The thiopurine drugs,6-mercaptopurine(6-MP) and azathioprine,are efficacious in the arsenal of inflammatory bowel disease(IBD) therapy.Previous reports indicate that 6-thioguanine nucleotide(6-TGN) levels correlate wi...The thiopurine drugs,6-mercaptopurine(6-MP) and azathioprine,are efficacious in the arsenal of inflammatory bowel disease(IBD) therapy.Previous reports indicate that 6-thioguanine nucleotide(6-TGN) levels correlate with therapeutic efficacy,whereas high 6-methylmercaptopurine(6-MMP) levels are associated with hepatotoxicity and myelotoxicity.Due to their complex metabolism,there is wide individual variation in patient response therein,both in achieving therapeutic drug levels as well as in developing adverse reactions.Several strategies to optimize 6-TGN while minimizing 6-MMP levels have been adopted to administer the thiopurine class of drugs to patients who otherwise would not tolerate these drugs due to side-effects.In this report,we will review different approaches to administer the thiopurine medications,including the administration of 6-mercaptopurine in those unsuccessfully treated with azathioprine;coadministration of thiopurine with allopurinol;co-administration of thiopurine with anti-tumor necrosis factor α;6-TGN administration;desensitization trials;and split dosing of 6-MP.展开更多
AIM: To determine the tolerability and safety profile of a low-dose maintenance therapy with 6-TG in azathioprine (AZA) or 6-mercaptopurine (6-MP) intolerant inflammatory bowel disease (IBD) patients over a treatment ...AIM: To determine the tolerability and safety profile of a low-dose maintenance therapy with 6-TG in azathioprine (AZA) or 6-mercaptopurine (6-MP) intolerant inflammatory bowel disease (IBD) patients over a treatment period of at least 1 year.METHODS: Database analysis.RESULTS: Twenty out of ninety-five (21%) patients discontinued 6-TG (mean dose 24.6 mg; mean 6-TGN level 540 pmol/8×108 RBC) within 1 year. Reasons for discontinuation were GI complaints (31%), malaise (15%)and hepatotoxicity (15%). Hematological events occurred in three patients, one discontinued treatment. In the 6-TG-tolerant group, 9% (7/75) could be classified as hepatotoxicity. An abdominal ultrasound was performed in 54% of patients, one patient had splenomegaly.CONCLUSION: The majority of AZA or 6-MP-intolerant IBD patients (79%) is able to tolerate maintenance treatment with 6-TG (dosages between 0.3 and 0.4 mg/kg per d). 6-TG may still be considered as an escape maintenance immunosuppressant in this difficult to treat group of patients, taking into account potential toxicity and efficacy of other alternatives. The recently reported hepatotoxicity is worrisome and 6-TG should therefore be administered only in prospective trials.展开更多
AIM:To investigate the efficacy of 6-mercaptopurine (6-MP) in cases of azathioprine (AZA) hypersensitivity in patients with inflammatory bowel disease. METHODS: Twenty nine previously confirmed Crohn’s disease (CD) (...AIM:To investigate the efficacy of 6-mercaptopurine (6-MP) in cases of azathioprine (AZA) hypersensitivity in patients with inflammatory bowel disease. METHODS: Twenty nine previously confirmed Crohn’s disease (CD) (n = 14) and ulcerative colitis (UC) (n = 15) patients with a known previous (AZA) hypersensitivity reaction were studied prospectively. The 6-MP doses were gradually increased from 0.5 up to 1.0-1.5 mg/kg per day. Clinical activity indicies (CDAI/CAI), laboratory variables and daily doses of oral 5-ASA, corticosteroids, and 6-MP were assessed before and in the first, sixth and twelfth months of treatment. RESULTS: In 9 patients, 6-MP was withdrawn in the first 2 wk due to an early hypersensitivity reaction. Medication was ineffective within 6 mo in 6 CD patients, and myelotoxic reaction was observed in two. Data were evaluated at the end of the sixth month in 12 (8 UC, 4 CD) patients, and after the first year in 9 (6 UC, 3 CD) patients. CDAI decreased transiently at the end of the sixth month, but no significant changes were observed in the CDAI or the CAI values at the end of the year. Leukocyte counts (P = 0.01), CRP (P = 0.02), and serum iron (P = 0.05) values indicated decreased inflammatory reactions, especially in the UC patients at the end of the year, making the possibility to taper oral steroid doses. CONCLUSION: About one-third of the previously AZA- intolerant patients showed adverse effects on taking 6MP. In our series, 20 patients tolerated 6MP, but it was ineffective in 8 CD cases, and valuable mainly in ulcerative colitis patients.展开更多
Arbitrarily, modern day treatment of inflammatory bowel disease begins with the introduction of immuno- suppressives for ulcerative colitis. Clinical improvement with sulfasalazine had been meaningful but modest. Trea...Arbitrarily, modern day treatment of inflammatory bowel disease begins with the introduction of immuno- suppressives for ulcerative colitis. Clinical improvement with sulfasalazine had been meaningful but modest. Treatment with adrenocorticotropic hormone and corti- costeroids led to clinical responses never before realized but it took much too long to recognize that they were not capable of maintaining remission, that adverse reactions were subtle but potentially devastating and that some other agent would be necessary to capitalize on their transient advantage. This of course was true in the treatment of Crohn's disease as well. Not much was ever made of the role of sulfasalazine for Crohn' s disease, but with the severing of the diazobond and the elimination of the sulphur component, the 5-ami- nosalacylic acid (5-ASA) products clearly led to clinical improvement, especially in cases of Crohn's colitis and those with ileitis where the 5-ASA product was released in the terminal ileum and more proximal in the small bowel as well as in ulcerative colitis. The induction of remission was first demonstrated by 6-mercaptopurine (6-MP) with case reports and uncontrolled trials in pa- tients with ulcerative colitis, but its placebo controlled trial for Crohn's disease firmly established its role in inducing remission. No subsequent trial has confirmed its similar role for ulcerative colitis, but nevertheless cli- nicians know well that 6-MP works at least as well and probably more effectively for ulcerative colitis than for Crohn's disease. What changes have taken place utiliz- ing 6-MP in the management of inflammatory bowel disease since its introduction in the 1960's and 1970's and its trial for Crohn's disease published in the New England Journal of Medicine in 1980?展开更多
The development of a simple and accurate quantitative method for the determination of 6-mercaptopurine (6-MP) is of great importance because of its serious side effects. Ratiometric fluorescence (RF) sensors are not s...The development of a simple and accurate quantitative method for the determination of 6-mercaptopurine (6-MP) is of great importance because of its serious side effects. Ratiometric fluorescence (RF) sensors are not subject to interference from environmental factors, and exhibit enhanced precision and accuracy. Therefore, a novel RF sensor for the selective detection of 6-MP was developed. The present work reports a sensitive and selective RF sensor for the detection of 6-mercaptopurine, by hybridizing carbon nanodots (CDots) and gold nanoclusters (AuNCs) capped with bovine serum albumin (BSA). The CDots serve as the reference signal and the AuNCs as the reporter. On addition of the 6-MP, AuNCs formed aggregates, because the existing cross-links within the AuNCs and BSA structure were broken in favour of the Au-S bonds, which can enhance the fluorescence of AuNCs, while the fluorescence of CDots is stable against 6-MP, leading to distinct ratiometric fluorescence changes when exposed to 6-MP. 6-MP could be detected in the range of 0 - 30.22 μM with a detection limit of 54 nM. The developed sensor was applied for the determination of 6-MP in human serum samples and satisfactory results were obtained.展开更多
<abstract>Aim: To describe the reproductive outcome following intracytoplasmic sperm injection (ICSI) for male factor infertility associated with Crohn's disease and 6-mercap-topurine (6-MP) chemotherapy. Me...<abstract>Aim: To describe the reproductive outcome following intracytoplasmic sperm injection (ICSI) for male factor infertility associated with Crohn's disease and 6-mercap-topurine (6-MP) chemotherapy. Methods: The male partner of a couple suffered from severe Crohn's disease and received a 3-month course of 6-MP for this condition. Two spontaneous conceptions were established before 6-MP, although post-chemotherapy semen analysis found the sperm concentration to be 8,000/mL. In vitro fertilization (IVF) with ICSI and embryo transfer was performed. Results: The woman underwent an uncomplicated controlled ovarian hyperstimulation sequence using a combined rec-FSH+hMG protocol, following late luteal phase pituitary downregulation. This culminated in the retrieval of 18 oocytes, 11 of which were fertilized with ICSI. She later delivered a normal male infant without urogenital anomaly. Four nontransferred blastocysts were cryopreserved. Conclusion: This report describes the first successful birth after ICSI for severe oligozoospermia associated with Crohn's disease and 6-MP therapy. We outline salient features of Crohn's disease, 6-MP pharmacology, and their relevance to human fertility.展开更多
The Ag clusters have been investigated widely theoretically and experimentally. In particular, it has recently shown that the neutral Ag8 clusters embedded in an argon matrix have a strong fluorescence signal. As we c...The Ag clusters have been investigated widely theoretically and experimentally. In particular, it has recently shown that the neutral Ag8 clusters embedded in an argon matrix have a strong fluorescence signal. As we can know, the metal clusters may have important effects on the structures and properties of biomolecules. More and more attention is paid to the interaction between nanomaterials and biomolecules. In this work, the B3LYP method in density functional theory was used on the complexes between the 6-mercaptopurine（6MP） and Ag8 clusters combined with 6-311＋＋G＊＊ as well as LANL2DZ base sets. The geometries of all the complexes were optimized with full degree of freedom and the structures, chemical bonds, orbital properties as well as Mulliken charges for ten possible complexes were analyzed based on the same theory level. In addition, the influence of temperature and pressure on the stabilities of the four complexes was further explored using standard statistical thermodynamic methods ranging from 50 to 500 K and at 100 kPa or 100 bar. The results show that the complex Ag8-6 MP-7-5 can be the most stable one among the investigated complexes, in which the Ag（11） atom interacts with the S（10） atom forming the strong chemical bond. The Mulliken charges also show that the Ag–S chemical bond is formed and the related charge has transferred. Additionally, the temperature and pressure can significantly influence the stability of the four stable complexes.展开更多
The Polarographic and voltammetric behavior of 6-mercaptopurine were studied by several electrochemical techniques There are two reduction peaks in HAC buffer solution at PH 4.0. The characteriatics of the second Pea...The Polarographic and voltammetric behavior of 6-mercaptopurine were studied by several electrochemical techniques There are two reduction peaks in HAC buffer solution at PH 4.0. The characteriatics of the second Peak(P2) were studied in detail. The relationship between P: current(ip2 and concentration of 6-mercaptopurine is linear in the range of lx10-7-lx10 mol/L It has beeb applied to quantitative analysis of an anticancer tablet with satisfying results.The mechaniam,of the electrode reaction was proposed alao.展开更多
An inclusion-interaction assembly strategy was used to construct novel pH/redox responsive core-shell micelles with hydrophobic drug as the core and hydrophilic polymer as the shell. At first, a dimer of hydrophobic d...An inclusion-interaction assembly strategy was used to construct novel pH/redox responsive core-shell micelles with hydrophobic drug as the core and hydrophilic polymer as the shell. At first, a dimer of hydrophobic drug 6-mercaptopurine and a hydrophilic β-CD grafted carboxymethyl chitosan were synthesized. Then, a novel amphiphilic inclusion complex was prepared with the dimer being partially embedded into the cavity of β-CD moiety. It self-assembled into pH/redox responsive core-shell micelles in distilled water. TEM confirmed that the micelles possessed a spherical core-shell configuration with a mean size of about 160 nm. DLS showed that the micelles were stable in aqueous solution. Their particle diameters altered with pH values as well as glutathione (GSH) concentrations and respectively attained a maximum value at pH 6.0 and 20 mM GSH. Release profiles of 6-mercaptopurine showed a low release rate (about 27 wt% after 48 h) in pH 7.4 medium with 10 μM GSH, and a marked increase (over 88 wt% after 48 h) in pH 5.0 medium with 20 mM GSH. In vitro cytotoxicity test showed that the micelles had a dose-dependent toxicity for HeLa cells, indicating a great potential for controlled release of 6-mercaptopurine in tumor cells.展开更多
Malaria is a disease that has drawn worldwide attention due to the alarming rise of mortality rates particularly in third world countries. During the Plasmodium parasite intraerythrocytic life cycle, metabolic process...Malaria is a disease that has drawn worldwide attention due to the alarming rise of mortality rates particularly in third world countries. During the Plasmodium parasite intraerythrocytic life cycle, metabolic processes include the formation of hemozoin or malaria pigment. This pigment functions in the prevention of oxygen radical-mediated damage to the parasite. Drugs targeting hemozoin formation such as chloroquine and amodaquine are effective and are still used, but recently Plasmodium parasites have become resistant to these drugs, especially against chloroquine. In this study we looked at the potential use of two heterocyclic pyrimidine derivatives as anti-malaria drugs; 2,4-Diamino-6-Mercaptopyrimidine （DAMP） and 2-Mercaptopyrimidine （2-MP）. These compounds bear various coordination sites that enable them to react with metal ions to form coordination compounds. We used two methods for testing the inhibition of ferriprotoporphyrin IX （FP） biomineralisation： semi-quantitative microassay used by Deharo, and a quantitative assay used by G. Blaner and M. Akkawi. We report here the finding that （DAMP） has an in vitro inhibitory effect on I%hematin formation at concentrations and magnitude of nearly similar order to that of chloroquine, 2-MP was found to be effective but to a lower degree than DAMP.展开更多
Many anticancer drugs have limited clinical applications owing to their unsatisfactory therapeutic efficacy or side effects.This situation can be improved by drug delivery systems or drug modification strategies.Herei...Many anticancer drugs have limited clinical applications owing to their unsatisfactory therapeutic efficacy or side effects.This situation can be improved by drug delivery systems or drug modification strategies.Herein,to improve the therapeutic efficacy and safety of the traditional anticancer drug 6-mercaptopurine(6-MP),we dimerized 6-MP to form a disulfide bond-containing drug dimer and prepared a cysteine-based poly(disulfide amide)with redox-responsive capability as a drug carrier.Briefly,dimeric 6-MP(DMP)was synthesized via the oxidization of iodine and self-assembled with the poly(disulfide amide)to form dual redox-responsive DMP-loaded NPs(DMP-NPs).The 6-MP itself could hardly be loaded into nanoparticles(NPs)owing to its hydrophobicity,while the DMP-NPs showed a higher drug loading capacity over 6-MP,small particle size,and favorable stability.With abundant disulfide bonds in polymer backbones and drug payloads,DMP-NPs could rapidly respond to high levels of glutathione(GSH)and release drugs in a controllable manner.More importantly,both cellular and animal experiments demonstrated the enhanced anticancer efficacy of DMP-NPs against lymphoma and their high safety.Overall,this drug dimer-loaded dual redox-responsive drug delivery system provides new options for improving the applications of traditional drugs and developing drug delivery systems with enhanced drug effects and high safety.展开更多
BACKGROUND Despite the advent of biological drugs, conventional therapy continues to be used in moderate to severe inflammatory bowel disease(MS-IBD). This study hypothesized that as a standard of treatment and the pr...BACKGROUND Despite the advent of biological drugs, conventional therapy continues to be used in moderate to severe inflammatory bowel disease(MS-IBD). This study hypothesized that as a standard of treatment and the primary alternative to biologics, conventional therapy should present robust effectiveness results in IBD outcomes.AIM To investigate the effectiveness of conventional therapy for MS-IBD.METHODS A systematic review with no time limit was conducted in July 2017 through the Cochrane Collaboration, MEDLINE, and LILACS databases. The inclusion criteria encompassed meta-analyses, systematic reviews, randomized clinical trials, observational and case-control studies concerning conventional therapy in adult patients with MS-IBD, including Crohn's disease(CD) and ulcerative colitis(UC). Corticosteroids(prednisone, hydrocortisone, budesonide, prednisolone,dexamethasone), 5-aminosalicylic acid(5-ASA) derivatives(mesalazine and sulfasalazine) and immunosuppressants [azathioprine(AZA), methotrexate(MTX), mycophenolate, cyclosporine, tacrolimus, 6-mercaptopurine(6-MP)] were considered conventional therapy. The exclusion criteria were sample size below50; narrative reviews; specific subpopulations(e.g., pregnant women,comorbidities); studies on postoperative IBD; and languages other than English,Spanish, French or Portuguese. The primary outcome measures were clinical remission(induction or maintenance), clinical response and mucosal healing. As secondary outcomes, fecal calprotectin, hospitalization, death, and surgeries were analyzed. The quality of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation criteria.RESULTS The search strategy identified 1995 citations, of which 27 were considered eligible(7 meta-analyses, 20 individual studies). For induction of clinical remission, four meta-analyses were selected(AZA and 6-MP showed no advantage over placebo,MTX or 5-ASA in CD; MTX showed no statistically significant difference versus placebo, 6-MP, or 5-ASA in UC; tacrolimus was superior to placebo for UC in two meta-analyses). Only one meta-analysis evaluated clinical remission maintenance, showing no statistically significant difference between MTX and placebo, 5-ASA, or 6-MP in UC. AZA and 6-MP had no advantage over placebo in induction of clinical response in CD. Three meta-analyses showed the superiority of tacrolimus vs placebo for induction of clinical response in UC. The clinical response rates for cyclosporine were 41.7% in randomized controlled trials(RCTs) and 55.4% in non-RCTs for UC. For induction of mucosal healing,one meta-analysis showed a favorable rate with tacrolimus versus placebo for UC. For secondary outcomes, no meta-analyses specifically evaluated fecal calprotectin, hospitalization or death. Two meta-analyses were retrieved evaluating colectomy rates for tacrolimus and cyclosporine in UC. Most of the twenty individual studies retrieved contained a low or very low quality of evidence.CONCLUSION High-quality evidence assessing conventional therapy in MS-IBD treatment is scarce, especially for remission maintenance, mucosal healing and fecal calprotectin.展开更多
AIM To determine the distribution of anthropometric parameter(AP)-z-scores and characterize associations between medications/serum biomarkers and AP-z-scores in pediatric Crohn's disease(CD).METHODS CD patients [&...AIM To determine the distribution of anthropometric parameter(AP)-z-scores and characterize associations between medications/serum biomarkers and AP-z-scores in pediatric Crohn's disease(CD).METHODS CD patients [< chronological age(CA) 21 years] were enrolled in a cross-sectional study. Descriptive statistics were generated for participants' demographic characteristics and key variables of interest. Paired t-tests were used to compare AP-z-scores calculated based on CA(CA z-scores) and bone age(BA)(BA z-scores) for interpretation of AP's. Linear regression was utilized to examine associations between medications and serum biomarkers with AP-z-scores calculated based on CA(n = 82) and BA(n = 49). We reported regression coefficients as well as their corresponding p-values and 95% confidence intervals.RESULTS Mean CA at the time of the study visit was 15.3 ± 3.5(SD; range = 4.8-20.7) years. Mean triceps skinfold(P = 0.039), subscapular skinfold(P = 0.002) and midarm circumference(MAC)(P = 0.001) BA z-scores were higher than corresponding CA z-scores. Medications were positively associated with subscapular skinfold [adalimumab(P = 0.018) and methotrexate(P = 0.027)] and BMI CA z-scores [adalimumab(P = 0.029)]. Azathioprine/6-mercaptopurine were negatively associated with MAC(P = 0.045), subscapular skinfold(P = 0.014), weight(P = 0.002) and BMI(P = 0.013) CA z-scores. ESR, CRP, and WBC count were negatively associated, while albumin and IGF-1 BA z-scores were positively associated, with specific AP z-scores(P < 0.05). Mean height CA z-scores were higher in females, not males, treated with infliximab(P = 0.038). Hemoglobin(P = 0.018) was positively associated, while platelets(P = 0.005), ESR(P = 0.003) and CRP(P = 0.039) were negatively associated with height CA z-scores in males, not females. CONCLUSION Our results suggest poor efficacy of thiopurines and a possible sex difference in statural growth response to infliximab in pediatric CD. Prospective longitudinal studies are required.展开更多
Outstanding progress regarding the pathophysiology of Crohn's disease (CD) has led to the development of innovative therapeutic concepts. Numerous controlled trials have been performed in CD. This review concentra...Outstanding progress regarding the pathophysiology of Crohn's disease (CD) has led to the development of innovative therapeutic concepts. Numerous controlled trials have been performed in CD. This review concentrates on the results of randomized,placebo-controlled trials,and meta-analyses when available,that provide the highest degree of evidence. Current guidelines on the management of CD recommend a step-up approach to treatment involving the addition of more powerful therapies as the severity of disease and refractoriness to therapy increase. The advent of biological drugs has opened new therapeutic horizons for treating CD,modifying the treatment goals. However,the large majority of patients with CD will be managed through conventional therapy,even if they are a prelude to biological therapy.展开更多
基金Supported by Grant from Inflammatory Bowel and Immunobiology Research Institute,Cedars-Sinai Medical Center
文摘The thiopurine drugs,6-mercaptopurine(6-MP) and azathioprine,are efficacious in the arsenal of inflammatory bowel disease(IBD) therapy.Previous reports indicate that 6-thioguanine nucleotide(6-TGN) levels correlate with therapeutic efficacy,whereas high 6-methylmercaptopurine(6-MMP) levels are associated with hepatotoxicity and myelotoxicity.Due to their complex metabolism,there is wide individual variation in patient response therein,both in achieving therapeutic drug levels as well as in developing adverse reactions.Several strategies to optimize 6-TGN while minimizing 6-MMP levels have been adopted to administer the thiopurine class of drugs to patients who otherwise would not tolerate these drugs due to side-effects.In this report,we will review different approaches to administer the thiopurine medications,including the administration of 6-mercaptopurine in those unsuccessfully treated with azathioprine;coadministration of thiopurine with allopurinol;co-administration of thiopurine with anti-tumor necrosis factor α;6-TGN administration;desensitization trials;and split dosing of 6-MP.
文摘AIM: To determine the tolerability and safety profile of a low-dose maintenance therapy with 6-TG in azathioprine (AZA) or 6-mercaptopurine (6-MP) intolerant inflammatory bowel disease (IBD) patients over a treatment period of at least 1 year.METHODS: Database analysis.RESULTS: Twenty out of ninety-five (21%) patients discontinued 6-TG (mean dose 24.6 mg; mean 6-TGN level 540 pmol/8×108 RBC) within 1 year. Reasons for discontinuation were GI complaints (31%), malaise (15%)and hepatotoxicity (15%). Hematological events occurred in three patients, one discontinued treatment. In the 6-TG-tolerant group, 9% (7/75) could be classified as hepatotoxicity. An abdominal ultrasound was performed in 54% of patients, one patient had splenomegaly.CONCLUSION: The majority of AZA or 6-MP-intolerant IBD patients (79%) is able to tolerate maintenance treatment with 6-TG (dosages between 0.3 and 0.4 mg/kg per d). 6-TG may still be considered as an escape maintenance immunosuppressant in this difficult to treat group of patients, taking into account potential toxicity and efficacy of other alternatives. The recently reported hepatotoxicity is worrisome and 6-TG should therefore be administered only in prospective trials.
文摘AIM:To investigate the efficacy of 6-mercaptopurine (6-MP) in cases of azathioprine (AZA) hypersensitivity in patients with inflammatory bowel disease. METHODS: Twenty nine previously confirmed Crohn’s disease (CD) (n = 14) and ulcerative colitis (UC) (n = 15) patients with a known previous (AZA) hypersensitivity reaction were studied prospectively. The 6-MP doses were gradually increased from 0.5 up to 1.0-1.5 mg/kg per day. Clinical activity indicies (CDAI/CAI), laboratory variables and daily doses of oral 5-ASA, corticosteroids, and 6-MP were assessed before and in the first, sixth and twelfth months of treatment. RESULTS: In 9 patients, 6-MP was withdrawn in the first 2 wk due to an early hypersensitivity reaction. Medication was ineffective within 6 mo in 6 CD patients, and myelotoxic reaction was observed in two. Data were evaluated at the end of the sixth month in 12 (8 UC, 4 CD) patients, and after the first year in 9 (6 UC, 3 CD) patients. CDAI decreased transiently at the end of the sixth month, but no significant changes were observed in the CDAI or the CAI values at the end of the year. Leukocyte counts (P = 0.01), CRP (P = 0.02), and serum iron (P = 0.05) values indicated decreased inflammatory reactions, especially in the UC patients at the end of the year, making the possibility to taper oral steroid doses. CONCLUSION: About one-third of the previously AZA- intolerant patients showed adverse effects on taking 6MP. In our series, 20 patients tolerated 6MP, but it was ineffective in 8 CD cases, and valuable mainly in ulcerative colitis patients.
文摘Arbitrarily, modern day treatment of inflammatory bowel disease begins with the introduction of immuno- suppressives for ulcerative colitis. Clinical improvement with sulfasalazine had been meaningful but modest. Treatment with adrenocorticotropic hormone and corti- costeroids led to clinical responses never before realized but it took much too long to recognize that they were not capable of maintaining remission, that adverse reactions were subtle but potentially devastating and that some other agent would be necessary to capitalize on their transient advantage. This of course was true in the treatment of Crohn's disease as well. Not much was ever made of the role of sulfasalazine for Crohn' s disease, but with the severing of the diazobond and the elimination of the sulphur component, the 5-ami- nosalacylic acid (5-ASA) products clearly led to clinical improvement, especially in cases of Crohn's colitis and those with ileitis where the 5-ASA product was released in the terminal ileum and more proximal in the small bowel as well as in ulcerative colitis. The induction of remission was first demonstrated by 6-mercaptopurine (6-MP) with case reports and uncontrolled trials in pa- tients with ulcerative colitis, but its placebo controlled trial for Crohn's disease firmly established its role in inducing remission. No subsequent trial has confirmed its similar role for ulcerative colitis, but nevertheless cli- nicians know well that 6-MP works at least as well and probably more effectively for ulcerative colitis than for Crohn's disease. What changes have taken place utiliz- ing 6-MP in the management of inflammatory bowel disease since its introduction in the 1960's and 1970's and its trial for Crohn's disease published in the New England Journal of Medicine in 1980?
文摘The development of a simple and accurate quantitative method for the determination of 6-mercaptopurine (6-MP) is of great importance because of its serious side effects. Ratiometric fluorescence (RF) sensors are not subject to interference from environmental factors, and exhibit enhanced precision and accuracy. Therefore, a novel RF sensor for the selective detection of 6-MP was developed. The present work reports a sensitive and selective RF sensor for the detection of 6-mercaptopurine, by hybridizing carbon nanodots (CDots) and gold nanoclusters (AuNCs) capped with bovine serum albumin (BSA). The CDots serve as the reference signal and the AuNCs as the reporter. On addition of the 6-MP, AuNCs formed aggregates, because the existing cross-links within the AuNCs and BSA structure were broken in favour of the Au-S bonds, which can enhance the fluorescence of AuNCs, while the fluorescence of CDots is stable against 6-MP, leading to distinct ratiometric fluorescence changes when exposed to 6-MP. 6-MP could be detected in the range of 0 - 30.22 μM with a detection limit of 54 nM. The developed sensor was applied for the determination of 6-MP in human serum samples and satisfactory results were obtained.
文摘<abstract>Aim: To describe the reproductive outcome following intracytoplasmic sperm injection (ICSI) for male factor infertility associated with Crohn's disease and 6-mercap-topurine (6-MP) chemotherapy. Methods: The male partner of a couple suffered from severe Crohn's disease and received a 3-month course of 6-MP for this condition. Two spontaneous conceptions were established before 6-MP, although post-chemotherapy semen analysis found the sperm concentration to be 8,000/mL. In vitro fertilization (IVF) with ICSI and embryo transfer was performed. Results: The woman underwent an uncomplicated controlled ovarian hyperstimulation sequence using a combined rec-FSH+hMG protocol, following late luteal phase pituitary downregulation. This culminated in the retrieval of 18 oocytes, 11 of which were fertilized with ICSI. She later delivered a normal male infant without urogenital anomaly. Four nontransferred blastocysts were cryopreserved. Conclusion: This report describes the first successful birth after ICSI for severe oligozoospermia associated with Crohn's disease and 6-MP therapy. We outline salient features of Crohn's disease, 6-MP pharmacology, and their relevance to human fertility.
基金supported by the National Natural Science Foundation of China(No.21643014)the Special Natural Science Foundation of Science and Technology Bureau of Xi’an City Government(No.2016CXWL02 and SGH17H249)
文摘The Ag clusters have been investigated widely theoretically and experimentally. In particular, it has recently shown that the neutral Ag8 clusters embedded in an argon matrix have a strong fluorescence signal. As we can know, the metal clusters may have important effects on the structures and properties of biomolecules. More and more attention is paid to the interaction between nanomaterials and biomolecules. In this work, the B3LYP method in density functional theory was used on the complexes between the 6-mercaptopurine（6MP） and Ag8 clusters combined with 6-311＋＋G＊＊ as well as LANL2DZ base sets. The geometries of all the complexes were optimized with full degree of freedom and the structures, chemical bonds, orbital properties as well as Mulliken charges for ten possible complexes were analyzed based on the same theory level. In addition, the influence of temperature and pressure on the stabilities of the four complexes was further explored using standard statistical thermodynamic methods ranging from 50 to 500 K and at 100 kPa or 100 bar. The results show that the complex Ag8-6 MP-7-5 can be the most stable one among the investigated complexes, in which the Ag（11） atom interacts with the S（10） atom forming the strong chemical bond. The Mulliken charges also show that the Ag–S chemical bond is formed and the related charge has transferred. Additionally, the temperature and pressure can significantly influence the stability of the four stable complexes.
文摘The Polarographic and voltammetric behavior of 6-mercaptopurine were studied by several electrochemical techniques There are two reduction peaks in HAC buffer solution at PH 4.0. The characteriatics of the second Peak(P2) were studied in detail. The relationship between P: current(ip2 and concentration of 6-mercaptopurine is linear in the range of lx10-7-lx10 mol/L It has beeb applied to quantitative analysis of an anticancer tablet with satisfying results.The mechaniam,of the electrode reaction was proposed alao.
文摘An inclusion-interaction assembly strategy was used to construct novel pH/redox responsive core-shell micelles with hydrophobic drug as the core and hydrophilic polymer as the shell. At first, a dimer of hydrophobic drug 6-mercaptopurine and a hydrophilic β-CD grafted carboxymethyl chitosan were synthesized. Then, a novel amphiphilic inclusion complex was prepared with the dimer being partially embedded into the cavity of β-CD moiety. It self-assembled into pH/redox responsive core-shell micelles in distilled water. TEM confirmed that the micelles possessed a spherical core-shell configuration with a mean size of about 160 nm. DLS showed that the micelles were stable in aqueous solution. Their particle diameters altered with pH values as well as glutathione (GSH) concentrations and respectively attained a maximum value at pH 6.0 and 20 mM GSH. Release profiles of 6-mercaptopurine showed a low release rate (about 27 wt% after 48 h) in pH 7.4 medium with 10 μM GSH, and a marked increase (over 88 wt% after 48 h) in pH 5.0 medium with 20 mM GSH. In vitro cytotoxicity test showed that the micelles had a dose-dependent toxicity for HeLa cells, indicating a great potential for controlled release of 6-mercaptopurine in tumor cells.
文摘Malaria is a disease that has drawn worldwide attention due to the alarming rise of mortality rates particularly in third world countries. During the Plasmodium parasite intraerythrocytic life cycle, metabolic processes include the formation of hemozoin or malaria pigment. This pigment functions in the prevention of oxygen radical-mediated damage to the parasite. Drugs targeting hemozoin formation such as chloroquine and amodaquine are effective and are still used, but recently Plasmodium parasites have become resistant to these drugs, especially against chloroquine. In this study we looked at the potential use of two heterocyclic pyrimidine derivatives as anti-malaria drugs; 2,4-Diamino-6-Mercaptopyrimidine （DAMP） and 2-Mercaptopyrimidine （2-MP）. These compounds bear various coordination sites that enable them to react with metal ions to form coordination compounds. We used two methods for testing the inhibition of ferriprotoporphyrin IX （FP） biomineralisation： semi-quantitative microassay used by Deharo, and a quantitative assay used by G. Blaner and M. Akkawi. We report here the finding that （DAMP） has an in vitro inhibitory effect on I%hematin formation at concentrations and magnitude of nearly similar order to that of chloroquine, 2-MP was found to be effective but to a lower degree than DAMP.
基金This work was supported by the National Natural Science Foundation of China(Nos.51973243 and 52173150)International Cooperation and Exchange of the National Natural Science Foundation of China(No.51820105004)+1 种基金China Postdoctoral Science Foundation(No.2020M683058),the Science and Technology Planning Project of Shenzhen(No.JCYJ20190807155801657)Guangdong Innovative and Entrepreneurial Research Team Program(No.2016ZT06S029).
文摘Many anticancer drugs have limited clinical applications owing to their unsatisfactory therapeutic efficacy or side effects.This situation can be improved by drug delivery systems or drug modification strategies.Herein,to improve the therapeutic efficacy and safety of the traditional anticancer drug 6-mercaptopurine(6-MP),we dimerized 6-MP to form a disulfide bond-containing drug dimer and prepared a cysteine-based poly(disulfide amide)with redox-responsive capability as a drug carrier.Briefly,dimeric 6-MP(DMP)was synthesized via the oxidization of iodine and self-assembled with the poly(disulfide amide)to form dual redox-responsive DMP-loaded NPs(DMP-NPs).The 6-MP itself could hardly be loaded into nanoparticles(NPs)owing to its hydrophobicity,while the DMP-NPs showed a higher drug loading capacity over 6-MP,small particle size,and favorable stability.With abundant disulfide bonds in polymer backbones and drug payloads,DMP-NPs could rapidly respond to high levels of glutathione(GSH)and release drugs in a controllable manner.More importantly,both cellular and animal experiments demonstrated the enhanced anticancer efficacy of DMP-NPs against lymphoma and their high safety.Overall,this drug dimer-loaded dual redox-responsive drug delivery system provides new options for improving the applications of traditional drugs and developing drug delivery systems with enhanced drug effects and high safety.
文摘BACKGROUND Despite the advent of biological drugs, conventional therapy continues to be used in moderate to severe inflammatory bowel disease(MS-IBD). This study hypothesized that as a standard of treatment and the primary alternative to biologics, conventional therapy should present robust effectiveness results in IBD outcomes.AIM To investigate the effectiveness of conventional therapy for MS-IBD.METHODS A systematic review with no time limit was conducted in July 2017 through the Cochrane Collaboration, MEDLINE, and LILACS databases. The inclusion criteria encompassed meta-analyses, systematic reviews, randomized clinical trials, observational and case-control studies concerning conventional therapy in adult patients with MS-IBD, including Crohn's disease(CD) and ulcerative colitis(UC). Corticosteroids(prednisone, hydrocortisone, budesonide, prednisolone,dexamethasone), 5-aminosalicylic acid(5-ASA) derivatives(mesalazine and sulfasalazine) and immunosuppressants [azathioprine(AZA), methotrexate(MTX), mycophenolate, cyclosporine, tacrolimus, 6-mercaptopurine(6-MP)] were considered conventional therapy. The exclusion criteria were sample size below50; narrative reviews; specific subpopulations(e.g., pregnant women,comorbidities); studies on postoperative IBD; and languages other than English,Spanish, French or Portuguese. The primary outcome measures were clinical remission(induction or maintenance), clinical response and mucosal healing. As secondary outcomes, fecal calprotectin, hospitalization, death, and surgeries were analyzed. The quality of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation criteria.RESULTS The search strategy identified 1995 citations, of which 27 were considered eligible(7 meta-analyses, 20 individual studies). For induction of clinical remission, four meta-analyses were selected(AZA and 6-MP showed no advantage over placebo,MTX or 5-ASA in CD; MTX showed no statistically significant difference versus placebo, 6-MP, or 5-ASA in UC; tacrolimus was superior to placebo for UC in two meta-analyses). Only one meta-analysis evaluated clinical remission maintenance, showing no statistically significant difference between MTX and placebo, 5-ASA, or 6-MP in UC. AZA and 6-MP had no advantage over placebo in induction of clinical response in CD. Three meta-analyses showed the superiority of tacrolimus vs placebo for induction of clinical response in UC. The clinical response rates for cyclosporine were 41.7% in randomized controlled trials(RCTs) and 55.4% in non-RCTs for UC. For induction of mucosal healing,one meta-analysis showed a favorable rate with tacrolimus versus placebo for UC. For secondary outcomes, no meta-analyses specifically evaluated fecal calprotectin, hospitalization or death. Two meta-analyses were retrieved evaluating colectomy rates for tacrolimus and cyclosporine in UC. Most of the twenty individual studies retrieved contained a low or very low quality of evidence.CONCLUSION High-quality evidence assessing conventional therapy in MS-IBD treatment is scarce, especially for remission maintenance, mucosal healing and fecal calprotectin.
基金Supported by National Institutes of Health,No.DK077734(NG)Children’s Digestive Health and Nutrition Foundation(now known as North American Society for Pediatric Gastroenterology,Hepatology,and Nutrition Foundation)/Crohn’s and Colitis Foundation of America(now known as Crohn’s and Colitis Foundation)Award for New Investigators,No.CDHNF-06-002(NG)+2 种基金Crohn’s and Colitis Foundation of America(now known as Crohn’s and Colitis Foundation)Career Development Award,No.Award ID 1743(NG)University of California San Francisco Department of Pediatrics Pediatric Clinical Research Center Clinical Research Pilot Funding Award(NG)National Institutes of Health/National Center for Research Resources University of California San Francisco-Clinical and Translational Science Institute,No.UL1 RR024131
文摘AIM To determine the distribution of anthropometric parameter(AP)-z-scores and characterize associations between medications/serum biomarkers and AP-z-scores in pediatric Crohn's disease(CD).METHODS CD patients [< chronological age(CA) 21 years] were enrolled in a cross-sectional study. Descriptive statistics were generated for participants' demographic characteristics and key variables of interest. Paired t-tests were used to compare AP-z-scores calculated based on CA(CA z-scores) and bone age(BA)(BA z-scores) for interpretation of AP's. Linear regression was utilized to examine associations between medications and serum biomarkers with AP-z-scores calculated based on CA(n = 82) and BA(n = 49). We reported regression coefficients as well as their corresponding p-values and 95% confidence intervals.RESULTS Mean CA at the time of the study visit was 15.3 ± 3.5(SD; range = 4.8-20.7) years. Mean triceps skinfold(P = 0.039), subscapular skinfold(P = 0.002) and midarm circumference(MAC)(P = 0.001) BA z-scores were higher than corresponding CA z-scores. Medications were positively associated with subscapular skinfold [adalimumab(P = 0.018) and methotrexate(P = 0.027)] and BMI CA z-scores [adalimumab(P = 0.029)]. Azathioprine/6-mercaptopurine were negatively associated with MAC(P = 0.045), subscapular skinfold(P = 0.014), weight(P = 0.002) and BMI(P = 0.013) CA z-scores. ESR, CRP, and WBC count were negatively associated, while albumin and IGF-1 BA z-scores were positively associated, with specific AP z-scores(P < 0.05). Mean height CA z-scores were higher in females, not males, treated with infliximab(P = 0.038). Hemoglobin(P = 0.018) was positively associated, while platelets(P = 0.005), ESR(P = 0.003) and CRP(P = 0.039) were negatively associated with height CA z-scores in males, not females. CONCLUSION Our results suggest poor efficacy of thiopurines and a possible sex difference in statural growth response to infliximab in pediatric CD. Prospective longitudinal studies are required.
文摘Outstanding progress regarding the pathophysiology of Crohn's disease (CD) has led to the development of innovative therapeutic concepts. Numerous controlled trials have been performed in CD. This review concentrates on the results of randomized,placebo-controlled trials,and meta-analyses when available,that provide the highest degree of evidence. Current guidelines on the management of CD recommend a step-up approach to treatment involving the addition of more powerful therapies as the severity of disease and refractoriness to therapy increase. The advent of biological drugs has opened new therapeutic horizons for treating CD,modifying the treatment goals. However,the large majority of patients with CD will be managed through conventional therapy,even if they are a prelude to biological therapy.
