.Behavioral tests such as Morris water maze and elevated plus maze were conducted to check memory impairment caused by cladribine.On day 29,all rats were sacrificed,and the brains were separated for estimation of neuroinflammatory factors,biochemical parameters,neurotransmitters,Aβ(1-42),blood-brain barrier permeability,nuclear factor erythroid 2-related factor 2(Nrf2),and brain-derived neurotrophic factor(BDNF).Results:Treatment with cryptotanshinone dose-dependently enhanced spatial memory,improved the levels of neurotransmitter and antioxidant enzymes,and suppressed proinflammatory cytokine release.Cryptotanshinone also decreased Aβ(1-42)accumulation and increased the levels of Nrf2 and BDNF in the hippocampus.Additionally,the histopathological results showed that cryptotanshinone reduced cladribine-induced neuronal death in the hippocampus.Conclusions:Cryptotanshinone exhibits a promising neuroprotective effect against cladribine-induced cognitive impairment in preclinical studies,and may be a potential phytochemical for the treatment and management of cognitive impairment.展开更多
The pilot-scale process for preparing 2-amino-6-chloro-9-（2＇,3＇,5＇-tri-O-acetyl-Dq3-ribofuranosyl）-purine and 2-chloroadenosine has been developed with a total yield of the desired compounds 73% and 44.5%, respec...The pilot-scale process for preparing 2-amino-6-chloro-9-（2＇,3＇,5＇-tri-O-acetyl-Dq3-ribofuranosyl）-purine and 2-chloroadenosine has been developed with a total yield of the desired compounds 73% and 44.5%, respectively. These compounds are useful intermediates for enzymatic synthesis of active pharmaceutical ingredients Nelarabine and Cladribine. The starting material--commercially avaliable guanosine--was acetylated with acetic anhydride, yielding 2,3,5-tri-O-acetylguanosine, which was further deoxyhalogenated with phosphorous oxychloride in presence of tetraethylammonia chloride. Diazotization of the resulting intermediate with tert-butylnitrite leads to the corresponding ribofuranosyl-substituted 2,6-dichloropurine, which was converted to 6-chloroadenosine by reaction with methanolic ammonia.展开更多
Purpose: This study was aimed to assess the expression of caspase 8 and caspase 9 in the epidermis, during apoptosis after cladribine administration. Materials and Methods: The experiment was carried on 10 Wistar rats...Purpose: This study was aimed to assess the expression of caspase 8 and caspase 9 in the epidermis, during apoptosis after cladribine administration. Materials and Methods: The experiment was carried on 10 Wistar rats. The animals were placed into 2 groups: control group and experimental group. Animals in the control group, in addition to standard feed and water, were injected with a physiological salt in a quantity corresponding to the drug dosage, over the course of the experiment. The experimental group animals were treated with cladribine in the dose of 0.07 mg/kg/24h, for 6 consecutive days in the morning, in 3 cycles with a 5-week gap in administering the drug. After the completion of the experiment, the animals were decapitated, and full thickness slices of skin were taken from all the rats for immunohisto- chemical study. The results of the statistical surveys were analysed in Statistica 10.0. The difference in intensity of expression of caspase 9 and caspase 8 in the groups were investigated using the Chiquadrat test. Statistical significance was considered at p < 0.05. Results: The statistical analysis found significant correlation in expression of caspase 9 between examined groups (p < 0.0001). There were no statistical relationships in the presence of the expression of caspase 8 between examined groups (p = 0.0526). Conclusion: Our findings suggest that mechanism of apoptosis in the rats’ epidermis, induced by cladribine given in the scheme used in the treatment of MS in humans, involves caspase 9 activity. This means that 2-CdA initiates the intrinsic apoptosis pathway.展开更多
Objective To analyze efficacy and safety of CLAG regimen in patients with refractory or relapsed acute myeloid leukemia(AML).Methods Efficacy and adverse events of patients with refractory or relapsed AML who were tre...Objective To analyze efficacy and safety of CLAG regimen in patients with refractory or relapsed acute myeloid leukemia(AML).Methods Efficacy and adverse events of patients with refractory or relapsed AML who were treated with one course of CLAG from April 1st,2014 through December 9th,2015 in our hospital were retrospectively reviewed.Results Thirty-three展开更多
Mastocytosis is a clonal neoplastic disorder of the mast cells(MC) that can be limited to the skin(cutaneous mastocytosis) or involve one or more extracutaneous organs(systemic mastocytosis). The clinical manifestatio...Mastocytosis is a clonal neoplastic disorder of the mast cells(MC) that can be limited to the skin(cutaneous mastocytosis) or involve one or more extracutaneous organs(systemic mastocytosis). The clinical manifestations of mastocytosis are heterogeneous ranging from indolent disease with a long-term survival to a highly aggressive neoplasm with survival of about 6 mo. Although liver involvement in aggressive systemic mastocytosis(ASM) is relatively common, the development of portal hypertension with or without cirrhosis is rare. We report a case of ASM without skin involvement in a 72-year-old caucasian male who presented with non-cirrhotic portal hypertension based on clinical, analytical, imagiological and endoscopic findings. Given the hematological picture, the correct diagnosis was established based on ancillary tests for MC using bone marrow aspirates and biopsy. Extensive involvement of the liver and gastrointestinal tract was histologically documented. The disease progressed rapidly and severe pancytopenia and recurrent upper gastrointestinal bleeding became the dominant problem. This case illustrates the challenge in establishing a diagnosis of ASM especially when the clinical picture is atypical and without skin involvement. Gastroenterologists should consider infiltrative disease, particularly systemic mastocytosis, as a differential diagnosis in a clinical case of portal hypertension of unknown etiology.展开更多
Leukovir, an enteric-coated tablet, is the original drug product for internal use. The well-known nucleosides cladribine and ribavirin are the active ingredients of the drug product leukovir. Pharmacokinetic parameter...Leukovir, an enteric-coated tablet, is the original drug product for internal use. The well-known nucleosides cladribine and ribavirin are the active ingredients of the drug product leukovir. Pharmacokinetic parameters of the drug product for the internal use of leukovir active ingredients have been established. The cladribine half-absorption period was t<sub>1/2a</sub> = 49.5 h, C<sub>0</sub> = 276.4 μg/ml, C<sub>max</sub> = 6.0 μg/ml. Distribution and accumulation parameters (V<sub>d</sub>, V<sub>ss</sub> and AUC) have indicated that the drug distribution between the blood cells and blood plasma takes place in the same way, irrespective of the dosage form. Cladribine half-life period is t<sub>1/2e</sub> = 0.62 hours. The molecule total clearance and average lifetime in the body in the case of subcutaneous drug administration are approximately the same. Ribavirin is characterized by a half-absorption period of t<sub>1/2a</sub> = 0.71 h, C<sub>0</sub> = 115.6 μg/ml and C<sub>max</sub> = 75.5 μg/ml. Ribavirin total volume of distribution (V<sub>d</sub> = 1.3 l/kg) and stationary volume of distribution (V<sub>ss</sub> = 1.64 l/kg) were practically similar to leukovir when administered subcutaneously. The AUC value = 504.2 μg h/ml, which is 2.5 times less than that in the case of drug form administration. Leukovir was regarded as slightly toxic in an acute toxicity study. The risk of cumulation for this drug product is low.展开更多
Background The prognosis for relapsed or refractory acute myeloid leukemia(RR-AML)in children is poor,and the preferred salvage chemotherapy is unclear.One regimen is cladribine,cytarabine,and granulocyte-colony stimu...Background The prognosis for relapsed or refractory acute myeloid leukemia(RR-AML)in children is poor,and the preferred salvage chemotherapy is unclear.One regimen is cladribine,cytarabine,and granulocyte-colony stimulating factor(CLAG),but little is known about its efficacy and safety in children with RR-AML.Methods We enrolled RR-AML patients aged 0-18 years who received modified CLAG regimen for re-induction between July 1,2015 and April 1,2018,or conventional induction between August 1,2011 and April 1,2018.Patients were followed up to March 31,2019.Patients underwent allogeneic stem cell transplantation(allo-SCT)or chemotherapy after the induction of complete remission(CR).The CR rate,survival,and side effects were analyzed.Results The CR rate for induction was 66.7%after one cycle and 75.0%after two cycles of the CLAG regimen in 12 children.The nine children who received conventional chemotherapy had a CR rate of 22.2%after one cycle and 33.3%after two cycles(P=0.087 vs.CLAG).The 3-year event-free survival(EFS)of the CLAG group and the conventional treatment group were 44.4±15.7%and 22.2±13.8%(P=0.112).The 3-year overall survival of the two groups were 59.5±16.2%and 22.2%±13.8%(P=0.057).The 3-year EFS for allo-SCT and chemotherapy after CLAG regimen was 66.7±19.2%and 25.0±21.7%(P=0.015).A single case of chemotherapy-related death was recorded.Conclusion Our data suggest a promising CR rate using CLAG salvage treatment in childhood RR-AML.Allo-SCT after CR may improve the long-term outcome in these patients.展开更多
基金Supported by An Unrestricted Grant from Astra Zeneca
文摘AIM: To evaluate cladribine [2-chlorodeoxyadenosine (2-CdA)] therapy in refractory celiac disease (RCD) Ⅱ. METHODS: An open-label cohort-study of RCD Ⅱ patients treated with 2-CdA was performed between 2000 and 2010. Survival rate, enteropathy associated T-cell lymphoma (EATL) occurrence, clinical course, and histological and immunological response rates were evaluated. RESULTS: Overall, 32 patients were included with a median follow-up of 31 mo. Eighteen patients responded well to 2-CdA. Patients responsive to 2-CdA had a statistically significant increased survival compared to those who were unresponsive. The overall 3- and 5-year survival was 83% in the responder and 63% and 22% in the non-responder group, respectively. The overall 2-year clinical, histological and immunological response rates were 81%, 47% and 41%, respectively. Progression into EATL was reported in 16%, all of these patients died. CONCLUSION: Treatment of RCD Ⅱ with 2-CdA holds promise, showing excellent clinical and histological response rates, and probably less frequent transition into EATL.
基金funded by the Indian Council of Medical Research with Grant Number 2020-8817,New Delhi,India。
文摘Objective:To evaluate the neuroprotective effect of cryptotanshinone against cladribine-induced cognitive impairment in rats.Methods:Rats were administered with cladribine(1 mg/kg,p.o.)and cryptotanshinone(10 and 20 mg/kg,i.p.)for four weeks.Behavioral tests such as Morris water maze and elevated plus maze were conducted to check memory impairment caused by cladribine.On day 29,all rats were sacrificed,and the brains were separated for estimation of neuroinflammatory factors,biochemical parameters,neurotransmitters,Aβ(1-42),blood-brain barrier permeability,nuclear factor erythroid 2-related factor 2(Nrf2),and brain-derived neurotrophic factor(BDNF).Results:Treatment with cryptotanshinone dose-dependently enhanced spatial memory,improved the levels of neurotransmitter and antioxidant enzymes,and suppressed proinflammatory cytokine release.Cryptotanshinone also decreased Aβ(1-42)accumulation and increased the levels of Nrf2 and BDNF in the hippocampus.Additionally,the histopathological results showed that cryptotanshinone reduced cladribine-induced neuronal death in the hippocampus.Conclusions:Cryptotanshinone exhibits a promising neuroprotective effect against cladribine-induced cognitive impairment in preclinical studies,and may be a potential phytochemical for the treatment and management of cognitive impairment.
文摘The pilot-scale process for preparing 2-amino-6-chloro-9-（2＇,3＇,5＇-tri-O-acetyl-Dq3-ribofuranosyl）-purine and 2-chloroadenosine has been developed with a total yield of the desired compounds 73% and 44.5%, respectively. These compounds are useful intermediates for enzymatic synthesis of active pharmaceutical ingredients Nelarabine and Cladribine. The starting material--commercially avaliable guanosine--was acetylated with acetic anhydride, yielding 2,3,5-tri-O-acetylguanosine, which was further deoxyhalogenated with phosphorous oxychloride in presence of tetraethylammonia chloride. Diazotization of the resulting intermediate with tert-butylnitrite leads to the corresponding ribofuranosyl-substituted 2,6-dichloropurine, which was converted to 6-chloroadenosine by reaction with methanolic ammonia.
文摘Purpose: This study was aimed to assess the expression of caspase 8 and caspase 9 in the epidermis, during apoptosis after cladribine administration. Materials and Methods: The experiment was carried on 10 Wistar rats. The animals were placed into 2 groups: control group and experimental group. Animals in the control group, in addition to standard feed and water, were injected with a physiological salt in a quantity corresponding to the drug dosage, over the course of the experiment. The experimental group animals were treated with cladribine in the dose of 0.07 mg/kg/24h, for 6 consecutive days in the morning, in 3 cycles with a 5-week gap in administering the drug. After the completion of the experiment, the animals were decapitated, and full thickness slices of skin were taken from all the rats for immunohisto- chemical study. The results of the statistical surveys were analysed in Statistica 10.0. The difference in intensity of expression of caspase 9 and caspase 8 in the groups were investigated using the Chiquadrat test. Statistical significance was considered at p < 0.05. Results: The statistical analysis found significant correlation in expression of caspase 9 between examined groups (p < 0.0001). There were no statistical relationships in the presence of the expression of caspase 8 between examined groups (p = 0.0526). Conclusion: Our findings suggest that mechanism of apoptosis in the rats’ epidermis, induced by cladribine given in the scheme used in the treatment of MS in humans, involves caspase 9 activity. This means that 2-CdA initiates the intrinsic apoptosis pathway.
文摘Objective To analyze efficacy and safety of CLAG regimen in patients with refractory or relapsed acute myeloid leukemia(AML).Methods Efficacy and adverse events of patients with refractory or relapsed AML who were treated with one course of CLAG from April 1st,2014 through December 9th,2015 in our hospital were retrospectively reviewed.Results Thirty-three
文摘Mastocytosis is a clonal neoplastic disorder of the mast cells(MC) that can be limited to the skin(cutaneous mastocytosis) or involve one or more extracutaneous organs(systemic mastocytosis). The clinical manifestations of mastocytosis are heterogeneous ranging from indolent disease with a long-term survival to a highly aggressive neoplasm with survival of about 6 mo. Although liver involvement in aggressive systemic mastocytosis(ASM) is relatively common, the development of portal hypertension with or without cirrhosis is rare. We report a case of ASM without skin involvement in a 72-year-old caucasian male who presented with non-cirrhotic portal hypertension based on clinical, analytical, imagiological and endoscopic findings. Given the hematological picture, the correct diagnosis was established based on ancillary tests for MC using bone marrow aspirates and biopsy. Extensive involvement of the liver and gastrointestinal tract was histologically documented. The disease progressed rapidly and severe pancytopenia and recurrent upper gastrointestinal bleeding became the dominant problem. This case illustrates the challenge in establishing a diagnosis of ASM especially when the clinical picture is atypical and without skin involvement. Gastroenterologists should consider infiltrative disease, particularly systemic mastocytosis, as a differential diagnosis in a clinical case of portal hypertension of unknown etiology.
文摘Leukovir, an enteric-coated tablet, is the original drug product for internal use. The well-known nucleosides cladribine and ribavirin are the active ingredients of the drug product leukovir. Pharmacokinetic parameters of the drug product for the internal use of leukovir active ingredients have been established. The cladribine half-absorption period was t<sub>1/2a</sub> = 49.5 h, C<sub>0</sub> = 276.4 μg/ml, C<sub>max</sub> = 6.0 μg/ml. Distribution and accumulation parameters (V<sub>d</sub>, V<sub>ss</sub> and AUC) have indicated that the drug distribution between the blood cells and blood plasma takes place in the same way, irrespective of the dosage form. Cladribine half-life period is t<sub>1/2e</sub> = 0.62 hours. The molecule total clearance and average lifetime in the body in the case of subcutaneous drug administration are approximately the same. Ribavirin is characterized by a half-absorption period of t<sub>1/2a</sub> = 0.71 h, C<sub>0</sub> = 115.6 μg/ml and C<sub>max</sub> = 75.5 μg/ml. Ribavirin total volume of distribution (V<sub>d</sub> = 1.3 l/kg) and stationary volume of distribution (V<sub>ss</sub> = 1.64 l/kg) were practically similar to leukovir when administered subcutaneously. The AUC value = 504.2 μg h/ml, which is 2.5 times less than that in the case of drug form administration. Leukovir was regarded as slightly toxic in an acute toxicity study. The risk of cumulation for this drug product is low.
基金This study was supported by a grant from Shanghai Science and Technology Committee Projects No.14411950602 and No.18ZR1431200.
文摘Background The prognosis for relapsed or refractory acute myeloid leukemia(RR-AML)in children is poor,and the preferred salvage chemotherapy is unclear.One regimen is cladribine,cytarabine,and granulocyte-colony stimulating factor(CLAG),but little is known about its efficacy and safety in children with RR-AML.Methods We enrolled RR-AML patients aged 0-18 years who received modified CLAG regimen for re-induction between July 1,2015 and April 1,2018,or conventional induction between August 1,2011 and April 1,2018.Patients were followed up to March 31,2019.Patients underwent allogeneic stem cell transplantation(allo-SCT)or chemotherapy after the induction of complete remission(CR).The CR rate,survival,and side effects were analyzed.Results The CR rate for induction was 66.7%after one cycle and 75.0%after two cycles of the CLAG regimen in 12 children.The nine children who received conventional chemotherapy had a CR rate of 22.2%after one cycle and 33.3%after two cycles(P=0.087 vs.CLAG).The 3-year event-free survival(EFS)of the CLAG group and the conventional treatment group were 44.4±15.7%and 22.2±13.8%(P=0.112).The 3-year overall survival of the two groups were 59.5±16.2%and 22.2%±13.8%(P=0.057).The 3-year EFS for allo-SCT and chemotherapy after CLAG regimen was 66.7±19.2%and 25.0±21.7%(P=0.015).A single case of chemotherapy-related death was recorded.Conclusion Our data suggest a promising CR rate using CLAG salvage treatment in childhood RR-AML.Allo-SCT after CR may improve the long-term outcome in these patients.
