Magnetic Fe304 nanoparticles were synthesized by co-precipitation method and the mercaptopurine （MER） drug-loaded magnetic microspheres were obtained through emulsion cross-linking methods. The efficiency of this ap...Magnetic Fe304 nanoparticles were synthesized by co-precipitation method and the mercaptopurine （MER） drug-loaded magnetic microspheres were obtained through emulsion cross-linking methods. The efficiency of this approach was evaluated in terms of drug loading content （DLC）, encapsulation efficiency （EE） and delivery properties in vitro, determined by high performance liquid chromatograph （HPLC）. The microspheres showed good DLC values of 11.8%, as well as good EE values of 79.4%. The in vitro drug release study was carried out in phosphate buffer solution （PBS） simulated body fluid, at 37 ~C with pH=7.4. The release profiles showed an initial fast release rate, which decreased as time progressed and about 84 % had been released after 48 h. The experimental results indicated that the prepared magnetic microspheres may be useful for potential applications of MER for magnetically targeted chemotherapy.展开更多
A new chemically modified electrode(CME) immobilized on the surface of multi-wall carbon nanotubes functionalized with carboxylic groups was fabricated. The results indicate that the CME exhibits efficiently electroca...A new chemically modified electrode(CME) immobilized on the surface of multi-wall carbon nanotubes functionalized with carboxylic groups was fabricated. The results indicate that the CME exhibits efficiently electrocatalytic oxidation of 6-mercaptopurine(6-MP). The CME can be used as the working electrode in the liquid chromatography for the determination of 6-MP. The peak current of 6-MP is linearly changed with its concentration ranging from 4.0×10 -7 to 1.0×10 -4 mol/L with the calculated detection limit (S/N=3) of 2.0×10 -7 mol/L. Coupled with microdialysis sampling, the method has been successfully applied to assessing the content of 6-MP in rat blood.展开更多
In pH 4.8 Britton-Robinson (B-R) buffer solution, Mercaptopurine (MP) could react with Cu(II) to form stable chelate compound, a new Resonance Rayleigh scattering (RRS) spectrum generated and enhanced for the binary s...In pH 4.8 Britton-Robinson (B-R) buffer solution, Mercaptopurine (MP) could react with Cu(II) to form stable chelate compound, a new Resonance Rayleigh scattering (RRS) spectrum generated and enhanced for the binary system which the highest peak located at 453 nm as detection wavelength. But the RRS spectra could be quenched after adding her- ring milt DNA (hsDNA), salmon milt DNA (sDNA) and calf thymus DNA (ctDNA) into the binary system, respect- tively. And the weakened degree of spectra was directly proportional to the concentration of DNA. The reaction product of three nucleic acid system have identical spectral features, their range of linearity for the relation of spectral intensity with concentration respectively are 0.05 - 0.9 μg.mL-1 for hsDNA, 0.1 - 0.9 μg.mL-1 for sDNA and 0.3 - 0.9 μg.mL-1 for ctDNA;their detection limit respectively are 5 ng.mL-1for hsDNA, 6 ng.mL-1for sDNA, 6 ng?mL-1 for ctDNA. So a new method for determination of DNA was developed and successfully applied to determine the content of the DNA in artificial synthetized samples. At the same time the spectral features of absorption spectra and RRS spectra of the three reaction system, and the eligible reaction conditions and influencing factors were investigated in this paper.展开更多
Misconceptions are common in the care of patients with inflammatory bowel disease(IBD).In this paper,we state the most commonly found misconceptions in clinical practice and deal with the use of 5-aminosalicylates and...Misconceptions are common in the care of patients with inflammatory bowel disease(IBD).In this paper,we state the most commonly found misconceptions in clinical practice and deal with the use of 5-aminosalicylates and thiopurines,to review the related scientificevidence,and make appropriate recommendations.Prevention of errors needs knowledge to avoid making such errors through ignorance.However,the amount of knowledge is increasing so quickly that one new danger is an overabundance of information.IBD is a model of a very complex disease and our goal with this review is to summarize the key evidence for the most common daily clinical problems.With regard to the use of 5-aminosalicylates,the best practice may to be consider abandoning the use of these drugs in patients withsmall bowel Crohn's disease.The combined approach with oral plus topical 5-aminosalicylates should be the first-line therapy in patients with active ulcerative colitis;once-daily treatment should be offered as a first choice regimen due to its better compliance and higher efficacy.With regard to thiopurines,they seem to be as effective in ulcerative colitis as in Crohn's disease.Underdosing of thiopurines is a form of undertreatment.Thiopurines should probably be continued indefinitely because their withdrawal is associated with a high risk of relapse.Mercaptopurine is a safe alternative in patients with digestive intolerance or hepatotoxicity due to azathioprine.Finally,thiopurine methyltransferase(TPMT)screening cannot substitute for regular monitoring because the majority of cases of myelotoxicity are not TPMT-related.展开更多
Although a great variety of new drugs have been introduced for the therapy of inflammatory bowel diseases so far,a definite cure of the disease is still out of scope.An anti-inflammatory approach to induce remission f...Although a great variety of new drugs have been introduced for the therapy of inflammatory bowel diseases so far,a definite cure of the disease is still out of scope.An anti-inflammatory approach to induce remission followed by maintenance therapy with immunosupressants is still the mainstay of therapy.Thiopurines comprising azathioprine and its active metabolite mercaptopurine as well as tioguanine,are widely used in the therapy of chronic active inflammatory bowel disease(IBD).Their steroid sparing potential and efficacy in remission maintenance are out of doubt.Unfortunately,untoward adverse events are frequently observed and may preclude further administration or be life threatening.This review will focus on new aspects of thiopurine therapy in IBD,its efficacy and safety.展开更多
The use of thiopurines in inflammatory bowel disease(IBD) has been examined in numerous prospective, controlled trials, with a majority demonstrating a clinical benefit. We conducted this review to describe the histor...The use of thiopurines in inflammatory bowel disease(IBD) has been examined in numerous prospective, controlled trials, with a majority demonstrating a clinical benefit. We conducted this review to describe the historical and current evidence in the use of thiopurines in IBD. A systematic search was performed on MEDLINE between 1965 and 2016 to identify studies on thiopurines in IBD. The most robust evidence for thiopurines in IBD includes induction of remission in combination with anti-tumor necrosis factor(antiTNF) agents, and maintenance of remission and postoperative maintenance in Crohn's disease. Less evidence exists for thiopurine monotherapy in induction of remission, maintenance of ulcerative colitis, chemoprevention of colorectal cancer, and in preventing immunogenicity to anti-TNF. Evidence was often limited by trial design. Overall, thiopurines have demonstrated efficacy in a broad range of presentations of IBD. With more efficacious novel therapeutic agents, the positioning of thiopurines in the management of IBD will change and future studies will analyze the benefit of thiopurines alone and in conjunction with these new medications.展开更多
Thiopurines are widely used for maintenance treatment of inflammatory bowel disease. Interindividual variability in clinical response to thiopurines may be attributed to several factors including genetic polymorphisms...Thiopurines are widely used for maintenance treatment of inflammatory bowel disease. Interindividual variability in clinical response to thiopurines may be attributed to several factors including genetic polymorphisms, severity and chronicity of disease, comorbidities, duration of administration, compliance issues and use of concomitant medication, environmental factors and clinician and patient preferences. The purpose of this review is to summarise the current evidence on thiopurine safety and toxicity, to describe adverse drug events and emphasise the significance of drug interactions, and to discuss the relative safety of thiopurine use in adults, elderly patients, children and pregnant women. Thiopurines are safe to use and well tolerated, however dose adjustment or discontinuation of treatment must be considered in cases of non-response, poor compliance or toxicity. Drug safety, clinical response to treatment and short to long term risks and benefits must be balanced throughout treatment duration for different categories of patients. Treatment should be individualised and stratified according to patient requirements. Enzymatic testing prior to treatment commencement is advised. Surveillance with regular clinic follow-up and monitoring of laboratory markers is important. Data on long term efficacy, safety of thiopurine use and interaction with other disease modifying drugs are lacking, especially in paediatric inflammatory bowel disease. High quality, collaborative clinical research is required so as to inform clinical practice in the future.展开更多
AIM: To determine the incidence and predictors of thiopurine-related adverse events. METHODS: Subjects with Crohn's disease who were followed in the Alberta Inflammatory Bowel Disease Consortium patient database r...AIM: To determine the incidence and predictors of thiopurine-related adverse events. METHODS: Subjects with Crohn's disease who were followed in the Alberta Inflammatory Bowel Disease Consortium patient database registry were identified. Retrospective chart review was conducted between August 5th, 2010 and June 1st, 2012. We collected data on: age at diagnosis; sex; disease location and behaviour at time of prescribing thiopurine; perianal fistulising disease at or prior to thiopurine prescription; smoking status at time of thiopurine prescription, use of corticosteroid within 6 mo of diagnosis; dosage, age at onset, and cessation of 5-aminosalicyclic acid(5-ASA); anti-tumour necrosis factor medication exposure and intestinal resection before thiopurine prescription. The primary outcome of interest was the first adverse event that led to discontinuation of the first thiopurine medication used. Logistic regression models were used to associate clinical characteristics with outcomes after adjusting for potential confounders. Risk estimates were presented as odds ratios(OR) with 95% CI. Effect modification by age and sex were explored.RESULTS: Our cohort had a median follow-up duration of 5.8 years [interquartile range(IQR 25th-75th) 2.7-9.1]. Thiopurine therapy was discontinued in 31.3% of patients because of: hypersensitivity reactions(7.1%), acute pancreatitis(6.2%), gastrointestinal intolerance(5.4%), leucopenia(3.7%), hepatotoxicity(3.4%), infection(1.1%) and other reasons(4.3%). A higher incidence of thiopurine withdrawal was observed in patients over the age of 40(39.4%, P = 0.007). A sexby-age interaction(P = 0.04) was observed. Females older than 40 years of age had an increased risk of thiopurine discontinuation due to an adverse event(age above 40 vs age below 40, adjusted OR = 2.8; 95%CI: 1.4-5.6). In contrast, age did not influence thiopurine withdrawal in males(age above 40 vs below 40, adjusted OR = 0.9; 95%CI: 0.4-2.1). Other clinical variables(disease location and phenotype, perianal disease, smoking history, history of intestinal resection and prior 5-ASA or corticosteroid use) were not associated with an increased risk an adverse event leading to therapy cessation. CONCLUSION: Thiopurine withdrawal due to adverse events is commoner in women over the age of 40 at prescription. These findings need to be replicated in other cohorts.展开更多
AIM:To investigate the incidence of neoplasms in inflammatory bowel disease(IBD)patients and the potential causative role of thiopurines.METHODS:We performed an observational descriptive study comparing the incidence ...AIM:To investigate the incidence of neoplasms in inflammatory bowel disease(IBD)patients and the potential causative role of thiopurines.METHODS:We performed an observational descriptive study comparing the incidence of malignancies in IBD patients treated with thiopurines and patients not treated with these drugs.We included 812 patients which were divided in two groups depending on whether they have received thiopurines or not.We have studied basal characteristics of both groups(age when the disease was diagnosed,sex,type of IBD,etc.)and treatments received(Azathioprine,mercaptopurine,infliximab,adalimumab or other immunomodulators),as well as neoplasms incidence.Univariate analysis was performed with the student t test,χ 2 test or Wilcoxon exact test as appropriate.A logistic regression analysis was performed as multivariate analysis.Statistical significance was establish at P values of less than 0.05,and 95%CI were used for the odds ratios.RESULTS:Among 812 patients included,429(52.83%)have received thiopurines:79.5% azathioprine,14% mercaptopurine and 6.5% both drugs.44.76% of patients treated with thiopurines and 46,48% of patients who did not receive this treatment were women(P > 0.05).The proportion of ulcerative colitis patients treated with thiopurines was 30.3% compare to 66.67% of patients not treated(P < 0.001).Mean azathioprine dose was 123.79 ± 36.5 mg/d(range:50-250 mg/d),mean usage time was 72.16 ± 55.7 mo(range:1-300 mo)and the accumulated dose along this time was 274.32 ± 233.5 g(1.5-1350 g).With respect to mercaptopurine,mean dose was 74.7 ± 23.9 mg/d(range:25-150 mg/d),mean usage time of 23.37 ± 27.6 mo(range:1-118 mo),and the accumulated dose along this time was 52.2 ± 63.5 g(range:1.5-243 g).Thiopurine S-methyltransferase activity was tested in 66% of patients treated with thiopurines,among which 98.2% had an intermediate or high activity.Among the patients treated with thiopurines,27.27%(112 patients)and 11.66%(50 patients)received treatment with Infliximab and Adalimumab respectively,but only 1.83%(7 patients)and 0.78%(3 patients)received these drugs in the group of patients who did not received thiopurines(P < 0.001 and P < 0.001 respectively).Finally,6.8%(29 patients)among those treated with thiopurines have received other immunesupresants(Methotrexate,Tacrolimus,Cyclosporin),compare to 1%(4 patients)of patients not treated with thiopurines(P < 0.001).Among patients treated with thiopurines,3.97% developed a malignancy,and among those not treated neoplasms presented in 8.1%(P = 0.013).The most frequent neoplasms were colorectal ones(12 cases in patients not treated with thiopurines but none in treated,P < 0.001)followed by non-melanoma skin cancer(8 patients in treated with thiopurines and 6 in not treated,P > 0.05).CONCLUSION:In our experience,thiopurine therapy did not increase malignancies development in IBD patients,and was an efective and safe treatment for these diseases.展开更多
To identify which blood and mucosal lymphocyte populations are specifically depleted by thiopurine use in vivo.METHODSThe thiopurines azathioprine and 6-mercaptopurine have been a mainstay of inflammatory bowel diseas...To identify which blood and mucosal lymphocyte populations are specifically depleted by thiopurine use in vivo.METHODSThe thiopurines azathioprine and 6-mercaptopurine have been a mainstay of inflammatory bowel disease (IBD) therapy for decades, but their mechanism of action in vivo remains obscure. Although thiopurines are lymphotoxic at high doses, and have been reported to cause T cell apoptosis in vitro, their ability to control IBD at lower doses suggests that they may selectively deplete particular lymphocyte populations. Blood cells from 19 IBD patients on a thiopurine, 19 IBD patients not on a thiopurine, and 38 matched healthy control subjects were analyzed by multiple multi-color flow cytometry panels to quantify the immune cell subsets contained therein, both as a percent of cells, and as an absolute cell count. Similar analyses were performed on colon biopsies from 17 IBD patients on a thiopurine, 17 IBD patients not on a thiopurine, and 49 healthy screening colonoscopy recipients.RESULTSComplete blood counts revealed lower lymphocyte, but not monocyte or granulocyte, counts in IBD patients who were taking thiopurines at the time of sampling. This reduction was restricted to CD3-negative lymphocytes, wherein both natural killer (NK) and B cells were significantly reduced among thiopurine recipients. Among CD19+ B cells, the transitional B cells were particularly depleted, being nearly absent in both blood and colon biopsies of thiopurine recipients. No differences were associated with thiopurine use in CD8+ T cells, mucosa-associated invariant T (MAIT) cells, invariant natural killer T (iNKT) cells, gamma/delta T cells, Th1, Th17, regulatory T cells (Tregs) or naïve CD4+ T cells. However, patients with IBD had significantly more circulating FOXP3+, Helios+ Tregs and fewer iNKT and MAIT cells than healthy controls.CONCLUSIONThiopurine use is associated with reduced B and NK cell, but not T cell, subpopulations in the blood of IBD patients.展开更多
Thiopurines are essential drugs to maintain remission in patients with inflammatory bowel disease(IBD).Thiopurines used in IBD are azathioprine(2.0-2.5 mg/kg),mercaptopurine(1.0-1.5 mg/kg) and thioguanine(0.2-0.3 mg/k...Thiopurines are essential drugs to maintain remission in patients with inflammatory bowel disease(IBD).Thiopurines used in IBD are azathioprine(2.0-2.5 mg/kg),mercaptopurine(1.0-1.5 mg/kg) and thioguanine(0.2-0.3 mg/kg).However,mainly due to numerous adverse events associated with thiopurine use,almost 50% of the patients have to discontinue conventional thiopurine treatment.Extensive monitoring and the application of several treatment strategies,such as split-dose administration,co-administration with allopurinol or dose reduction/increase,may increase the chance of successful therapy.With this review,we provide practical information on how thiopurines are initiated and maintained in two thiopurine research centers in The Netherlands.We provide clinical information concerning safety issues,indications and management of therapy that may serve as a guide for the administration of thiopurines in IBD patients in daily practice.展开更多
A series of novel mono- and di-terpyridine derivatives with purinyl and pyrimidyl group were obtained from the reaction of 4′-p- bromomethylphenyl-2,2′：6,2″-terpyridine with 6-mercaptopurine, 2,6-dimercaptopurine ...A series of novel mono- and di-terpyridine derivatives with purinyl and pyrimidyl group were obtained from the reaction of 4′-p- bromomethylphenyl-2,2′：6,2″-terpyridine with 6-mercaptopurine, 2,6-dimercaptopurine and thymine, respectively. The active hydrogens on these alkaloids could be abstracted stepwise using different bases, which made the addition controllable.展开更多
Inflammatory bowel disease(IBD)is known to increase the risk of venous thromboembolism.Cerebral venous sinus thrombosis(CVST)is a rare but important complication of IBD.Timely diagnosis,particularly in younger patient...Inflammatory bowel disease(IBD)is known to increase the risk of venous thromboembolism.Cerebral venous sinus thrombosis(CVST)is a rare but important complication of IBD.Timely diagnosis,particularly in younger patients,requires a high level of suspicion in order to prevent potentially devastating complications such as hemorrhage or venous infarction.The paper presents a 44-year-old Caucasian woman with a previous history of Crohn’s disease and deep venous thrombosis.Magnetic resonance imaging confirmed the diagnosis of CVST.Achieving therapeutic anticoagulation with warfarin was difficult,due to presumed pharmacological interaction between warfarin and 6-mercaptopurine.Clinicians should have a high index of suspicion for CVST when a patient with Crohn’s disease presents with acute headache,and be aware of challenges related to medical management.展开更多
基金Funded by the Natural Science Foundation of Hubei Province(No.2011CDA056)the International Cooperation Funding of Hubei Province(No.2012IHA0120)+1 种基金the Fundamental Research Funds for the Central Universities of China(2012-IV-029)the Undergraduate innovation Funding of Wuhan University of Technology(136620004)
文摘Magnetic Fe304 nanoparticles were synthesized by co-precipitation method and the mercaptopurine （MER） drug-loaded magnetic microspheres were obtained through emulsion cross-linking methods. The efficiency of this approach was evaluated in terms of drug loading content （DLC）, encapsulation efficiency （EE） and delivery properties in vitro, determined by high performance liquid chromatograph （HPLC）. The microspheres showed good DLC values of 11.8%, as well as good EE values of 79.4%. The in vitro drug release study was carried out in phosphate buffer solution （PBS） simulated body fluid, at 37 ~C with pH=7.4. The release profiles showed an initial fast release rate, which decreased as time progressed and about 84 % had been released after 48 h. The experimental results indicated that the prepared magnetic microspheres may be useful for potential applications of MER for magnetically targeted chemotherapy.
文摘A new chemically modified electrode(CME) immobilized on the surface of multi-wall carbon nanotubes functionalized with carboxylic groups was fabricated. The results indicate that the CME exhibits efficiently electrocatalytic oxidation of 6-mercaptopurine(6-MP). The CME can be used as the working electrode in the liquid chromatography for the determination of 6-MP. The peak current of 6-MP is linearly changed with its concentration ranging from 4.0×10 -7 to 1.0×10 -4 mol/L with the calculated detection limit (S/N=3) of 2.0×10 -7 mol/L. Coupled with microdialysis sampling, the method has been successfully applied to assessing the content of 6-MP in rat blood.
文摘In pH 4.8 Britton-Robinson (B-R) buffer solution, Mercaptopurine (MP) could react with Cu(II) to form stable chelate compound, a new Resonance Rayleigh scattering (RRS) spectrum generated and enhanced for the binary system which the highest peak located at 453 nm as detection wavelength. But the RRS spectra could be quenched after adding her- ring milt DNA (hsDNA), salmon milt DNA (sDNA) and calf thymus DNA (ctDNA) into the binary system, respect- tively. And the weakened degree of spectra was directly proportional to the concentration of DNA. The reaction product of three nucleic acid system have identical spectral features, their range of linearity for the relation of spectral intensity with concentration respectively are 0.05 - 0.9 μg.mL-1 for hsDNA, 0.1 - 0.9 μg.mL-1 for sDNA and 0.3 - 0.9 μg.mL-1 for ctDNA;their detection limit respectively are 5 ng.mL-1for hsDNA, 6 ng.mL-1for sDNA, 6 ng?mL-1 for ctDNA. So a new method for determination of DNA was developed and successfully applied to determine the content of the DNA in artificial synthetized samples. At the same time the spectral features of absorption spectra and RRS spectra of the three reaction system, and the eligible reaction conditions and influencing factors were investigated in this paper.
文摘Misconceptions are common in the care of patients with inflammatory bowel disease(IBD).In this paper,we state the most commonly found misconceptions in clinical practice and deal with the use of 5-aminosalicylates and thiopurines,to review the related scientificevidence,and make appropriate recommendations.Prevention of errors needs knowledge to avoid making such errors through ignorance.However,the amount of knowledge is increasing so quickly that one new danger is an overabundance of information.IBD is a model of a very complex disease and our goal with this review is to summarize the key evidence for the most common daily clinical problems.With regard to the use of 5-aminosalicylates,the best practice may to be consider abandoning the use of these drugs in patients withsmall bowel Crohn's disease.The combined approach with oral plus topical 5-aminosalicylates should be the first-line therapy in patients with active ulcerative colitis;once-daily treatment should be offered as a first choice regimen due to its better compliance and higher efficacy.With regard to thiopurines,they seem to be as effective in ulcerative colitis as in Crohn's disease.Underdosing of thiopurines is a form of undertreatment.Thiopurines should probably be continued indefinitely because their withdrawal is associated with a high risk of relapse.Mercaptopurine is a safe alternative in patients with digestive intolerance or hepatotoxicity due to azathioprine.Finally,thiopurine methyltransferase(TPMT)screening cannot substitute for regular monitoring because the majority of cases of myelotoxicity are not TPMT-related.
文摘Although a great variety of new drugs have been introduced for the therapy of inflammatory bowel diseases so far,a definite cure of the disease is still out of scope.An anti-inflammatory approach to induce remission followed by maintenance therapy with immunosupressants is still the mainstay of therapy.Thiopurines comprising azathioprine and its active metabolite mercaptopurine as well as tioguanine,are widely used in the therapy of chronic active inflammatory bowel disease(IBD).Their steroid sparing potential and efficacy in remission maintenance are out of doubt.Unfortunately,untoward adverse events are frequently observed and may preclude further administration or be life threatening.This review will focus on new aspects of thiopurine therapy in IBD,its efficacy and safety.
文摘The use of thiopurines in inflammatory bowel disease(IBD) has been examined in numerous prospective, controlled trials, with a majority demonstrating a clinical benefit. We conducted this review to describe the historical and current evidence in the use of thiopurines in IBD. A systematic search was performed on MEDLINE between 1965 and 2016 to identify studies on thiopurines in IBD. The most robust evidence for thiopurines in IBD includes induction of remission in combination with anti-tumor necrosis factor(antiTNF) agents, and maintenance of remission and postoperative maintenance in Crohn's disease. Less evidence exists for thiopurine monotherapy in induction of remission, maintenance of ulcerative colitis, chemoprevention of colorectal cancer, and in preventing immunogenicity to anti-TNF. Evidence was often limited by trial design. Overall, thiopurines have demonstrated efficacy in a broad range of presentations of IBD. With more efficacious novel therapeutic agents, the positioning of thiopurines in the management of IBD will change and future studies will analyze the benefit of thiopurines alone and in conjunction with these new medications.
文摘Thiopurines are widely used for maintenance treatment of inflammatory bowel disease. Interindividual variability in clinical response to thiopurines may be attributed to several factors including genetic polymorphisms, severity and chronicity of disease, comorbidities, duration of administration, compliance issues and use of concomitant medication, environmental factors and clinician and patient preferences. The purpose of this review is to summarise the current evidence on thiopurine safety and toxicity, to describe adverse drug events and emphasise the significance of drug interactions, and to discuss the relative safety of thiopurine use in adults, elderly patients, children and pregnant women. Thiopurines are safe to use and well tolerated, however dose adjustment or discontinuation of treatment must be considered in cases of non-response, poor compliance or toxicity. Drug safety, clinical response to treatment and short to long term risks and benefits must be balanced throughout treatment duration for different categories of patients. Treatment should be individualised and stratified according to patient requirements. Enzymatic testing prior to treatment commencement is advised. Surveillance with regular clinic follow-up and monitoring of laboratory markers is important. Data on long term efficacy, safety of thiopurine use and interaction with other disease modifying drugs are lacking, especially in paediatric inflammatory bowel disease. High quality, collaborative clinical research is required so as to inform clinical practice in the future.
基金the Alberta Inflammatory Bowel Disease Consortium and the Alberta Innovates Health Solutions for funding support for this project
文摘AIM: To determine the incidence and predictors of thiopurine-related adverse events. METHODS: Subjects with Crohn's disease who were followed in the Alberta Inflammatory Bowel Disease Consortium patient database registry were identified. Retrospective chart review was conducted between August 5th, 2010 and June 1st, 2012. We collected data on: age at diagnosis; sex; disease location and behaviour at time of prescribing thiopurine; perianal fistulising disease at or prior to thiopurine prescription; smoking status at time of thiopurine prescription, use of corticosteroid within 6 mo of diagnosis; dosage, age at onset, and cessation of 5-aminosalicyclic acid(5-ASA); anti-tumour necrosis factor medication exposure and intestinal resection before thiopurine prescription. The primary outcome of interest was the first adverse event that led to discontinuation of the first thiopurine medication used. Logistic regression models were used to associate clinical characteristics with outcomes after adjusting for potential confounders. Risk estimates were presented as odds ratios(OR) with 95% CI. Effect modification by age and sex were explored.RESULTS: Our cohort had a median follow-up duration of 5.8 years [interquartile range(IQR 25th-75th) 2.7-9.1]. Thiopurine therapy was discontinued in 31.3% of patients because of: hypersensitivity reactions(7.1%), acute pancreatitis(6.2%), gastrointestinal intolerance(5.4%), leucopenia(3.7%), hepatotoxicity(3.4%), infection(1.1%) and other reasons(4.3%). A higher incidence of thiopurine withdrawal was observed in patients over the age of 40(39.4%, P = 0.007). A sexby-age interaction(P = 0.04) was observed. Females older than 40 years of age had an increased risk of thiopurine discontinuation due to an adverse event(age above 40 vs age below 40, adjusted OR = 2.8; 95%CI: 1.4-5.6). In contrast, age did not influence thiopurine withdrawal in males(age above 40 vs below 40, adjusted OR = 0.9; 95%CI: 0.4-2.1). Other clinical variables(disease location and phenotype, perianal disease, smoking history, history of intestinal resection and prior 5-ASA or corticosteroid use) were not associated with an increased risk an adverse event leading to therapy cessation. CONCLUSION: Thiopurine withdrawal due to adverse events is commoner in women over the age of 40 at prescription. These findings need to be replicated in other cohorts.
文摘AIM:To investigate the incidence of neoplasms in inflammatory bowel disease(IBD)patients and the potential causative role of thiopurines.METHODS:We performed an observational descriptive study comparing the incidence of malignancies in IBD patients treated with thiopurines and patients not treated with these drugs.We included 812 patients which were divided in two groups depending on whether they have received thiopurines or not.We have studied basal characteristics of both groups(age when the disease was diagnosed,sex,type of IBD,etc.)and treatments received(Azathioprine,mercaptopurine,infliximab,adalimumab or other immunomodulators),as well as neoplasms incidence.Univariate analysis was performed with the student t test,χ 2 test or Wilcoxon exact test as appropriate.A logistic regression analysis was performed as multivariate analysis.Statistical significance was establish at P values of less than 0.05,and 95%CI were used for the odds ratios.RESULTS:Among 812 patients included,429(52.83%)have received thiopurines:79.5% azathioprine,14% mercaptopurine and 6.5% both drugs.44.76% of patients treated with thiopurines and 46,48% of patients who did not receive this treatment were women(P > 0.05).The proportion of ulcerative colitis patients treated with thiopurines was 30.3% compare to 66.67% of patients not treated(P < 0.001).Mean azathioprine dose was 123.79 ± 36.5 mg/d(range:50-250 mg/d),mean usage time was 72.16 ± 55.7 mo(range:1-300 mo)and the accumulated dose along this time was 274.32 ± 233.5 g(1.5-1350 g).With respect to mercaptopurine,mean dose was 74.7 ± 23.9 mg/d(range:25-150 mg/d),mean usage time of 23.37 ± 27.6 mo(range:1-118 mo),and the accumulated dose along this time was 52.2 ± 63.5 g(range:1.5-243 g).Thiopurine S-methyltransferase activity was tested in 66% of patients treated with thiopurines,among which 98.2% had an intermediate or high activity.Among the patients treated with thiopurines,27.27%(112 patients)and 11.66%(50 patients)received treatment with Infliximab and Adalimumab respectively,but only 1.83%(7 patients)and 0.78%(3 patients)received these drugs in the group of patients who did not received thiopurines(P < 0.001 and P < 0.001 respectively).Finally,6.8%(29 patients)among those treated with thiopurines have received other immunesupresants(Methotrexate,Tacrolimus,Cyclosporin),compare to 1%(4 patients)of patients not treated with thiopurines(P < 0.001).Among patients treated with thiopurines,3.97% developed a malignancy,and among those not treated neoplasms presented in 8.1%(P = 0.013).The most frequent neoplasms were colorectal ones(12 cases in patients not treated with thiopurines but none in treated,P < 0.001)followed by non-melanoma skin cancer(8 patients in treated with thiopurines and 6 in not treated,P > 0.05).CONCLUSION:In our experience,thiopurine therapy did not increase malignancies development in IBD patients,and was an efective and safe treatment for these diseases.
基金Supported by Virginia Mason Medical Center,Digestive Disease Institute Research Grant Award,No.0506812-2011
文摘To identify which blood and mucosal lymphocyte populations are specifically depleted by thiopurine use in vivo.METHODSThe thiopurines azathioprine and 6-mercaptopurine have been a mainstay of inflammatory bowel disease (IBD) therapy for decades, but their mechanism of action in vivo remains obscure. Although thiopurines are lymphotoxic at high doses, and have been reported to cause T cell apoptosis in vitro, their ability to control IBD at lower doses suggests that they may selectively deplete particular lymphocyte populations. Blood cells from 19 IBD patients on a thiopurine, 19 IBD patients not on a thiopurine, and 38 matched healthy control subjects were analyzed by multiple multi-color flow cytometry panels to quantify the immune cell subsets contained therein, both as a percent of cells, and as an absolute cell count. Similar analyses were performed on colon biopsies from 17 IBD patients on a thiopurine, 17 IBD patients not on a thiopurine, and 49 healthy screening colonoscopy recipients.RESULTSComplete blood counts revealed lower lymphocyte, but not monocyte or granulocyte, counts in IBD patients who were taking thiopurines at the time of sampling. This reduction was restricted to CD3-negative lymphocytes, wherein both natural killer (NK) and B cells were significantly reduced among thiopurine recipients. Among CD19+ B cells, the transitional B cells were particularly depleted, being nearly absent in both blood and colon biopsies of thiopurine recipients. No differences were associated with thiopurine use in CD8+ T cells, mucosa-associated invariant T (MAIT) cells, invariant natural killer T (iNKT) cells, gamma/delta T cells, Th1, Th17, regulatory T cells (Tregs) or naïve CD4+ T cells. However, patients with IBD had significantly more circulating FOXP3+, Helios+ Tregs and fewer iNKT and MAIT cells than healthy controls.CONCLUSIONThiopurine use is associated with reduced B and NK cell, but not T cell, subpopulations in the blood of IBD patients.
文摘Thiopurines are essential drugs to maintain remission in patients with inflammatory bowel disease(IBD).Thiopurines used in IBD are azathioprine(2.0-2.5 mg/kg),mercaptopurine(1.0-1.5 mg/kg) and thioguanine(0.2-0.3 mg/kg).However,mainly due to numerous adverse events associated with thiopurine use,almost 50% of the patients have to discontinue conventional thiopurine treatment.Extensive monitoring and the application of several treatment strategies,such as split-dose administration,co-administration with allopurinol or dose reduction/increase,may increase the chance of successful therapy.With this review,we provide practical information on how thiopurines are initiated and maintained in two thiopurine research centers in The Netherlands.We provide clinical information concerning safety issues,indications and management of therapy that may serve as a guide for the administration of thiopurines in IBD patients in daily practice.
基金the Natural Science Foundation for colleges and University in Jiangsu province (No.07KJD320013)the Natural Science Foundation of Huaihai Institute of Technologe(Nos.Z2006006,Z2007043)for financial support.
文摘A series of novel mono- and di-terpyridine derivatives with purinyl and pyrimidyl group were obtained from the reaction of 4′-p- bromomethylphenyl-2,2′：6,2″-terpyridine with 6-mercaptopurine, 2,6-dimercaptopurine and thymine, respectively. The active hydrogens on these alkaloids could be abstracted stepwise using different bases, which made the addition controllable.
基金The authors would like to thank Thinesh Sivapatham,MD and Michael T.Madison,MD of Saint Paul Radiology for reviewing the images enclosed in this manuscript.
文摘Inflammatory bowel disease(IBD)is known to increase the risk of venous thromboembolism.Cerebral venous sinus thrombosis(CVST)is a rare but important complication of IBD.Timely diagnosis,particularly in younger patients,requires a high level of suspicion in order to prevent potentially devastating complications such as hemorrhage or venous infarction.The paper presents a 44-year-old Caucasian woman with a previous history of Crohn’s disease and deep venous thrombosis.Magnetic resonance imaging confirmed the diagnosis of CVST.Achieving therapeutic anticoagulation with warfarin was difficult,due to presumed pharmacological interaction between warfarin and 6-mercaptopurine.Clinicians should have a high index of suspicion for CVST when a patient with Crohn’s disease presents with acute headache,and be aware of challenges related to medical management.
