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Sample records for 6-mercaptopurine

  1. Crystal structures of five 6-mercaptopurine derivatives

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    Lígia R. Gomes

    2016-03-01

    Full Text Available The crystal structures of five 6-mercaptopurine derivatives, viz. 2-[(9-acetyl-9H-purin-6-ylsulfanyl]-1-(3-methoxyphenylethan-1-one (1, C16H14N4O3S, 2-[(9-acetyl-9H-purin-6-ylsulfanyl]-1-(4-methoxyphenylethan-1-one (2, C16H14N4O3S, 2-[(9-acetyl-9H-purin-6-ylsulfanyl]-1-(4-chlorophenylethan-1-one (3, C15H11ClN4O2S, 2-[(9-acetyl-9H-purin-6-ylsulfanyl]-1-(4-bromophenylethan-1-one (4, C15H11BrN4O2S, and 1-(3-methoxyphenyl-2-[(9H-purin-6-ylsulfanyl]ethan-1-one (5, C14H12N4O2S. Compounds (2, (3 and (4 are isomorphous and accordingly their molecular and supramolecular structures are similar. An analysis of the dihedral angles between the purine and exocyclic phenyl rings show that the molecules of (1 and (5 are essentially planar but that in the case of the three isomorphous compounds (2, (3 and (4, these rings are twisted by a dihedral angle of approximately 38°. With the exception of (1 all molecules are linked by weak C—H...O hydrogen bonds in their crystals. There is π–π stacking in all compounds. A Cambridge Structural Database search revealed the existence of 11 deposited compounds containing the 1-phenyl-2-sulfanylethanone scaffold; of these, only eight have a cyclic ring as substituent, the majority of these being heterocycles.

  2. Effect of the anticarcinogenic drug 6-mercaptopurine on mineral metabolism

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    Amemiya, K.

    1987-01-01

    The effect of 6-mercaptopurine (6-MP) on mineral metabolism was investigated using rats and mice. A single 6-mercaptopurine injection in pregnant rats on day 11 of gestation proved to be highly teratogenic. At term, fetuses from 6-MP injected dams had lower livers zinc concentrations than non-injected or vehicle injected controls while dams showed no differences in liver zinc. Fetuses from dams injected with 6-MP and fed supplemental levels of zinc had a lower frequency of malformations and had higher hepatic zinc concentrations than fetuses from dams fed less zinc with drug injection. Non-pregnant mice injected with 6-MP had higher zinc concentrations compared to controls. In addition, iron, copper and calcium concentrations were higher in the livers of 6-MP injected mice than in controls, indicating that the drug affected several elements. Hepatic concentrations of metallothionein (MT) were also elevated in 6-MP injected mice, suggesting that the change in zinc concentrations associated with drug administration was the result of a drug induction of MT. Dams injected with 6-MP on day 13 of pregnancy had livers which retained more of an absorbed dose of /sup 65/zinc than non-injected dams. Plasma from these drug injected dams also retained less of the absorbed dose than control dams. In contrast, day 14 from dams injected with 6-MP, retained less of an absorbed dose than control embryos.

  3. 6-mercaptopurine promotes energetic failure in proliferating T cells.

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    Fernández-Ramos, Ana A; Marchetti-Laurent, Catherine; Poindessous, Virginie; Antonio, Samantha; Laurent-Puig, Pierre; Bortoli, Sylvie; Loriot, Marie-Anne; Pallet, Nicolas

    2017-06-27

    The anticancer drug 6-mercaptopurine (6-MP) inhibits de novo purine synthesis and acts as an antiproliferative agent by interfering with protein, DNA and RNA synthesis and promoting apoptosis. Metabolic reprogramming is crucial for tumor progression to foster cancer cells growth and proliferation, and is regulated by mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) as well as the oncogenes Myc and hypoxia inducible factor 1α (HIF-1α). We hypothesized that 6-MP impacts metabolic remodeling through its action on nucleotide synthesis. The aim of our study is to provide a comprehensive characterization of the metabolic changes induced by 6-MP in leukemic T cells. Our results indicate that exposition to 6-MP rapidly reduces intracellular ATP concentration, leading to the activation of AMPK. In turn, mTOR, an AMPK target, was inhibited, and the expression of HIF-1α and Myc was reduced upon 6-MP incubation. As a consequence of these inhibitions, glucose and glutamine fluxes were strongly decreased. Notably, no difference was observed on glucose uptake upon exposition to 6-MP. In conclusion, our findings provide new insights into how 6-MP profoundly impacts cellular energetic metabolism by reducing ATP production and decreasing glycolytic and glutaminolytic fluxes, and how 6-MP modifies human leukemic T cells metabolism with potential antiproliferative effects.

  4. Resonance light scattering determination of 6-mercaptopurine coupled with HPLC technique

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    Li, Ai Ping; Peng, Jing Dong; Zhou, MingQiong; Zhang, Jin

    2016-02-01

    A simple, fast, costless, sensitive and selective method of resonance light scattering coupled with HPLC was established for the determination of 6-mercaptopurine in human urine sample. In a Britton-Robinson buffer solution of pH 5.5, the formation of coordination complex between 6-mercaptopurine and metal palladium (II) led to enhance the RLS intensity of the system. The RLS signal was detected by fluorescence detector at λex = λem = 315 nm. The analytical parameters were provided by the coupled system, the linear of 6-mercaptopurine response from 0.0615 to 2.40 μg L- 1 and the limit of detection (S/N = 3) was 0.05 μg L- 1. The presented method has been applied to determine 6-mercaptopurine in human urine samples which obtained satisfactory results. Moreover, the reaction mechanism and possible reasons for enhancement of RLS were fully discussed.

  5. Evaluation of a pediatric liquid formulation to improve 6-mercaptopurine therapy in children

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    Tiphaine, Adam de Beaumais; Hjalgrim, Lisa Lynqsie; Nersting, Jacob

    2016-01-01

    BACKGROUND: 6-mercaptopurine (6-MP), a key drug for treatment of acute lymphoblastic leukemia (ALL), has until recently had no adequate formulation for pediatric patients. Several approaches have been taken but the only oral paraben-free 6-MP liquid formulation named Loulla was developed and eval......BACKGROUND: 6-mercaptopurine (6-MP), a key drug for treatment of acute lymphoblastic leukemia (ALL), has until recently had no adequate formulation for pediatric patients. Several approaches have been taken but the only oral paraben-free 6-MP liquid formulation named Loulla was developed...

  6. Measures of 6-mercaptopurine and methotrexate maintenance therapy intensity in childhood acute lymphoblastic leukemia

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    Nielsen, Stine Nygaard; Grell, Kathrine; Nersting, Jacob

    2016-01-01

    PURPOSE: Normal white blood cell counts (WBC) are unknown in children with acute lymphoblastic leukemia (ALL). Accordingly, 6-mercaptopurine (6MP) and methotrexate (MTX) maintenance therapy is adjusted by a common WBC target of 1.5-3.0 × 10(9)/L. Consequently, the absolute degree...

  7. Formation of 6-thioguanine and 6-mercaptopurine from their 9-alkyl derivatives in mice.

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    Nelson, J A; Vidale, E

    1986-01-01

    Several 9-alkyl, 6-thiopurines have been reported to have more favorable therapeutic indexes than do the parent drugs, 6-mercaptopurine (MP) and 6-thioguanine (TG). Some of these compounds were reported to be active against cells in culture resistant to 6-thiopurines, and it has been assumed that their mechanisms of action may differ from those of TG and MP. 9-(n-Butyl)-6-thioguanine was essentially inactive toward Chinese hamster ovary cells in vitro when compared with TG (50% effective dose, 250 and 1 microM, respectively). However, lethal doses of 9-(n-butyl)-6-thioguanine and TG in mice were similar when these agents were given i.p. daily for 9 consecutive days (50% lethal dose, 13 and 9 mg/kg/day). Similar organ toxicities were observed upon histopathological examination of dying animals. The cumulative, daily urinary excretion of TG was virtually identical in mice given 20- and 10-mg/kg/day of doses of 9-(n-butyl)-6-thioguanine or TG, respectively, for 9 days. The TG formed was identified by ultraviolet light (340 nm) detection following separation on a reverse phase high performance liquid chromatography system and by fluorescent detection of the permanganate oxidation product separated on a strong anion-exchange system. Dealkylation of 9-(n-butyl)-6-mercaptopurine and 9-ethyl-6-mercaptopurine also occurred in AKR mice. At near equitoxic doses, the daily cumulative urinary excretion of MP from 9-(n-butyl)-6-mercaptopurine and 9-ethyl-6-mercaptopurine was about 20-30% of that observed in mice receiving MP. The MP was confirmed in each case by enzymatic peak-shift of MP to 6-thiouric acid and ultraviolet light detection using the high performance liquid chromatography systems referred to above. The results suggest that these 9-alkyl derivatives serve as prodrugs for TG and MP, a finding that explains a number of their pharmacological and toxicological properties.

  8. Preparation and characterization of 6-mercaptopurine-coated magnetite nanoparticles as a drug delivery system

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    Dorniani D

    2013-09-01

    Full Text Available Dena Dorniani,1 Mohd Zobir bin Hussein,1 Aminu Umar Kura,2 Sharida Fakurazi,2 Abdul Halim Shaari,3 Zalinah Ahmad4 1Materials Synthesis and Characterization Laboratory, Institute of Advanced Technology, 2Vaccines and Immunotherapeutics Laboratory, 3Physics Department, Faculty of Science, 4Chemical Pathology Unit, Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, Malaysia Background: Iron oxide nanoparticles are of considerable interest because of their use in magnetic recording tape, ferrofluid, magnetic resonance imaging, drug delivery, and treatment of cancer. The specific morphology of nanoparticles confers an ability to load, carry, and release different types of drugs. Methods and results: We synthesized superparamagnetic nanoparticles containing pure iron oxide with a cubic inverse spinal structure. Fourier transform infrared spectra confirmed that these Fe3O4 nanoparticles could be successfully coated with active drug, and thermogravimetric and differential thermogravimetric analyses showed that the thermal stability of iron oxide nanoparticles coated with chitosan and 6-mercaptopurine (FCMP was markedly enhanced. The synthesized Fe3O4 nanoparticles and the FCMP nanocomposite were generally spherical, with an average diameter of 9 nm and 19 nm, respectively. The release of 6-mercaptopurine from the FCMP nanocomposite was found to be sustained and governed by pseudo-second order kinetics. In order to improve drug loading and release behavior, we prepared a novel nanocomposite (FCMP-D, ie, Fe3O4 nanoparticles containing the same amounts of chitosan and 6-mercaptopurine but using a different solvent for the drug. The results for FCMP-D did not demonstrate “burst release” and the maximum percentage release of 6-mercaptopurine from the FCMP-D nanocomposite reached about 97.7% and 55.4% within approximately 2,500 and 6,300 minutes when exposed to pH 4.8 and pH 7.4 solutions, respectively

  9. Thiopurine Drugs Azathioprine and 6-Mercaptopurine Inhibit Mycobacterium paratuberculosis Growth In Vitro

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    Shin, Sung Jae; Collins, Michael T.

    2008-01-01

    The in vitro susceptibility of human- and bovine-origin Mycobacterium paratuberculosis to the thioupurine drugs 6-mercaptopurine (6-MP) and azathioprine (AZA) was established using conventional plate counting methods and the MGIT 960 ParaTB culture system. Both 6-MP and AZA had antibacterial activity against M. paratuberculosis; isolates from Crohn's disease patients tended to be more susceptible than were bovine-origin isolates. Isolates of Mycobacterium avium, used as controls, were general...

  10. Optimizing 6-mercaptopurine and azathioprine therapy in the management of inflammatory bowel disease

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    Kara Bradford; David Q Shih

    2011-01-01

    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; co-administration of thiopurine with allopurinol; co-administration of thiopurine with anti-tumor necrosis factor a; 6-TGN administration; desensitization trials; and split dosing of 6-MP.

  11. Metronomic therapy with oral 6-mercaptopurine in elderly acute myeloid leukemia: A prospective pilot study

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    Akhil Kapoor

    2016-01-01

    Full Text Available Introduction: Acute myeloid leukemia (AML in elderly patients differs biologically from that in younger patients and is known to have unfavorable chromosomal rearrangements, higher resistance, and lower tolerance to chemotherapy. In such circumstances, instead of giving full-blown chemotherapy, palliative metronomic chemotherapy (MCT could be a treatment option. Patients and Methods: We performed a prospective pilot study of old AML patients (age >60 years not amenable to curative treatment. Thirty-two patients were enrolled into the study and were treated with daily oral 6-mercaptopurine 75 mg/m 2 . The following inclusion criteria were used: age >60 years, nonpromyelocytic AML, the absence of uncontrolled comorbidities, and patient not amenable to curative treatment. Overall survival (OS was calculated using Kaplan-Meier method and Cox regression analysis were used to calculate the hazards ratio of significant factors. Results: The median age of the patients was 69 years (range: 61-86 years with male: female ratio of 2.5:1. About 59.4% of patients had Eastern Cooperative Oncology Group performance status of 2 while rest had the status of 3. The median OS was 6 months (95% confidence interval [CI]: 4.4-7.6. Males had median OS of 7 months (95% CI: 5.4-8.6 versus females with OS of 3 months (95% CI: 1.5-4.4; P = 0.008. There was no survival difference on the basis of baseline hemoglobin or French-American-British class. There were no Grade 4 toxicities and no episode of febrile neutropenia. Conclusions: MCT with oral 6-mercaptopurine is an attractive treatment option in elderly AML patients who are not amenable to curative therapy with minimal toxicities.

  12. Harmful effects of the azathioprine metabolite 6-mercaptopurine in vascular cells: induction of mineralization.

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    Jasmin Prüfer

    Full Text Available Vascular mineralization contributes to the high cardiovascular morbidity and mortality in patients who suffer from chronic kidney disease and in individuals who have undergone solid organ transplantation. The immunosuppressive regimen used to treat these patients appears to have an impact on vascular alterations. The effect of 6-mercaptopurine (6-MP on vascular calcification has not yet been determined. This study investigates the effect of 6-MP on vascular mineralization by the induction of trans-differentiation of rat vascular smooth muscle cells in vitro. 6-MP not only induces the expression of osteo-chondrocyte-like transcription factors and proteins but also activates alkaline phosphatase enzyme activity and produces calcium deposition in in vitro and ex vivo models. These processes are dependent on 6-MP-induced production of reactive oxygen species, intracellular activation of mitogen-activated kinases and phosphorylation of the transcription factor Cbfa1. Furthermore, the metabolic products of 6-MP, 6-thioguanine nucleotides and 6-methyl-thio-inosine monophosphate have major impacts on cellular calcification. These data provide evidence for a possible harmful effect of the immunosuppressive drug 6-MP in vascular diseases, such as arteriosclerosis.

  13. Thiopurine drugs azathioprine and 6-mercaptopurine inhibit Mycobacterium paratuberculosis growth in vitro.

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    Shin, Sung Jae; Collins, Michael T

    2008-02-01

    The in vitro susceptibility of human- and bovine-origin Mycobacterium paratuberculosis to the thioupurine drugs 6-mercaptopurine (6-MP) and azathioprine (AZA) was established using conventional plate counting methods and the MGIT 960 ParaTB culture system. Both 6-MP and AZA had antibacterial activity against M. paratuberculosis; isolates from Crohn's disease patients tended to be more susceptible than were bovine-origin isolates. Isolates of Mycobacterium avium, used as controls, were generally resistant to both AZA and 6-MP, even at high concentrations (> or =64.0 microg/ml). Among rapidly growing mycobacteria, Mycobacterium phlei was susceptible to 6-MP and AZA whereas Mycobacterium smegmatis strains were not. AZA and 6-MP limited the growth of, but did not kill, M. paratuberculosis in a dose-dependent manner. Anti-inflammatory drugs in the sulfonamide family (sulfapyridine, sulfasalazine, and 5-aminosalycilic acid [mesalamine]) had little or no antibacterial activity against M. paratuberculosis. The conventional antibiotics azithromycin and ciprofloxacin, used as control drugs, were bactericidal for M. paratuberculosis, exerting their killing effects on the organism relatively quickly. Simultaneous exposure of M. paratuberculosis to 6-MP and ciprofloxacin resulted in significantly higher CFU than use of ciprofloxacin alone. These data may partially explain the paradoxical response of Crohn's disease patients infected with M. paratuberculosis to treatment with immunosuppressive thiopurine drugs, i.e., they do not worsen with anti-inflammatory treatment as would be expected with a microbiological etiologic pathogen. These findings also should influence the design of therapeutic trials to evaluate antibiotic treatments of Crohn's disease: AZA drugs may confound interpretation of data on therapeutic responses for both antibiotic-treated and control groups.

  14. Stents Eluting 6-Mercaptopurine Reduce Neointima Formation and Inflammation while Enhancing Strut Coverage in Rabbits.

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    Matthijs S Ruiter

    Full Text Available The introduction of drug-eluting stents (DES has dramatically reduced restenosis rates compared with bare metal stents, but in-stent thrombosis remains a safety concern, necessitating prolonged dual anti-platelet therapy. The drug 6-Mercaptopurine (6-MP has been shown to have beneficial effects in a cell-specific fashion on smooth muscle cells (SMC, endothelial cells and macrophages. We generated and analyzed a novel bioresorbable polymer coated DES, releasing 6-MP into the vessel wall, to reduce restenosis by inhibiting SMC proliferation and decreasing inflammation, without negatively affecting endothelialization of the stent surface.Stents spray-coated with a bioresorbable polymer containing 0, 30 or 300 μg 6-MP were implanted in the iliac arteries of 17 male New Zealand White rabbits. Animals were euthanized for stent harvest 1 week after implantation for evaluation of cellular stent coverage and after 4 weeks for morphometric analyses of the lesions.Four weeks after implantation, the high dose of 6-MP attenuated restenosis with 16% compared to controls. Reduced neointima formation could at least partly be explained by an almost 2-fold induction of the cell cycle inhibiting kinase p27Kip1. Additionally, inflammation score, the quantification of RAM11-positive cells in the vessel wall, was significantly reduced in the high dose group with 23% compared to the control group. Evaluation with scanning electron microscopy showed 6-MP did not inhibit strut coverage 1 week after implantation.We demonstrate that novel stents coated with a bioresorbable polymer coating eluting 6-MP inhibit restenosis and attenuate inflammation, while stimulating endothelial coverage. The 6-MP-eluting stents demonstrate that inhibition of restenosis without leaving uncovered metal is feasible, bringing stents without risk of late thrombosis one step closer to the patient.

  15. Reassuring results on birth outcomes in children fathered by men treated with azathioprine/6-mercaptopurine within 3 months before conception

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    Nørgård, B M; Magnussen, B; Larsen, M D;

    2017-01-01

    OBJECTIVE: Information on the safety of paternal use of azathioprine (AZA) and 6-mercaptopurine (6-MP) prior to conception is limited. Based on nationwide data from the Danish health registries, we examined the association between paternal use of AZA/6-MP within 3 months before conception and adv...

  16. Individualized toxicity-titrated 6-mercaptopurine increments during high-dose methotrexate consolidation treatment of lower risk childhood acute lymphoblastic leukemia

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    Frandsen, Thomas Leth; Abrahamsson, Jonas; Lausen, Birgitte Frederiksen

    2011-01-01

    This study explored the feasibility and toxicity of individualized toxicity-titrated 6-mercaptopurine (6MP) dose increments during post-remission treatment with High-dose methotrexate (HDM) (5000 mg/m2, ×3) in 38 patients with Childhood (ALL). Patients were increased in steps of 25 mg 6MP/m2 per ...

  17. Simultaneous Determination of 6-Mercaptopurine and its Oxidative Metabolites in Synthetic Solutions and Human Plasma using Spectrophotometric Multivariate Calibration Methods

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    Mohammad-Reza Rashidi

    2011-06-01

    Full Text Available Introduction: 6-Mercaptopurine (6MP is an important chemotherapeutic drug in the conventional treatment of childhood acute lymphoblastic leukemia (ALL. It is catabolized to 6-thiouric acid (6TUA through 8-hydroxo-6-mercaptopurine (8OH6MP or 6-thioxanthine (6TX intermediates. Methods: High-performance liquid chromatography (HPLC is usually used to determine the contents of therapeutic drugs, metabolites and other important biomedical analytes in biological samples. In the present study, the multivariate calibration methods, partial least squares (PLS-1 and principle component regression (PCR have been developed and validated for the simultaneous determination of 6MP and its oxidative metabolites (6TUA, 8OH6MP and 6TX without analyte separation in spiked human plasma. Mixtures of 6MP, 8-8OH6MP, 6TX and 6TUA have been resolved by PLS-1 and PCR to their UV spectra. Results: Recoveries (% obtained for 6MP, 8-8OH6MP, 6TX and 6TUA were 94.5-97.5, 96.6-103.3, 95.1-96.9 and 93.4-95.8, respectively, using PLS-1 and 96.7-101.3, 96.2-98.8, 95.8-103.3 and 94.3-106.1, respectively, using PCR. The NAS (Net analyte signal concept was used to calculate multivariate analytical figures of merit such as limit of detection (LOD, selectivity and sensitivity. The limit of detections for 6MP, 8-8OH6MP, 6TX and 6TUA were calculated to be 0.734, 0.439, 0.797 and 0.482 µmol L-1, respectively, using PLS and 0.724, 0.418, 0783 and 0.535 µmol L-1, respectively, using PCR. HPLC was also applied as a validation method for simultaneous determination of these thiopurines in the synthetic solutions and human plasma. Conclusion: Combination of spectroscopic techniques and chemometric methods (PLS and PCR has provided a simple but powerful method for simultaneous analysis of multicomponent mixtures.

  18. Silver nanoparticles enhanced a novel TCPO-H₂O₂-safranin O chemiluminescence system for determination of 6-mercaptopurine.

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    Biparva, Pourya; Abedirad, Seyed Mohammad; Kazemi, Sayed Yahya

    2015-06-15

    The present study deals with first attempt to introduce safranin O as the fluorophore for peroxyoxalate chemiluminescence system. The reaction of bis-(2,4,6-trichlorophenyl) oxalate (TCPO) with H2O2 catalyzed by silver nanoparticles can transfer energy to safranin O via the formation of dioxetanedione intermediate and emits orange-red light. The relationship between CL intensity and the concentration of TCPO, fluorophore, hydrogen peroxide and nanocatalyst was investigated. The Ag nanoparticles were synthesized by chemical reduction method and characterized using scanning electron microscopy, particle size analyzer and UV-spectroscopy. Moreover, the system was applied successfully to detect a drug, 6-mercaptopurine (6-MP) in pharmaceuticals. Under optimum conditions, a linear working range for 6-MP concentrations from 5.5 × 10(-7) to 5.5 × 10(-5)mol L(-1) (r>0.9831, n=6) was obtained with a detection limit of 1.6 × 10(-7)mol L(-1). The relative standard deviation for 6 repetitive determinations was less than 3.8% and recoveries of 98% and 103% were obtained.

  19. Determination of intracellular levels of 6-mercaptopurine metabolites in erythrocytes utilizing capillary electrophoresis with laser-induced fluorescence detection.

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    Rabel, S R; Stobaugh, J F; Trueworthy, R

    1995-01-01

    Capillary electrophoresis proved to be a useful technique for the analysis of intracellular levels of 6-thioguanosine mono-, di-, and triphosphate with analysis times of 20 min. Conditions required for baseline separation of the thioguanine nucleotides consisted of a 25 mM KH2PO4 (pH 8.0) buffer and a separation voltage of +28 kV. Laser-induced fluorescence detection (lambda ex = 325 nm, lambda em = 410 nm) of the thioguanine nucleotide metabolites of 6-mercaptopurine (6-MP) was possible following oxidation of the thiol functionality. Tedious extraction procedures involving mercury cellulose resins or phenyl mercury adduct formation, which had been required previously for the selective extraction of thiopurines from erythrocytes, were unnecessary due to the overall specificity of the approach. However, the inclusion of 50 mM EDTA in the sample preparation was required to inhibit the anabolic/catabolic enzymatic activity, which was responsible for the degradation of the analytes. The method demonstrated linearity from 5 to 1700 pmol/100 microliters red blood cells for the three analytes (RSDs < or = 8%). The feasibility of the method was demonstrated for the quantitation of 6-thioguanine nucleotides in patients receiving either oral or intravenous 6-MP therapy.

  20. Decrease in cytotoxicity of copper-based intrauterine devices (IUD) pretreated with 6-mercaptopurine and pterin as biocompatible corrosion inhibitors.

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    Alvarez, Florencia; Grillo, Claudiaa; Schilardi, Patricial; Rubert, Aldo; Benítez, Guillermo; Lorente, Carolina; de Mele, Mónica Fernández Lorenzo

    2013-01-23

    The copper intrauterine device (IUD) based its contraceptive action on the release of cupric ions from a copper wire. Immediately after the insertion, a burst release of copper ions occurs, which may be associated to a variety of side effects. 6-Mercaptopurine (6-MP) and pterin (PT) have been proposed as corrosion inhibitors to reduce this harmful release. Pretreatments with 1 × 10(-4) M 6-MP and 1 × 10(-4) M PT solutions with 1h and 3h immersion times were tested. Conventional electrochemical techniques, EDX and XPS analysis, and cytotoxicity assays with HeLa cell line were employed to investigate the corrosion behavior and biocompatibility of copper with and without treatments. Results showed that copper samples treated with PT and 6-MP solutions for 3 and 1 h, respectively, are more biocompatible than those without treatment. Besides, the treatment reduces the burst release effect of copper in simulated uterine solutions during the first week after the insertion. It was concluded that PT and 6-MP treatments are promising strategies able to reduce the side effects related to the "burst release" of copper-based IUD without altering the contraceptive action.

  1. Selective recognition of 6-mercaptopurine based on luminescent metal-organic frameworks Fe-MIL-88NH₂.

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    Sun, Zhengjuan; Liu, Yali; Li, Yuanfang

    2015-03-15

    A novel and rapid spectrofluorometry method for the recognition of 6-mercaptopurine (6-MP) has been developed based on luminescent metal-organic frameworks Fe-MIL-88NH2 as fluorescent probe. The strong fluorescence of Fe-MIL-88NH2 at 430 nm could be quenched by 6-MP directly, and the Fe-MIL-88NH2 shows high selectivity for 6-MP compared to other thiol-containing amino acids such as homocysteine (Hcy), cysteine (Cys), glutathione (GSH), etc. Under optimal conditions, the relative fluorescence intensity was linearly proportional to the concentration of 6-MP in the range of 5-600 μM with the detection limit at 1.17 μM (S/N=3). Furthermore, the present approach has been successfully applied to the determination of 6-MP in human serum samples. The possible fluorescence quenching mechanism has also been investigated, where it is revealed that the quenching was attributed to competition of absorption of the light source energy as well as electron transfer between Fe-MIL-88NH2 and 6-MP.

  2. Characterization of 6-mercaptopurine binding to bovine serum albumin and its displacement from the binding sites by quercetin and rutin

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    Ehteshami, Mehdi [Nutrition Research Center, School of Health and Nutrition, Tabriz University of Medical Sciences, Tabriz 51644-14766 (Iran, Islamic Republic of); Rasoulzadeh, Farzaneh [Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz 51644-14766 (Iran, Islamic Republic of); Mahboob, Soltanali [Nutrition Research Center, School of Health and Nutrition, Tabriz University of Medical Sciences, Tabriz 51644-14766 (Iran, Islamic Republic of); Rashidi, Mohammad-Reza, E-mail: rashidi@tbzmed.ac.ir [Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz 51644-14766 (Iran, Islamic Republic of)

    2013-03-15

    Binding of a drug to the serum albumins as major serum transport proteins can be influenced by other ligands leading to alteration of its pharmacological properties. In the present study, binding characteristics of 6-mercaptopurine (6-MP) with bovine serum albumin (BSA) together with its displacement from its binding site by quercetin and rutin have been investigated by the spectroscopic method. According to the binding parameters, a static quenching component in overall dynamic quenching process is operative in the interaction between 6-MP and BSA. The binding of 6-MP to BSA occurred spontaneously due to entropy-driven hydrophobic interactions. The synchronous fluorescence spectroscopy study revealed that the secondary structure of BSA is changed in the presence of 6-MP and both Tyr and Trp residues participate in the interaction between 6-MP and BSA with the later one being more dominant. The binding constant value of 6-MP-BSA in the presence of quercetin and rutin increased. 6-MP was displaced by ibuprofen indicating that the binding site of 6-MP on albumin is site II. Therefore, the change of the pharmacokinetic and pharmacodynamic properties of 6-MP by quercetin and rutin through alteration of binding capacity of 6-MP to the serum albumin cannot be ruled out. In addition, the displacement study showed that 6-MP is located in site II of BSA. - Highlights: Black-Right-Pointing-Pointer Participation of both Tyr and particularly Trp residues in the interaction between 6-MP and BSA. Black-Right-Pointing-Pointer Involvement of a static quenching component in an overall dynamic quenching process. Black-Right-Pointing-Pointer Ability of quercetin and rutin to change the binding constants of 6-MP-BSA complex. Black-Right-Pointing-Pointer Binding of 6-MP to BSA through entropy-driven hydrophobic interactions.

  3. Methotrexate/6-mercaptopurine maintenance therapy influences the risk of a second malignant neoplasm after childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study

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    Schmiegelow, Kjeld; Al-Modhwahi, Ibrahim; Andersen, Mette Klarskov;

    2009-01-01

    acute myeloid leukemias or myelodysplastic syndromes had monosomy 7 (n = 7) or 7q deletions (n = 2). In Cox multivariate analysis, longer duration of oral 6-mercaptopurine (6MP)/methotrexate (MTX) maintenance therapy (P = .02; longest for standard-risk patients) and presence of high hyperdiploidy (P......Among 1614 children with acute lymphoblastic leukemia (ALL) treated with the Nordic Society for Paediatric Haematology and Oncology (NOPHO) ALL-92 protocol, 20 patients developed a second malignant neoplasm (SMN) with a cumulative risk of 1.6% at 12 years from the diagnosis of ALL. Nine of the 16...

  4. Sun light mediated synthesis of gold nanoparticles as carrier for 6-mercaptopurine: Preparation, characterization and toxicity studies in zebrafish embryo model

    Energy Technology Data Exchange (ETDEWEB)

    Ganeshkumar, Moorthy [Department of Biochemistry, Central Leather Research Institute, Council of Scientific and Industrial Research, Chennai 600020 (India); Sastry, Thotapalli Parvathaleswara [Bioproducts Laboratory, Central Leather Research Institute, Chennai 600020 (India); Sathish Kumar, Muniram [Department of Pharmaceutics, Anna University, Trichy, Tamilnadu (India); Dinesh, Murugan Girija [Thanthai Hansroever College, Perambalur, Tamilnadu (India); Kannappan, Sudalyandi [Central Institute of Brackish Water Aquaculture, Chennai 600028 (India); Suguna, Lonchin, E-mail: slonchin@yahoo.co.uk [Department of Biochemistry, Central Leather Research Institute, Council of Scientific and Industrial Research, Chennai 600020 (India)

    2012-09-15

    Highlights: ► Gold nanoparticles prepared using eco-friendly method with good in vitro stability. ► Can be used as drug delivery system. ► Did not show any toxicity in zebrafish embryo. ► More toxic to cancer cells when compared to N-Au-Mp and Mp. -- Abstract: The objective of this study is to synthesize green chemistry based gold nanoparticles by sun light irradiation method. The prepared gold nanoparticles (AuNPs) were modified using folic acid and then coupled with 6-mercaptopurine. These modified nanoparticles were used as a tool for targeted drug delivery to treat laryngeal cancer. In the present study, novel bionanocomposites containing nutrient agar coated gold nano particles (N-AuNPs) coupled with 6-mercaptopurine (drug) (N-AuNPs-Mp), folic acid (ligand) (N-AuNPs-Mp-Fa) and rhodamine (dye) (N-AuNPs-Rd), a fluorescent agent, were prepared and characterized by IR, UV, TEM, Particle size analysis and in vitro stability. The toxicity and fluorescence of N-Au was studied using zebrafish embryo model. The in vitro cytotoxicity of free Mp, N-Au-Mp and N-Au-Mp-Fa against HEp-2 cells was compared and found that the amount of Mp required to achieve 50% of growth of inhibition (IC{sub 50}) was much lower in N-Au-Mp-Fa than in free Mp and N-Au-Mp.

  5. Release Behavior and Toxicity Profiles towards Leukemia (WEHI-3B Cell Lines of 6-Mercaptopurine-PEG-Coated Magnetite Nanoparticles Delivery System

    Directory of Open Access Journals (Sweden)

    Dena Dorniani

    2014-01-01

    Full Text Available The coating of an active drug, 6-mercaptopurine, into the iron oxide nanoparticles-polyethylene glycol (FNPs-PEG in order to form a new nanocomposite, FPEGMP-2, was accomplished using coprecipitation technique. The resulting nanosized with a narrow size distribution magnetic polymeric particles show the superparamagnetic properties with 38.6 emu/g saturation magnetization at room temperature. Fourier transform infrared spectroscopy and the thermal analysis study supported the formation of the nanocomposite and the enhancement of thermal stability in the resulting nanocomposite comparing with its counterpart in free state. The loading of 6-mercaptopurine (MP in the FPEGMP-2 nanocomposite was estimated to be about 5.6% and the kinetic experimental data properly correlated with the pseudo-second order model. Also, the release of MP from the FPEGMP-2 nanocomposite shows the sustained release manner which is remarkably lower in phosphate buffered solution at pH 7.4 than pH 4.8, due to different release mechanism. The maximum percentage release of MP from the nanocomposite reached about 60% and 97% within about 92 and 74 hours when exposed to pH 7.4 and 4.8, respectively.

  6. Pneumocystis jiroveci pneumonia prophylaxis during maintenance therapy influences methotrexate/6-mercaptopurine dosing but not event-free survival for childhood acute lymphoblastic leukemia

    DEFF Research Database (Denmark)

    Levinsen, Mette; Shabaneh, Diana; Bohnstedt, Cathrine

    2012-01-01

    Trimethoprim-sulfamethoxazole (TMP/SMX) is used in children with acute lymphoblastic leukemia (ALL) to prevent Pneumocystis pneumonia (PCP). We explored to which extent TMP/SMX influenced methotrexate (MTX)/6-mercaptopurine (6MP) dosage, myelosuppression, and event-free survival (EFS) during.......06) were related to reduced EFS. ANC had no effect on EFS among TMP/SMX2–7 patients (P = 0.40) but did for TMP/SMXnever patients (P = 0.02). The difference in the effect on EFS between TMP/SMX2–7 and TMP/SMXnever patients was not significant (P = 0.46). EFS did not differ between TMP/SMX2–7 and TMP....../SMXnever patients (0.83 vs. 0.83; P = 0.82). These results suggest that TMP/SMX is effective in preventing PCP and may have an antileukemic effect. TMP/SMX should be given the entire duration of maintenance therapy...

  7. Determination of 6-Mercaptopurine in Rat Blood by Microdialysis Coupled with High Performance Liquid Chromatography on a Functionalized Multi-wall Carbon Nanotubes Modified Electrode

    Institute of Scientific and Technical Information of China (English)

    LIN Li; QIU Pei-hong; XIE Xia-feng; CAO Xu-ni; JIN Li-tong

    2005-01-01

    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.

  8. Meta-analysis of the impact of thioprine S-methyltransferase polymorphisms on the tolerable 6-mercaptopurine dose considering initial dose and ethnic difference

    Directory of Open Access Journals (Sweden)

    Kim MG

    2016-11-01

    Full Text Available Myeong Gyu Kim, Minoh Ko, In-Wha Kim, Jung Mi Oh College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea Abstract: A meta-analysis was conducted to decide whether to reduce an initial 6-mercaptopurine (6-MP dose in TPMT heterozygote in the case of an initial 6-MP dose of <75 mg/m2/d and to compare the tolerable 6-MP dose among different ethnic groups. The study was undertaken according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The differences in mean values of the tolerable 6-MP dose were calculated by using Comprehensive Meta-Analysis version 3. The results of the meta-analysis indicated that the tolerable 6-MP dose was significantly lower in the TPMT heterozygote group (difference in mean values =11.729, 95% confidence interval =7.617–15.842, P<0.001 even when the initial 6-MP dose was <75 mg/m2/d. The TPMT*3C allele-dominant ethnic group (Asian needed less reduction in mean 6-MP dose in comparison to the TPMT*3A allele-dominant ethnic group (Caucasian, Mediterranean, South American (difference in mean values =8.884 vs 15.324. In conclusion, the initial 6-MP dose needs to be reduced in TPMT heterozygote when compared to the wild-type, and ethnic difference might influence the tolerable 6-MP dose in TPMT heterozygotes. Keywords: 6-mercaptopurine, thiopurine S-methyltransferase, polymorphism, meta-analysis 

  9. Myelotoxicity after high-dose methotrexate in childhood acute leukemia is influenced by 6-mercaptopurine dosing but not by intermediate thiopurine methyltransferase activity

    DEFF Research Database (Denmark)

    Levinsen, Mette; Rosthøj, Susanne; Nygaard, Ulrikka

    2015-01-01

    , since TPMTIA had lower blood counts at initiation of HD-MTX compared with TPMTHA patients (median WBC 2.8 vs. 3.3 × 109/L, P = 0.01; median ANC 1.4 vs. 1.7 × 109/L, P = 0.02), TPMTIA continued to have lower WBC and ANC levels compared with TPMTHA during all 28 days after HD-MTX [relative difference 9......Purpose: Through enhancement of 6-mercaptopurine (6MP) bioavailability and inhibition of purine de novo synthesis, high-dose methotrexate (HD-MTX) may increase incorporation into DNA of 6-thioguanine nucleotides, the cytotoxic metabolites of 6MP. Patients with intermediate activity of thiopurine...... methyltransferase (TPMTIA) have higher cytosol 6-thioguanine nucleotide levels. We investigated toxicity following HD-MTX during MTX/6MP maintenance therapy in relation to 6MP and TPMT. Methods: Using linear mixed models, we explored myelo- and hepatotoxicity in relation to 6MP dosage and TPMT phenotype following 1...

  10. Hydrogen bonding and stacking pi-pi interactions in solid 6-thioguanine and 6-mercaptopurine (antileukemia and antineoplastic drugs) studied by NMR-NQR double resonance spectroscopy and density functional theory.

    Science.gov (United States)

    Latosińska, J N; Seliger, J; Zagar, V; Burchardt, D V

    2009-07-30

    A chemotherapeutic drug 6-thioguanine (2-amino-1,7-dihydro-6H-purine-6-thione, 6-TG) has been studied experimentally in the solid state by NMR-NQR double resonance and theoretically by the density functional theory. Fourteen resonance frequencies on (14)N have been detected and assigned to particular nitrogen sites in the 6-TG molecule. A valid assignment of NQR frequencies for 6-mercaptopurine (6-MP) has been proposed. The effects of molecular aggregations, related to intermolecular hydrogen bonding and stacking pi-pi interactions on the NQR parameters have been analyzed within the DFT and AIM (atoms in molecules) formalism for 6-TG and 6-mercaptopurine (6-MP). The so-called global reactivity descriptors have been calculated to compare the properties of molecules of 6-TG and 6-MP, to check the effect of -NH(2) group as well as to identify the differences in crystal packing.

  11. Individualized toxicity-titrated 6-mercaptopurine increments during high-dose methotrexate consolidation treatment of lower risk childhood acute lymphoblastic leukaemia. A Nordic Society of Paediatric Haematology and Oncology (NOPHO) pilot study

    DEFF Research Database (Denmark)

    Frandsen, Thomas L; Abrahamsson, Jonas; Lausen, Birgitte;

    2011-01-01

    This study explored the feasibility and toxicity of individualized toxicity-titrated 6-mercaptopurine (6MP) dose increments during post-remission treatment with High-dose methotrexate (HDM) (5000 mg/m(2), ×3) in 38 patients with Childhood (ALL). Patients were increased in steps of 25 mg 6MP/m(2...... the remaining patients (P = 0·03). This study shows individualized toxicity-titrated 6MP dosing during consolidation is feasible without increased risk of toxicity....

  12. Hydrogen bonding motifs, spectral characterization, theoretical computations and anticancer studies on chloride salt of 6-mercaptopurine: An assembly of corrugated lamina shows enhanced solubility

    Science.gov (United States)

    Suresh Kumar, S.; Athimoolam, S.; Sridhar, B.

    2015-10-01

    6-Mercaptopurine (an anti cancer drug), is coming under the class II Biopharmaceutics Classification System (BCS). In order to enhance the solubility with retained physiochemical/pharmaceutical properties, the present work was attempted with its salt form. The single crystals of 6-mercaptopurinium chloride (6MPCl) were successfully grown by slow evaporation technique under ambient temperature. The X-ray diffraction study shows that the crystal packing is dominated by N-H⋯Cl classical hydrogen bonds leading to corrugated laminar network. The hydrogen bonds present in the lamina can be dismantled as three chain C21(6), C21(7) and C21(8) motifs running along ab-diagonal of the unit cell. These primary chain motifs are interlinked to each other forming ring R63(21) motifs. These chain and ring motifs are aggregated like a dendrimer structure leading to the above said corrugated lamina. This low dimensional molecular architecture differs from the ladder like arrays in pure drug though it possess lattice water molecule in lieu of the chloride anion in the present compound. Geometrical optimizations of 6MPCl were done by Density Functional Theory (DFT) using B3LYP function with two different basis sets. The optimized molecular geometries and computed vibrational spectra are compared with their experimental counterparts. The Natural Bond Orbital (NBO) analysis was carried out to interpret hyperconjugative interaction and Intramolecular Charge Transfer (ICT). The chemical hardness, electronegativity, chemical potential and electrophilicity index of 6MPCl were found along with the HOMO-LUMO plot. The lower band gap value obtained from the Frontier Molecular Orbital (FMO) analysis reiterates the pharmaceutical activity of the compound. The anticancer studies show that 6MPCl retains its activity against human cervical cancer cell line (HeLa). Hence, this anticancer efficacy and improved solubility demands 6MPCl towards the further pharmaceutical applications.

  13. A sensitive inhibition chemiluminescence method for the determination of 6-mercaptopurine in tablet and biological fluid using the reaction of luminol-Ag(III) complex in alkaline medium

    Energy Technology Data Exchange (ETDEWEB)

    Sun, Hanwen, E-mail: hanwen@hbu.edu.cn [College of Chemistry and Environmental Science, Hebei University, Key Laboratory of Analytical Science and Technology of Hebei Province, Baoding 071002 (China); Wang, Ting; Liu, Xuyang; Chen, Peiyun [College of Chemistry and Environmental Science, Hebei University, Key Laboratory of Analytical Science and Technology of Hebei Province, Baoding 071002 (China)

    2013-02-15

    A sensitive inhibition chemiluminescence (CL) method for the determination of 6-mercaptopurine (6-MP) is developed. The mechanism of the CL reaction between Ag(III) complex {l_brace}[Ag(HIO{sub 6}){sub 2}]{sup 5-}{r_brace} and luminol in alkaline solution was proposed, along with the inhibition mechanism of 6-MP on the CL emission. The inhibition degree of CL emission was proportional to the logarithm of 6-MP concentration. The effects of the reaction conditions on CL emission and inhibition were examined. Under the optimized conditions, the detection limit (s/n=3) was 3.7 Multiplication-Sign 10{sup -10} g ml{sup -1}. The recoveries of 6-MP were in the range of 97.7-105% with the RSD of 2.1-3.4% (n=5) for tablet samples, 103-106% with the RSDs of 1.1-2.1% for spiked serum sample, and 97.2-101% with the RSD of 2.0-4.5% for spiked urine sample. The accuracy of this method for the tablet analysis was examined by comparing with the pharmacopoeia method. The proposed method was used for the determination of 6-MP at clinically relevant concentrations in real urine and serum samples with satisfactory results. - Highlights: Black-Right-Pointing-Pointer A sensitive inhibition chemiluminescence (CL) method for the determination of 6-MP is developed. Black-Right-Pointing-Pointer The inhibition mechanism of 6-MP on the CL emission was proposed. Black-Right-Pointing-Pointer The detection limit was 3.7 Multiplication-Sign 10{sup -10} g ml{sup -1}. Black-Right-Pointing-Pointer The accuracy was examined by comparing with the pharmacopoeia method.

  14. Patterns of 6-mercaptopurine and azathioprine maintenance therapy among a cohort of commercially insured individuals diagnosed with Crohn's disease in the United States

    Directory of Open Access Journals (Sweden)

    Lund JL

    2013-12-01

    Full Text Available Jennifer L Lund,1 Suzanne F Cook,2 Jeffery K Allen,2 Charlotte F Carroll,2 Michael D Kappelman3 1Department of Clinical Epidemiology, Aarhus University, Aarhus, Denmark; 2Worldwide Epidemiology, GlaxoSmithKline, Research Triangle Park, NC, USA; 3Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Background and aims: Thiopurines, including 6-mercaptopurine (6-MP and azathioprine (AZA, are the mainstay of maintenance therapy for Crohn's disease (CD. However, studies examining their effectiveness in routine practice among diverse patient populations are lacking. Among a cohort of new users of 6MP/AZA, we described treatment patterns and changes in subsequent therapy. Methods: Using the Truven Health Analytics databases, we identified all individuals diagnosed with CD and initiating 6-MP/AZA monotherapy from 2001–2008 (n=3,657. We estimated the proportion of CD patients remaining on 6-MP/AZA monotherapy, using Kaplan–Meier methods, and identified predictors of treatment noncontinuation, using multivariable Cox regression. Among the “noncontinuers,” we described subsequent patterns of maintenance therapy and summarized the diagnosis and procedure codes and prescription drug claims preceding treatment discontinuation. Results: The 1-year 6-MP/AZA treatment continuation rate was 42%. Children (age ≤18 years and individuals with no prior anti-tumor necrosis factor (TNF use were more likely to continue 6-MP/AZA, while those dispensed more (>4 outpatient prescriptions for any drug before initiation of 6-MP/AZA were less likely to continue maintenance treatment. Overall, 1,128 (39% and 105 (4% individuals experienced a clinical event potentially indicating active disease or 6-MP/AZA-intolerance prior to discontinuation, respectively. Most patients discontinued therapy; among the remaining patients who failed to continue 6-MP/AZA, most augmented with an anti-TNF. Conclusion: Most patients initiating 6-MP

  15. Oral methotrexate/6-mercaptopurine may be superior to a multidrug LSA2L2 Maintenance therapy for higher risk childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study

    DEFF Research Database (Denmark)

    Schmiegelow, Kjeld; Heyman, Mats; Kristinsson, Jon;

    2009-01-01

    The importance of maintenance therapy for higher risk childhood acute lymphoblastic leukemia (ALL) is uncertain. Between 1992 and 2001 the Nordic Society for Pediatric Haematology/Oncology compared in a nonrandomized study conventional oral methotrexate (MTX)/6-mercaptopurine (6MP) maintenance th...... significance. These results indicate that oral MTX/6MP maintenance therapy administered after the first year of remission can improve the cure rates of children with T-lineage or with higher risk B-lineage ALL.......The importance of maintenance therapy for higher risk childhood acute lymphoblastic leukemia (ALL) is uncertain. Between 1992 and 2001 the Nordic Society for Pediatric Haematology/Oncology compared in a nonrandomized study conventional oral methotrexate (MTX)/6-mercaptopurine (6MP) maintenance...... therapy with a multidrug cyclic LSA2L2 regimen. 135 children with B-lineage ALL and a white blood count > or =50 x 10/L and 98 children with T-lineage ALL were included. Of the 234 patients, the 135 patients who received MTX/6MP maintenance therapy had a lower relapse risk than the 98 patients who...

  16. Fluorescence analysis of 6-mercaptopurine with the use of a nano-composite consisting of BSA-capped Au nano-clusters and core-shell Fe3O4-SiO2 nanoparticles.

    Science.gov (United States)

    Li, Zhuo; Wang, Yong; Ni, Yongnian; Kokot, Serge

    2015-08-15

    A magnetic and fluorescent nano-composite was prepared. It comprised of a core of Fe3O4 nanoparticles (NPs), a silica shell and satellitic Au nano-clusters (AuNCs) capped with bovine serum albumin (BSA). This nano-composite has many desirable properties, e.g. magnetism, red emission, high water solubility, and high resistance to photo-bleaching. On addition of the analyte, 6-mercaptopurine (6-MP) or indeed other similar thiols, AuNCs formed aggregates because the existing cross-links within the Fe3O4 NPs@SiO2 and AuNC structure were broken in favor of the gold-thiol bonds. On suitable irradiation of such aggregates, red fluorescence was emitted at 613 nm. It decreased significantly as a function of the added 6-MP concentration, and the quenching ratio (F0 - F) / F0 was related linearly to the concentration of 6-MP in the range of 0.01 to 0.5 μmol L(-1). The detection limit was 0.004 μmol L(-1) (S/N=3). The method was strongly selective for 6-MP in the presence of oxidants, phenols, heavy-metal ions, and especially bio-thiols.

  17. 严重不耐受巯嘌呤的急性淋巴细胞白血病患儿的临床特征%Clinical features of acute lymphoblastic leukemia in children with 6-mercaptopurine to severe intolerant

    Institute of Scientific and Technical Information of China (English)

    王彬; 马晓莉; 郑杰; 金眉; 张大伟; 张瑞东; 解谨; 李志刚

    2013-01-01

    目的 分析严重不耐受巯嘌呤(6-MP)的ALL患儿的临床特征,并根据随访结果进一步了解这些患儿停化疗后不良反应的恢复情况.方法 选取2004年10月至2007年9月规范应用北京儿童医院-2003-急性淋巴细胞白血病(BCH-2003-ALL)化疗方案的ALL儿童,且处于6-MP维持化疗期间.按NCI-CTC V2.0评价6-MP的不良反应,详细记录出现3~4度不良反应(严重不耐受6-MP)患儿的临床资料和治疗情况,随访至2011年3月31日.结果 61例ALL患儿于服用标准剂量6-MP的2~4周出现3~4度不良反应,其中3~4度骨髓不良反应48例(78.7%),包括单纯骨髓不良反应39例(63.9%),同时伴有肝脏不良反应9例.单纯3~4度肝脏不良反应12例(19.7%),1例(1.6%)皮肤3度不良反应.严重不耐受6-MP的不良反应类型与ALL患儿年龄、性别、初诊时白细胞数及中枢侵犯均无明显关系(P=0.605,0.053,0.342,0.983),而与免疫类型和临床危险度密切相关(P =0.039,0.006).61例ALL患儿随访时间18~77个月(中位随访53个月),5例于治疗18~41个月后复发,其中6-MP维持治疗中复发4例,1例为停化疗5个月后,其余56例患儿均已停化疗,中位停药时间20个月(4.5 ~47.0个月),存活至今.除1例停药后1年仍轻度贫血,骨髓红细胞系增生不良,其余患儿骨髓不良反应恢复时间12~48周(平均15周),肝功能恢复时间4~25周(平均8周).免疫功能恢复时间6~12个月,1例皮肤不良反应患儿,停化疗后皮疹4周消失.结论 严重不耐受6-MP的ALL患儿近期随访结果表明,骨髓毒性和肝脏毒性是可逆的.这些患儿停化疗后预后良好,均未发现严重的脏器功能不良.但临床需要继续随访这些患儿,进一步了解与6-MP可能相关的第二肿瘤等远期不良反应,以明确严重不耐受6-MP的ALL患儿的远期预后.%Objective To analyze the clinical features of acute lymphoblastic leukemia (ALL)patients with severe intolerance to 6

  18. SYNTHESIS OF NEW TWO DERIVATIVES OF 6-MERCAPTOPURINE (6MP 6-[5-PYRIDINE-4-YL- 1, 2, 3, 4-OXADIAZOLE-2-YLDITHIOL]-9H-PURINE (38 AND 9H-PURINE-6-YL-BENYLDITHIOCARBAMATE (45 WITH CYTOTOXICITY RESULTS FROM THE NATIONAL CANCER INSTITUTE'S ANTICANCER DRUG SCREEN

    Directory of Open Access Journals (Sweden)

    Mohammed Hassan Mohammed et al

    2012-08-01

    Full Text Available 6-[(5-pyridine-yl-1, 2, 3, 4-oxadiazole-2-yldithiol]-9H-purine (38 and 9H-purine-6yl-benzyldithiocarbamate (45 are synthesized as possible prodrugs for 6-mercaptopurine(6-MP. The generation of the compounds 38, 42, 45 and 48 were accomplished following multistep reaction procedures. The reaction and purity of the products were checked by TLC, the structure of the final compounds and their intermediates were confirmed by their melting points, infra red spectroscopy and whether differences elemental microanalysis. To determine exist among in sensitivity different tissue types toward treatment with 38 and 45. The cytotoxicity of the two compounds and their intermediates were confirmed by their melting points, infra red spectroscopy and elemental microanalysis. The cytotoxicity of two derivatives (38 and 45 was assessed in National Cancer Institute's anticancer screening program, and the results were compared with the cytotoxicity of 6-MP obtained in the same screen. The results show that the compound 38 and 45 were more cytotoxic than 6-MP. Additionally the prodrugs are less effective against leukemia cell line than 6-MP. Both derivatives exhibited high growth-inhibitory activities in renal cell line. However, compound 45 is more cytotoxic than 38 against ovarian cell line.

  19. Determination of 6-mercaptopurine in human plasma by RP -HPLC%反相高效液相色谱法测定硫唑嘌呤代谢产物6-巯基嘌呤血浆药物浓度

    Institute of Scientific and Technical Information of China (English)

    朱妍妍; 柏智能; 唐丽琴

    2016-01-01

    Objective To establish a reversed phase high -performance liquid chromatography(RP -HPLC)method to determine 6-mercaptopurine (6-MP)in human plasma,thereby providing the foundation for clinical blood concentration monitoring.Methods U-sing Hypersil ODS2 column (250 nm ×4.6 nm,5 μm),the mobile phase was acetonitrile -0.3% glacial acetic acid (3∶97),the flow rate was 0.8 mL · min -1 ,the detection wavelength was set at 323 nm,and plasma samples were extracted by 20 μL 15% perchloric acid.Results A linearity was observed within the rangefrom 0.02 mg ·L -1 to 2.00 mg ·L -1 ,the lowest detection limit was 0.02 mg ·L -1 ,the average method recovery rate of four concentrations were 85.71%,92.93%,103.53% and 96.02%,respectively,and the intra -day and inter -day precision are <15% and in line with the Chinese Pharmacopoeia biological sample analysis regulations.Con-clusions The experiment successfully established a simple,fast,and low cost 6-MP plasma concentration measuring method with high sensitivity and good stability.Particularly,the method needs less blood.It is also in line with the relevant provisions of the AZA blood drug concentration monitoring and pharmacokinetics study.%目的:建立反相高效液相色谱法(RP -HPLC)检测人血浆中硫唑嘌呤(AZA)代谢产物6-巯基嘌呤(6-MP)的浓度,为临床进行血药浓度监测提供基础。方法采用 Hypersil ODS2色谱柱(250 nm ×4.6 nm,5μm),流动相为乙腈-0.3%冰乙酸化(3∶97),流速为0.8 mL·min -1,检测波长323 nm,血浆样品经15%高氯酸去蛋白后加氢氧钠(NaOH)调节 pH 后20μL 进样分析。结果6-MP 血浆样品在0.02~2.00 mg·L -1范围内线性关系良好,最低检测下限(LLOQ)为0.02 mg·L -1;LLOQ、高浓度(1.5 mg·L -1)、中浓度(1 mg·L -1)和低浓度(0.05 mg·L -1)提取回收率分别为85.71%、92.93%、103.53%和96.02%,质控四个浓度

  20. Study on the Inclusion Interactions of Cucurbit[7]uril with 6-Mercaptopurine and Adenine by Fluorescence Spectrometric Method%荧光光谱法研究葫芦[7]脲与6-巯嘌呤和腺嘌呤的包结作用

    Institute of Scientific and Technical Information of China (English)

    何小英; 李来生; 方奕珊; 陈红

    2012-01-01

    The inclusion interactions of cucurbit [7] uril (CB[7]) with 6-mercaptopurine (6-MP) and adenine(ADP) were studied by fluorescence spectrometric method. Several effect factors such as time, the pH value and temperature on the fluorescence intensity and the stability of the complex were investigated. The complex constants of CB[7] with 6-MP and ADP were determined according to the Benesi-Hildebrand equation,respectively. The results indicated that the pH value had a significant effect on the inclusion interactions. 6-MP and ADP had the optimal and stable excitation and emission wavelength as the pH value were 8. 0 for 6-MP and 2. 0 for ADP within 5 min. With the increasing of the concentrations of CB[7],the fluorescence of the two complexes increased obviously. The inclusion constants were 3. 6797× 102 L·mol-1 for 6-MP-CB[7] and 2. 2033 × 102 L·mol-1 for ADP-CB[7] at 298 K with the same inclusive ratio of It 1. The main interaction forces between CB[7] and the above purines were discussed based on the thermodynamic parameters. CB[7] is only well water-soluble superamolecules among cucurbituril family members, and has great potential as drug carriers with safety and low toxicity.%采用荧光光谱法分别研究了葫芦[7]脲(CB[7])对6-巯嘌呤(6-MP)和腺嘌呤(ADP)的包结作用.实验考察了时间、pH值以及温度对荧光强度和包结作用的影响,利用Benesi-Hildebrand方程分别计算出6-MP和ADP与CB[7]的包结常数.结果表明:酸度对体系的包结有明显的影响.在pH值为8.0和2.0左右时,6-MP和ADP分别具有稳定和最佳激发和发射波长,随着CB[7]浓度的增大,体系的荧光强度都有明显增强,包结作用迅速(小于5 min).实验得出CB[7]与6-MP和ADP的包结比均为1∶1,在298 K时的包结常数分别为3.6797×102 L·mol-1和2.2033×102 L·mo1-1.通过热力学参数的变化,探讨了维系包结物稳定性的主要作用力.CB[7]是葫芦脲家族中水溶性最强的主体分子,作为一种

  1. Activation of nuclear receptor Nur77 by 6-mercaptopurine protects against neointima formation

    NARCIS (Netherlands)

    Pires, N.M.M.; Pols, T.W.H.; Vries, M.R. de; Tiel, C.M.van; Bonta, P.I.; Vos, M.; Arkenbout, E.K.; Pannekoek, H.; Jukema, J.W.; Quax, P.H.A.; Vries, C.J.M. de

    2007-01-01

    BACKGROUND - Restenosis is a common complication after percutaneous coronary interventions and is characterized by excessive proliferation of vascular smooth muscle cells (SMCs). We have shown that the nuclear receptor Nur77 protects against SMC-rich lesion formation, and it has been demonstrated th

  2. Factitious Disorder in Crohn's Disease: Recurrent Pancytopenia Caused by Surreptitious Ingestion of 6-Mercaptopurine

    OpenAIRE

    Allon Kahn; Boroff, Erika S.; Martin, Kari A.; Northfelt, Donald W.; Heigh, Russell I

    2015-01-01

    Factitious disorder is a rare psychiatric illness characterized by the willful and deceptive induction of illness for the purpose of assuming the sick role. It presents a substantial diagnostic challenge, as patients often go to great lengths to conceal their deception. Accordingly, its presence in the full spectrum of gastrointestinal diseases is likely underappreciated. While factitious gastrointestinal bleeding, abdominal pain and diarrhea are relatively common, factitious non-gastrointest...

  3. Activation of nuclear receptor Nur77 by 6-mercaptopurine protects against neointima formation

    NARCIS (Netherlands)

    Pires, N.M.M.; Pols, T.W.H.; Vries, M.R. de; Tiel, C.M.van; Bonta, P.I.; Vos, M.; Arkenbout, E.K.; Pannekoek, H.; Jukema, J.W.; Quax, P.H.A.; Vries, C.J.M. de

    2007-01-01

    BACKGROUND - Restenosis is a common complication after percutaneous coronary interventions and is characterized by excessive proliferation of vascular smooth muscle cells (SMCs). We have shown that the nuclear receptor Nur77 protects against SMC-rich lesion formation, and it has been demonstrated

  4. 6-Mercaptopurine for Azathioprine Intolerant Inflammatory Bowel Disease: Literature Search and Reappraisal of Own Data.

    Science.gov (United States)

    Actis, Giovanni Clemente; Pellicano, Rinaldo; Rosina, Floriano

    2015-01-01

    Thiopurines have been shown to effectively maintain remission of both Crohn's disease (CD) and ulcerative colitis (UC), and to behave as disease modifiers if used for >12 months in UC. Gastric intolerance manifesting as nausea constitutes a demanding drawback of thiopurines, at times forcing treatment discontinuance. A few studies have now indicated that some patients might tolerate mercaptopurine (6-MP) for azathioprine. In this paper, we review the literature, and reappraise our own data against the published figures. The data which form the basis for this study span over all visit reports that were released between January 2008 and December 2011 in a primary care Hospital, in Turin, Italy. For the aim of this study we searched our own database and the MedLine using the key-words "azathioprine", "mercaptopurine", "thiopurine", "inflammatory bowel disease", "Crohn's disease", "ulcerative colitis". We retrieved 85 azathioprine prescriptions for 42 UC, 37 CD, and 6 miscellaneous patients. There were 10 episodes of gastric intolerance to azathioprine, which were switched to 6-MP: 6 out of 10 (60%) responded and tolerated the switch drug in a median follow-up of 66 months. Female gender prevailed (p=0.038) in the azathioprine intolerant subset. A trial with 6-MP is worth being offered to azathioprine intolerant inflammatory bowel disease subjects at any center matching the standard figures of specific performance.

  5. RETRACTED: Clinical significance of ITPA rs67002563 polymorphism in patients with acute lymphoblastic leukemia treated with 6-mercaptopurine.

    Science.gov (United States)

    Azimi, Fatemeh; Esmaeilzadeh, Abdolreza; Ramazani, Ali

    2015-12-01

    This article has been retracted at the request of the Authors as it was published without the knowledge of the full research group, using data that had already been published by the same research group in another study in Leukemia Research (http://dx.doi.org/10.1016/j.leukres.2015.06.016).

  6. Use of thiopurines in inflammatory bowel disease

    DEFF Research Database (Denmark)

    Frei, Pascal; Biedermann, Luc; Nielsen, Ole Haagen;

    2013-01-01

    The use of thiopurines as immunosuppression for the treatment of refractory or chronic active inflammatory bowel disease is established for both Crohn's disease and ulcerative colitis. Nevertheless, many questions remain concerning the optimal treatment regimens of azathioprine, 6-mercaptopurine...

  7. Hepatotoxicity During Maintenance Therapy and Prognosis in Children With Acute Lymphoblastic Leukemia

    DEFF Research Database (Denmark)

    Ebbesen, Maria S.; Nygaard, Ulrikka; Rosthøj, Susanne

    2017-01-01

    Hepatotoxicity is a known toxicity to treatment of childhood acute lymphoblastic leukemia. Hepatotoxicity occurs during maintenance therapy and is caused by metabolites of 6-Mercaptopurine (6 MP) and Methotrexate (MTX). Our objective was to investigate the association between alanine...

  8. Electrochemical Synthesis of 5-Purin-6'-ylthiocatechols in Aqueous Medium

    Institute of Scientific and Technical Information of China (English)

    LIU Fu-Jian; ZENG Cheng-Chu; PING Da-Wei; CAI Yuan-Li; ZHONG Ru-Gang

    2008-01-01

    The electrochemical synthesis of 5-purin-6'-ylthiocatechols was carried out by anodic oxidation of catechol derivatives la--ld in the presence of 6-mercaptopurine (2) in aqueous solution.Results of cyclic voltammetry and controlled-potential electrolysis indicated that the starting catechols were first oxidized to the corresponding o-benzoquinone,which underwent further Michael addition with 6-mercaptopurine to produce titled products 3a--3d following an EC (E=electrochemical and C=chemical step) mechanism.Such work further demonstrates the versatility of the anodic oxidation of catechols and their in-situ transformation for the synthesis of derivatized catechols.

  9. Maintenance therapy of childhood acute lymphoblastic leukemia revisited—Should drug doses be adjusted by white blood cell, neutrophil, or lymphocyte counts?

    DEFF Research Database (Denmark)

    Schmiegelow, Kjeld; Nersting, Jacob; Nielsen, Stine Nygaard

    2016-01-01

    BACKGROUND: 6-Mercaptopurine (6MP) and methotrexate (MTX) based maintenance therapy is a critical phase of childhood acute lymphoblastic leukemia treatment. Wide interindividual variations in drug disposition warrant frequent doses adjustments, but there is a lack of international consensus on do...

  10. The Circadian Schedule for Childhood Acute Lymphoblastic Leukemia Maintenance Therapy does not Influence Event-Free Survival in the NOPHO ALL92 Protocol

    DEFF Research Database (Denmark)

    Clemmensen, Kim K. B.; Christensen, Regitse H.; Shabaneh, Diana N.

    2014-01-01

    BACKGROUND: The event-free survival of childhood acute lymphoblastic leukemia (ALL) has been reported to be superior when oral methotrexate (MTX) and 6-mercaptopurine (6MP) maintenance therapy (MT) is administered in the evening compared to the morning. PROCEDURE: In the ALL92 MT study we prospec...

  11. Azathioprine-associated acute myeloid leukemia in a patient with Crohn's disease and thiopurine S-methyltransferase deficiency

    DEFF Research Database (Denmark)

    Yenson, P.R.; Forrest, D.; Schmiegelow, K.

    2008-01-01

    Immunosuppressive thiopurines like azathioprine, 6-mercaptopurine, and thioguanine are commonly used in inflammatory and neoplastic disorders. A subset of these patients are genetically slow metabolizers due to point-mutations in enzyme thiopurine S-methyltransferase (TPMT), and are at a higher r...

  12. Drug: D04931 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available 3], SLC28A3 [HSA:64078], SLC29A1 [HSA:2030], SLC29A2 [HSA:3177] Genomic biomarker: TPMT [HSA:7172] map07041 Antineoplastics... classification [BR:br08302] Antineoplastics Antimetabolites Mercaptopurine D04931 Mercaptopurine (INN) Immu...nological Agents Immune Suppressants 6-Mercaptopurine D04931 Mercaptopurine (INN) Antineoplastics [BR:br0830

  13. Drug: D01678 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available 284.2917 D01678.gif Antineoplastic map07041 Antineoplastics - antimetabolic agents CAS: 574-25-4 PubChem: 7...D01678 Drug Thioinosine (JAN); 6-Mercaptopurine riboside (JAN) C10H12N4O4S 284.0579

  14. The role and advances of immunomodulator therapy for inflammatory bowel disease

    DEFF Research Database (Denmark)

    Nielsen, Ole Haagen; Coskun, Mehmet; Steenholdt, Casper;

    2015-01-01

    Immune modulating drugs such as thiopurines (azathioprine and 6-mercaptopurine) and methotrexate has been a mainstay for treatment of inflammatory bowel disease (IBD) for decades. However, despite widely used in IBD, questions still remain concerning the most rational treatment regimens of these ...

  15. 1905-IJBCS-Article-Onanuga Ismaél

    African Journals Online (AJOL)

    hp

    damage to testicular structure, and this cannot be ameliorated by the use of ascorbic acid. © 2014 International ... white blood cells, Azathioprine makes the individual more ... Following oral ingestion of azathioprine, it is metabolized into the active. 6-mercaptopurine ... abdominal cavity to access the reproductive organs.

  16. Development of a Gene Cloning System in Methanogens.

    Science.gov (United States)

    1987-03-27

    resistance genes, and genes coding for enzymes that produce colored products will be tested as markers for plasmid transformation. A functional plasmid... Halobacterium volcanii 99 0 0 0 Escherichia coli 216 0 0 0 None 348 0 0 0 abbreviations: FU, 5-fluorouracil; MP, 6-mercaptopurine. Colonies were

  17. Cytostatic activity of some compounds from the unsaponifiable fraction obtained from virgin olive oil.

    Science.gov (United States)

    Saenz, M T; Garcia, M D; Ahumada, M C; Ruiz, V

    1998-06-30

    Oleuropein, tyrosol, squalene and the fraction of sterols and triterpenoid dialcohols from the unsaponifiable fraction obtained from virgin olive oil have been tested for possible cytostatic activity against McCoy cells, using 6-mercaptopurine as a positive control. The samples of sterols and triterpenic dialcohols showed a strong activity.

  18. Designer Thiopurine-analogues for Optimised Immunosuppression in Inflammatory Bowel Diseases.

    Science.gov (United States)

    Atreya, Imke; Diall, Alexandra; Dvorsky, Radovan; Atreya, Raja; Henninger, Christian; Grün, Mathias; Hofmann, Ute; Schaeffeler, Elke; López-Posadas, Rocío; Daehn, Ilse; Zenker, Stefanie; Döbrönti, Michael; Neufert, Clemens; Billmeier, Ulrike; Zundler, Sebastian; Fritz, Gerhard; Schwab, Matthias; Neurath, Markus F

    2016-10-01

    The clinical use of azathioprine and 6-mercaptopurine is limited by their delayed onset of action and potential side effects such as myelosuppression and hepatotoxicity. As these drugs specifically target the Vav1/Rac1 signalling pathway in T lamina propria lymphocytes via their metabolite 6-thio-GTP, we studied expression and optimised suppression of this pathway in inflammatory bowel diseases [IBD]. Rac1 and Vav1 expressions were analysed in mucosal immune cells in IBD patients. Targeted molecular modelling of the 6-thio-GTP molecule was performed to optimise Rac1 blockade; 44 modified designer thiopurine-analogues were tested for apoptosis induction, potential toxicity, and immunosuppression. Activation of the Vav1/Rac1 pathway in lymphocytes was studied in IBD patients and in lamina propria immune cells in the presence or absence of thiopurine-analogues. Several thiopurine-analogues induced significantly higher T cell apoptosis than 6-mercaptopurine. We identified a compound, denoted B-0N, based on its capacity to mediate earlier and stronger induction of T cell apoptosis than 6-mercaptopurine. B-0N-treatment resulted in accelerated inhibition of Rac1 activity in primary peripheral blood T cells as well as in intestinal lamina propria immune cells. Compared with 6-thio-GTP and 6-mercaptopurine, B-0N-treatment was associated with decreased myelo- and hepatotoxicity. The Vav1/Rac1 pathway is activated in mucosal immune cells in IBD. The designer thiopurine-analogue B-0N induces immunosuppression more potently than 6-mercaptopurine. Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  19. Update on thiopurine pharmacogenetics in inflammatory bowel disease.

    Science.gov (United States)

    Roberts, Rebecca L; Barclay, Murray L

    2015-07-01

    Azathioprine and 6-mercaptopurine remain pivotal therapies for the maintenance of disease remission in patients with Crohn's disease and ulcerative colitis. While thiopurine S-methyltransferase deficiency was the first pharmacogenetic phenomenon to be recognized to influence thiopurine toxicity and reliably predict leukopenia, it does not predict other adverse effects, nor does it explain most cases of thiopurine resistance. In recent years, a number of other genetic polymorphisms have received increasing attention in the literature. In particular, SNPs in NUDT15 and in the class II HLA locus have been shown to predict thiopurine-related leukopenia and pancreatitis. The aim of this review is to provide a concise update of genetic variability which may influence patient response to azathioprine and 6-mercaptopurine.

  20. Mercaptopurine/Methotrexate Maintenance Therapy of Childhood Acute Lymphoblastic Leukemia

    DEFF Research Database (Denmark)

    Schmiegelow, K.; Nielsen, Stine N; Frandsen, Thomas L;

    2014-01-01

    The antileukemic mechanisms of 6-mercaptopurine (6MP) and methotrexate (MTX) maintenance therapy are poorly understood, but the benefits of several years of myelosuppressive maintenance therapy for acute lymphoblastic leukemia are well proven. Currently, there is no international consensus on drug...... intensive and toxic earlier treatment phases, and often more challenging. Ongoing research address the applicability of drug metabolite measurements for dose adjustments, extensive host genome profiling to understand diversity in treatment efficacy and toxicity, and alternative thiopurine dosing regimens...

  1. [Problems in maintenance therapy in acute myeloid leukemias in adults].

    Science.gov (United States)

    Gürtler, R; Raderecht, C

    1975-01-01

    Problems of maintaining therapy for acute myelocytic leukemias in adults are discussed. The analysis of the maintaining therapy in 22 patients affected with an acute myelocytic leukemia and living for more than 6 months revealed that the interval therapy with a high dosage of cytostatic combinations in the sense of the COAP scheme is preferable compared with the daily administration of 6-mercaptopurin, in addition methotrexate twice a week. Reasons for this are discussed.

  2. Transportation of drug-gold nanocomposites by actinomyosin motor system

    Energy Technology Data Exchange (ETDEWEB)

    Kaur, Harsimran, E-mail: microsimbac@gmail.com; Chaudhary, Archana; Kaur, Inderpreet [Council of Scientific and Industrial Research (CSIR), Biomolecular Electronics and Nanotechnology Division (BEND), Central Scientific Instruments Organization - CSIO (India); Singh, Kashmir [Panjab University, Department of Biotechnology (India); Bharadwaj, Lalit M. [Council of Scientific and Industrial Research (CSIR), Biomolecular Electronics and Nanotechnology Division (BEND), Central Scientific Instruments Organization - CSIO (India)

    2011-06-15

    Nanotechnology is playing an important role in drug delivery to overcome limitations of conventional drug delivery systems in terms of solubility, in vivo stability, pharmacokinetics, and bio-distribution. The controlled transportation of drug into the cell and within the cell is a major challenge to be addressed. Cellular molecular motors have been exploited for their cargo carrying capacity for various applications including engineering and health care. Combination of nanotechnology and biomolecular motors can address some of the challenges in drug delivery. In the present study, transportation of drug nanocomposites has been demonstrated. Nanocomposites of 6-mercaptopurine and levodopa drugs (cancer and Parkinson's disease, respectively) were prepared with gold nanoparticles (GNPs) by covalent attachment and these nanocomposites were attached to actin filaments. These nanocomposites were in-turn transported by actin filaments on myosin tracks. Characterization of drug nanocomposites formation was done by UV-Vis spectroscopy, field emission scanning electron microscopy, transmission electron microscopy, and confocal microscopy. GNP composites of 6-mercaptopurine and levodopa were formed by sulfide and amide bond formation, respectively. Average velocity of actin filament attached to nanocomposites was found to be 3.17 and 3.89 {mu}m/s for levodopa and 6-mercaptopurine, respectively, as compared to actin filaments with velocity of 4.0-6.0 {mu}m/s. Three concepts have been proposed for the study of drug transportation into the cell based on polycationic complex formation, interaction of actin with cellular myosin and Biomolecular Adaptor for Retrograde Transport (BART) technology. The aspects of this study heads toward the development of an approach to utilize molecular motors for nanoscale transportation endogenously.

  3. [Azathioprine-induced pancytopenia: case series].

    Science.gov (United States)

    Martínez Faci, Cristina; Ros Arnal, Ignacio; Martínez de Zabarte Fernández, José M; Sorribes Estorch, Jordi; López Campos, Mónica; Rodríguez-Vigil Iturrate, Carmen

    2016-08-01

    Azathioprine is an immunosuppressive drug that has shown effectiveness in inflammatory bowel disease treatment. Its metabolite, 6-mercaptopurine, is metabolized through thiopurine methyltransferase. Patients with low enzyme activity may have more frequent and severe side effects. The most common is leukopenia, and rarely pancytopenia. The thiopurine methyltransferase activity monitoring shows an individualized profile of enzymatic activity but it should not replace monitoring by performing serial blood counts. In patients with fever and severe neutropenia, early empirical antibiotic treatment should be initiated to prevent severe and disseminated infection. Two patients with this condition are reported.

  4. Annual Research Progress Report Fiscal Year 1990. Volume 2. Department of Clinical Investigation (Brooke Army Medical Center)

    Science.gov (United States)

    1990-10-01

    W7-r5 CON AdI -f-O AT NUMBEf’l(’q CHARLES P. KINGSLEY Major, MC i 9. PERFORMING ORGANIZATION NlAME ANO ADDRESS 10 PROGRAM rLEmN . PROJECT. TASK...efficacy, toxicity and feasibility of administration of PEG -L-asparaginase versus native L-asparaginase as part of a standard combination chemotherapy...describe the pharmacokinetics and cytotoxic effect within the cerebrospi- nal fluid (CSF) of intravenous 6-mercaptopurine (6-MP) given -as a single agent

  5. Liquid chromatography-tandem mass spectrometry quantification of 6-thioguanine in DNA using endogenous guanine as internal standard

    DEFF Research Database (Denmark)

    Jacobsen, Jack Hummeland; Schmiegelow, Kjeld; Nersting, Jakob

    2012-01-01

    Thiopurines are S-substituted antimetabolites that are widely used in the treatment of hematological malignancies and as immunosuppressants. Because of extensive inter-individual variation in drug disposition and the significant toxicity associated with thiopurine therapy, there is a need...... was estimated at 63% (RSD 26%), which is corrected for by the internal standard resulting in stable quantification. The TG levels found were above the LOQ in 18 out of 18 childhood leukemia patients on 6-mercaptopurine/methotrexate maintenance therapy (median 377, range 45-1190 fmol/μg DNA) with intra...

  6. Vulvar ulcer as a presentation of systemic langerhans cell histiocytosis

    Directory of Open Access Journals (Sweden)

    Nina A Madnani

    2011-01-01

    Full Text Available We report a 38-year-old housewife with systemic Langerhans cell histiocytosis (LCH presenting as a chronic vulvar and peri-anal ulcer. She had systemic involvement in the form of diabetes insipidus and bone "hot-spots". She responded favorably to etoposide, 6-mercaptopurine, and systemic steroids, and has been in remission since 10 years. Chronic vulvar ulcers not responding to routine therapy should not be neglected and need to be biopsied repeatedly to come to a specific diagnosis. The vulvar ulcer in our case provided a vital clue to a systemic LCH, with a successful outcome.

  7. A child with pulmonary and liver Langerhans'-cell histiocytosis

    Institute of Scientific and Technical Information of China (English)

    MA Xiao-li; SHEN Kun-ling; WANG Bin

    2012-01-01

    Clinical categories of Langerhans cell histiocytosis (LCH) include single and multi-system disease.Pulmonary LCH is rare,which is an unusual interstitial lung disease with the characteristics of monoclonal proliferation and infiltration of Langerhans' cells to organs.We report our experience of a rare LCH case of multiple organs such as pulmonary and liver as the main clinical manifestation.The patient was treated with chemotherapy which included prednisone,vinblastine,methotrexate and 6-mercaptopurine for 52 weeks and follow up all along.The patient has a favorable clinical outcome.

  8. Remission induction and remission maintenance in adult acute nonlymphocytic leukemia employing a modified cytostatic (COAP) regimen.

    Science.gov (United States)

    Gerecke, D; Hirschmann, W D; Voigtmann, R; Gross, R

    1979-07-01

    Thirty adult patients suffering from acute nonlymphocytic leukemia (ANLL) were treated according to a modified COAP regimen. Vincristine, cyclophosphamide, and prednisone were given by push injection, while cytosine arabinoside was infused over periods of 8 h. Nineteen patients (63%) achieved complete remission. Remission maintenance therapy consisted of 6-mercaptopurine daily and methotrexate twice weekly. Later in the study, COAP consolidation and reinduction was added, which improved the median duration of complete remission from 7 to 24 months. Comparison of the results with the literature shows that the modified COAP regimen is one of the most effective treatment schedules for adult ANLL.

  9. [Differential diagnosis of chronic myeloic leucemia in infancy (author's transl)].

    Science.gov (United States)

    Binder, C; Pichler, E; Radaskiewicz, T; Scheibenreiter, S

    1976-01-01

    A 3 months old girl presented with significant enlargement of liver, spleen and lymphnodes, with moderate anemia, thrombopenia and leucocytosis. In the differential count there was a shift to the left and an increase of monocyte-like cells (35%). Differential diagnosis included leucemoid reaction, infectious mononucleosis, myelo-proliferative disorder with a missing C chromosome and chronic myeloid leucemia. Clinical symptoms, cytochemistry and caryotype of bone marrow cells suggested infantile chronic myeloic leucemia and normal ALP index and possibly normal HbF. Treatment with 6-mercaptopurine was followed by partial remission. The therapeutic consequences of exact differential diagnosis are discussed.

  10. Bayseian genomic models for the incorporation of pathway topology knowledge into association studies.

    Science.gov (United States)

    Brisbin, Abra; Fridley, Brooke L

    2013-08-01

    Pathway topology and relationships between genes have the potential to provide information for modeling effects of mRNA gene expression on complex traits. For example, researchers may wish to incorporate the prior belief that "hub" genes (genes with many neighbors) are more likely to influence the trait. In this paper, we propose and compare six Bayesian pathway-based prior models to incorporate pathway topology information into association analyses. Including prior information regarding the relationships among genes in a pathway was effective in somewhat improving detection rates for genes associated with complex traits. Through an extensive set of simulations, we found that when hub (central) effects are expected, the diagonal degree model is preferred; when spoke (edge) effects are expected, the spatial power model is preferred. When there is no prior knowledge about the location of the effect genes in the pathway (e.g., hub versus spoke model), it is worthwhile to apply multiple models, as the model with the best DIC is not always the one with the best detection rate. We also applied the models to pharmacogenomic studies for the drugs gemcitabine and 6-mercaptopurine and found that the diagonal degree model identified an association between 6-mercaptopurine response and expression of the gene SLC28A3, which was not detectable using the model including no pathway information. These results demonstrate the value of incorporating pathway information into association analyses.

  11. [Treatment of chronic refractory idiopathic thrombocytopenia purpura. 10 years experience at the Salvador Zubiran National Institute of Nutrition].

    Science.gov (United States)

    Pita-Ramírez, L; Hurtado-Monroy, R; Labardini-Méndez, J

    1992-01-01

    A total of 126 patients with chronic idiopathic thrombocytopenic purpura were diagnosed from January 1980 to January 1990 in our institute. In this group of patients, 21 were refractory to prednisone therapy, splenectomy or both, or had had a relapse after a good response with these treatments. They were given other therapies. There was enough information for evaluation in 16 of the 21 patients. The treatment responses were classified according to the post-therapy platelet counts: complete response (CR) = > 150 x 10(9)/L for more than three months; partial response (PR) = 50-150 x 10(9)/L for more than three months; any response (AR) = CR + PR; no response (NR) = < 50 x 10(9)/L. There were 15 women and one male. The median age was 41 years (range 11 to 65). 6-mercaptopurine was given in all patients with CR = 31.2%, PR = 18.8%, AR = 50% and NR = 50%. Seven patients received cyclophosphamide with CR = 28.6%, PR = 14.3%, AR = 42.9% and NR = 57%. Vincristine was given in four patients with only one PR. Interferon alpha 2B was given in four patients with two transitory PR. One patient received colchicine and vitamin C without response. It is concluded that 6-mercaptopurine and cyclophosphamide are useful drugs in refractory thrombocytopenic purpura.

  12. A case of adult Langerhans cell histiocytosis showing successfully regenerated osseous tissue of the skull after chemotherapy.

    Science.gov (United States)

    Suzuki, Takahiro; Izutsu, Koji; Kako, Shinichi; Ohta, Satoshi; Hangaishi, Akira; Kanda, Yoshinobu; Motokura, Toru; Chiba, Shigeru; Kurokawa, Mineo

    2008-04-01

    Langerhans cell histiocytosis (LCH) is a proliferative disorder of Langerhans cells and extremely rare in adults. Adult LCH is often associated with osteolytic bone lesions, but large bone-defective lesions have been rarely reported. We report an adult case of LCH accompanied by large osteolytic lesions in the skull that successfully responded to chemotherapy. A 47-year-old woman with LCH who had multiple, large osteolytic areas of more than 3 cm in diameter in the skull was admitted to our hospital. She was treated with systemic chemotherapy consisting of prednisolone, vinblastine, and 6-mercaptopurine. Twelve months later, when she completed the treatment, osteolytic areas were covered with hard osseous tissue, and X-ray examination confirmed regeneration of the bone. This case indicates that chemotherapy can be effective even for the treatment of large osteolytic lesions in adult LCH patients.

  13. Analytical detection and biological assay of antileukemic drug using gold nanoparticles

    Energy Technology Data Exchange (ETDEWEB)

    Selvaraj, V. [Department of Chemical Engineering, Alagappa College of Technology, Anna University, Chennai 600025 (India)]. E-mail: rajselva_77@yahoo.co.in; Alagar, M. [Department of Chemical Engineering, Alagappa College of Technology, Anna University, Chennai 600025 (India)]. E-mail: mkalagar@yahoo.com; Hamerton, I. [Chemistry Division, School of Biomedical and Molecular Sciences, University of Surrey, Guildford, Surrey GU2 7XH (United Kingdom)

    2006-11-12

    Gold nanoparticles are reported and evaluated as probes for the detection of anticancer drug 6-mercaptopurine (6-MP). The nature of binding between 6-MP and the gold nanoparticles via complexation is investigated using ultraviolet-visible spectrum, cyclic voltammetry, transmission electron microscopy, fluorescence and Fourier transform infrared (FT-IR) spectroscopy. The bound antileukemic drug is fluorescent and the quenching property of gold nanoparticles could be exploited for biological investigations. The 6-MP-colloidal gold complex is observed to have appreciable antibacterial and antifungal activity against Micrococcus luteus, Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Aspergillus fumigatus, and Aspergillus niger. The experimental studies suggest that gold nanoparticles have the potential to be used as effective carriers for anticancer drugs.

  14. Current medical therapy of inflammatory bowel disease

    Institute of Scientific and Technical Information of China (English)

    Kiron M. Das; Sherif A. Farag

    2000-01-01

    The current established drugs used to treat inflammatory bowel disease include glucocorticoids includingnewer agent budesonide, sulfasalazine and 5-ASA compounds such as Asacol, Pentasa, Dipentum andBalsalazide and immunomodulatory agents such as azathioprine, and 6-mercaptopurine. Additional drugswhich have been found to be useful, particularly in refractory cases of Crohn's disease including fistulizingtype of Crohn's disease, include cyclosporine A, methotrexate, humanized antibody against TNFa(cA2),FK506, IL-10, IL-11 and Probiotics. Various agents, whether used alone or in combination, have to betailored for each patient and none is ideal. Exciting new developments directed against proinflammatorypathways, cytokines, free oxygen radicals and cell surface related immune targets are areas of intense recentinvestigations and many novel therapeutic agents are expected to be available in the near future for medicaltreatment of inflammatory bowel disease.

  15. Role of radiation therapy in the treatment of pediatric non-Hodgkin's lymphomas. [Complications of local irradiation and chemotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Carabell, S.C.; Cassady, J.R.; Weinstein, H.J.; Jaff, N.

    1978-11-01

    Between 1971 and 1976, 64 patients less than 18 years of age with non-Hodgkin's lymphoma were treated at Boston's Children's Hospital Medical Center-Joint Center for Radiation Therapy. A multimodality approach was used, consisting of radiation therapy (3500 to 4500 rad), surgery, and chemotherapy. Since 1973, all patients have received a regimen initially comprising Adriamycin, Prednisone, 6-Mercaptopurine, Vincristine, and L-Asparaginase. Methotrexate was substituted for Adriamycin following a cumulative total dose of 450 mg/m/sup 2/. The 5-year actuarial survival for all patients was 61%, while relapse-free survival was 54%. The actuarial and relapse-free survival for patients presenting with localized disease was 75% and 72%, respectively. Median follow-up was 40 months and all relapses occurred within 24 months of initial therapy. A multidisciplinary approach, such as the current regimen, offers a good prognosis for this disease.

  16. Influence of methylene tetrahydrofolate reductase polymorphisms and coadministration of antimetabolites on toxicity after high dose methotrexate

    DEFF Research Database (Denmark)

    Niekerk, P.B. van Kooten; Schmiegelow, K.; Schroeder, H.

    2008-01-01

    BACKGROUND AND OBJECTIVE: Through interruption of maintenance treatment with 6-mercaptopurine (6MP), toxicity after high-dose methotrexate (HDMTX) may compromise the efficiency of the treatment of children with acute lymphocytic leukaemia (ALL). We investigated the influence of polymorphisms......-intensity co-treatment (6MP 75 mg/m(2)/d + MTX 20 mg/m(2)/wk) was found associated with increased odds of haematological toxicity (OR's: 3.47-7.88; P's: fever (OR = 2.2; P = 0.004) and interruption maintenance treatment (OR = 15.9; P ....006-0.027), fever (OR = 2.65; P = 0.037) and interruption of maintenance treatment (OR = 3.04; P = 0.032). No convincing associations were found between the MTHFR C677T or A1298C polymorphisms and toxicity. CONCLUSION: Our findings demonstrate that toxicity after HDMTX is influenced by coadministrated...

  17. [Long-term survival in childhood acute lymphocitic leukemia (author's transl)].

    Science.gov (United States)

    González-Martín, M C; Muñóz Villa, A; García-Miguel, P; Herrero Díez, A; Hurtado Ruano, T; Fernández Epifanio, J L

    1978-01-01

    Long-term results in the treatment of 116 patients of acute lymphocitic leukemia with ages between six months and seven years are reported. A first group A, formed by 76 patients, was treated with prednisone and vincristine as induction protocol and maintenance therapy with 6-mercaptopurine or methotrexate. No neuromeningeal prophylaxis was made, except some cases in which intratecal methotrexate was applied. 27 patients are alive, 21 of them (27,6%) remain in complete remission for more than three years. A second group B, formed by 40 patients, was treated more recently; with an induction protocol composed by prednisone, vincristine and L-asparaginase. All patients in this group received cranial irradiation and intratecal methotrexate. 31 patients are alive (77,5%), 13 of them (32,5%) remain in complete remission for more than two years. The evolution period in this group B is shorter, but some features are exposed which suggest the possibility of long-term better results.

  18. [Crohn's disease--standards of treatment 2004].

    Science.gov (United States)

    Kruis, W

    2005-10-12

    In Crohn's disease therapeutic concepts are according to distinct conditions. Course of the disease, the individual disease pattern and the aim of treatment are of particular significance. Care of patients with Crohn's disease requires interdisciplinary cooperation between gastroenterologists and surgeons. Primary therapy in mild to moderate disease comprises aminosalicylates and budesonide. Treatment of refractory or severe cases are corticosteroids. Immunosuppressive therapy is indicated in all kinds of complicated disease. First line immunosuppressants are Azathioprine and 6-Mercaptopurine while Methotrexate, Infliximab, Mycophenolatmofetil and other compounds represent alternative or rescue medications. Maintenance of remission should not be done on a regular basis but rather regarding the individual patients' situation. Risks have to be carefully balanced with possible benefits. The most important aim of treatment is quality of life.

  19. Newer treatments for inflammatory bowel disease.

    Science.gov (United States)

    Stotland, B R; Lichtenstein, G R

    1998-02-01

    Inflammatory bowel disease represents chronic idiopathic disorders which involve either the colon exclusively (ulcerative colitis) of any part of the gastrointestinal tract (Crohn's disease). The course of these entities is typified by periods of symptomatic exacerbation interspersed with clinical remissions. Management is based upon regimens which decrease mucosal inflammation. Colonic disease distal to the splenic flexure may be treated with topical therapy, but other regions generally necessitate oral therapy. Currently used medications include the aminosalicylates, glucocorticoids, antibiotics and immunomodulators. The immunomodulator class of medications includes azathioprine, 6-mercaptopurine, cyclosporine A and methotrexate. Newer agents include short-chain fatty acids, omega-3 fatty acids and antibodies directed to tumor necrosis factor. Medical management also occasionally involves optimizing nutritional status with the addition of elemental diets or total parenteral nutrition. Management of specific clinical presentations is discussed.

  20. Development of ulcerative colitis in a patient with multiple sclerosis following treatment with interferonβ 1a

    Institute of Scientific and Technical Information of China (English)

    Eckart Schott; Friedemann Paul; Jens T Wuerfel; Frauke Zipp; Birgit Rudolph; Bertram Wiedenmann; Daniel C Baumgart

    2007-01-01

    To alert clinicians to a potential novel adverse drug effect of interferonβ 1a, we herein report a patient with relapsing-remitting multiple sclerosis who developed ulcerative colitis following treatment with interferonβ 1a. Ulcerative colitis persisted despite discontinuation of interferonβ 1a treatment and switching the patient to glatiramer acetate. Tacrolimus (FK506),6-mercaptopurine, and prednisolone were required to induce remission. Both ulcerative colitis and multiple sclerosis were eventually well controlled using this regimen. Our report underscores that caution should be exercised when prescribing immunostimulatory agents in patients with inflammatory bowel disease (IBD) and challenges current efforts to stimulate innate immunity as a novel therapeutic concept for IBD.

  1. Successful treatment of idiopathic pulmonary capillaritis with intravenous cyclophosphamide.

    LENUS (Irish Health Repository)

    Flanagan, Frances

    2013-03-01

    Idiopathic pulmonary hemosiderosis (IPH), a subtype of diffuse alveolar hemorrhage is a rare condition, first described by Virchow in 1864. Historically, it manifests in children in the first decade of life with the combination of hemoptysis, iron deficiency anemia, and alveolar infiltrates on chest radiograph. More recently, diffuse alveolar hemorrhage has been classified by the absence or presence of pulmonary capillaritis (PC), the latter carrying a potential for a poorer outcome. While systemic corticosteroids remain the first line treatment option, other immune modulators have been trailed including hydroxychloroquine, azathioprine, 6-mercaptopurine, and cyclophosphamide with varying results. Our case demonstrates for the first time, the successful use of intravenous cyclophosphamide in the management of chronic idiopathic PC.

  2. Glutathione transferases in the bioactivation of azathioprine.

    Science.gov (United States)

    Modén, Olof; Mannervik, Bengt

    2014-01-01

    The prodrug azathioprine is primarily used for maintaining remission in inflammatory bowel disease, but approximately 30% of the patients suffer adverse side effects. The prodrug is activated by glutathione conjugation and release of 6-mercaptopurine, a reaction most efficiently catalyzed by glutathione transferase (GST) A2-2. Among five genotypes of GST A2-2, the variant A2*E has threefold-fourfold higher catalytic efficiency with azathioprine, suggesting that the expression of A2*E could boost 6-mercaptopurine release and adverse side effects in treated patients. Structure-activity studies of the GST A2-2 variants and homologous alpha class GSTs were made to delineate the determinants of high catalytic efficiency compared to other alpha class GSTs. Engineered chimeras identified GST peptide segments of importance, and replacing the corresponding regions in low-activity GSTs by these short segments produced chimeras with higher azathioprine activity. By contrast, H-site mutagenesis led to decreased azathioprine activity when active-site positions 208 and 213 in these favored segments were mutagenized. Alternative substitutions indicated that hydrophobic residues were favored. A pertinent question is whether variant A2*E represents the highest azathioprine activity achievable within the GST structural framework. This issue was addressed by mutagenesis of H-site residues assumed to interact with the substrate based on molecular modeling. The mutants with notably enhanced activities had small or polar residues in the mutated positions. The most active mutant L107G/L108D/F222H displayed a 70-fold enhanced catalytic efficiency with azathioprine. The determination of its structure by X-ray crystallography showed an expanded H-site, suggesting improved accommodation of the transition state for catalysis.

  3. Prognosis for nonoperative management of small-bowel obstruction in Crohn's disease.

    Science.gov (United States)

    Yaffe, B H; Korelitz, B I

    1983-06-01

    Small-bowel obstruction has been the most common indication for surgical intervention in Crohn's disease. If, however, obstruction relents without surgery, new programs of management may reduce or eliminate the need for resection. Over 7 years, 25 of 26 patients were relieved of an index episode of ileal obstruction--in most cases aided by a small-bowel tube and intravenous ACTH. They were then maintained on medical therapy, sulfasalazine (SASZ) alone in seven, SASZ and intermittent prednisone in 18, and then 6-mercaptopurine with or without SASZ in 14 of those 18. Seven patients have had no recurrence of obstruction after an average follow-up of 52 months. Recurrent obstruction occurred 52 times in 18 patients over the next 16-106 months; in all the obstruction was again relieved nonoperatively. Twelve patients underwent elective surgery, for recurrent obstruction in nine. Eight months seemed to offer a useful cutoff criterion for the likelihood of recurrence. When recurrence of obstruction took place within 8 months, surgery was ultimately required in six of seven patients. In contrast, patients who weathered the first 8 months without obstruction did well; only three of 11 ultimately required resection. Of 18 patients without recurrent obstruction for 8 months, only five were eventually operated upon, two for other indications; in 11 of the 13 patients who underwent no operation, the quality of life was excellent or good. We conclude that if the initial episode of small-bowel obstruction can be reversed, subsequent maintenance therapy including SASZ, and/or 6-mercaptopurine with an intermittent liquid diet in some patients eliminates or postpones the need for resection without compromise of the quality of life.

  4. Acute myelogenous leukemia following chemotherapy and radiation for rectal cancer

    Energy Technology Data Exchange (ETDEWEB)

    Aso, Teijiro; Hirota, Yuichi; Kondou, Seiji; Matsumoto, Isao; Matsuzaka, Toshimitsu; Iwashita, Akinori

    1989-03-01

    In August 1982, a 44-year-old man was diagnosed as having rectal cancer, histologically diagnosed as well differentiated adenocarcinoma, and abdominoperineal resection and colostomy were performed. Postoperatively, he received chemotherapy with mitomycin C up to a total dose of 100 mg. In September 1986, lung metastasis occurred and he was treated with a combination chemotherapy consisting of cisplatin, pirarubicin and 5-fluorouracil. In the following year, radiation treatment (total: 6900 rad) was given for a recurrent pelvic lesion. Peripheral blood on April 30, 1988, showed anemia, thrombocytopenia and appearance of myeloblasts, and a diagnosis of acute myelogenous leukemia (FAB: M1) was made. Combination chemotherapy (including aclarubicin, vincristine, behenoyl ara-C, daunorubicin, 6-mercaptopurine, cytarabine, etoposide and prednisolone) failed to induce remission and the patient died in June 1988. This case was thought to be one of secondary leukemia occurring after chemotherapy and radiation treatment for rectal cancer. This case clearly indicates the need for a careful follow-up of long-term survivors who have received cancer therapy. (author).

  5. Overexpression of P-glycoprotein induces acquired resistance to imatinib in chronic myelogenous leukemia cells

    Institute of Scientific and Technical Information of China (English)

    Xing-Xiang Peng; Amit K. Tiwari; Hsiang-Chun Wu; Zhe-Sheng Chen

    2012-01-01

    Imatinib,a breakpoint cluster region (BCR)-Abelson murine leukemia (ABL) tyrosine kinase inhibitor (TKI),has revolutionized the treatment of chronic myelogenous leukemia (CML).However,development of multidrug resistance(MDR) limits the use of imatinib.In the present study,we aimed to investigate the mechanisms of cellular resistance to imatinib in CML.Therefore,we established an imatinib-resistant human CML cell line (K562-imatinib) through a stepwise selection process.While characterizing the phenotype of these cells,we found that K562-imatinib cells were 124.6-fold more resistant to imatinib than parental K562 cells.In addition,these cells were cross-resistant to second- and third-generation BCR-ABL TKIs.Western blot analysis and reverse transcription-polymerase chain reaction(RT-PCR) demonstrated that P-glycoprotein (P-gp) and MDR1 mRNA levels were increased in K562-imatinib cells.In addition,accumulation of [14C]6-mercaptopurine (6-MP) was decreased,whereas the ATP-dependent efflux of [14C] 6-MP and [3H]methotrexate transport were increased in K562-imatinib cells.These data suggest that the overexpression of P-gp may play a crucial role in acquired resistance to imatinib in CML K562-imatinib cells.

  6. [Acute myeloid leukemia originating from the same leukemia clone after the complete remission of acute lymphoid leukemia].

    Science.gov (United States)

    Matsuda, Isao; Nakamaki, Tsuyoshi; Amaya, Hiroshi; Kiyosaki, Masanobu; Kawakami, Keiichiro; Yamada, Kazunari; Yokoyama, Akihiro; Hino, Ken-ichiro; Tomoyasu, Shigeru

    2003-09-01

    A 22-year-old female was diagnosed as having acute lymphoid leukemia (ALL) in February 1995, from the findings of peroxidase negative, CD10+, CD19+, TdT+ and rearrangement of IgH and TCR beta. AdVP (doxorubicin, vincristine and prednisolone) therapy achieved a complete remission (CR). Bone marrow transplantation had to be abandoned because of the lack of an HLA-identical donor. Intensification therapy was thus carried out repeatedly. In June 1998, myeloblast with Auer rods, peroxidase positive, CD13+, CD33+ and HLA-DR+, appeared. The patient was diagnosed as having lineage switch acute myeloid leukemia (AML) from ALL. Though A-DMP (cytosine arabinoside, daunorubicin, 6-mercaptopurine) therapy was resistant, AdVP therapy led to a CR. The patient died of cardiotoxicity from anthracyclines in February 1999. From the results of the Ramasamy method using the clonal rearrangements of the Ig heavy chain gene locus, the origin of the pathological cells of ALL and AML was indicated to be the same leukemia clone.

  7. The effect of immunosuppressive molecules on T-cell metabolic reprogramming.

    Science.gov (United States)

    Fernández-Ramos, Ana A; Poindessous, Virginie; Marchetti-Laurent, Catherine; Pallet, Nicolas; Loriot, Marie-Anne

    2016-08-01

    T lymphocytes undergo metabolic reprogramming to adapt to extracellular and intracellular cues. Specifically, T-cell metabolism results into ATP production, anabolism and catabolism pathways that not only support rapid cell growth and proliferation, but also differentiation and effector functions, recently referred as "immunometabolism". Quiescent naïve T cells rely on oxidative phosphorylation whereas aerobic glycolysis (Warburg effect) occurs in activated T cells (effector CD4(+) and CD8(+)). The molecular mechanisms that sense metabolic status and influence T-cell function require metabolic checkpoints including sensors of metabolic signals and transducers (Myc, HIF-1α, AMPK and mTOR). These metabolic checkpoints represent a novel therapeutic strategy for immune modulation. Interestingly, many immunosuppressive drugs including mTOR inhibitors (rapamycin), calcineurin inhibitors (tacrolimus, cyclosporine A) and inhibitors of de novo purine synthesis (6-mercaptopurine, mycophenolic acid and methotrexate) provide examples into how modulating these metabolic checkpoints can regulate T-cell activation, differentiation and function. In this Review we highlight emerging concepts about metabolic reprogramming in T-cell responses and we discuss the potential therapeutic interventions to influence T-cell fate and effector function. Copyright © 2016 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

  8. Clinical Study on Prospective Efficacy of All-Trans Acid, Realgar-Indigo Naturalis Formula Combined with Chemotherapy as Maintenance Treatment of Acute Promyelocytic Leukemia

    Directory of Open Access Journals (Sweden)

    Li Xiang-Xin

    2014-01-01

    Full Text Available Objectives. To test the efficiency and safety of sequential application of retinoic acid (ATRA, Realgar-Indigo naturalis formula (RIF and chemotherapy (CT were used as the maintenance treatment in patients with acute promyelocytic leukemia (APL. Methods. This was a retrospective study of 98 patients with newly diagnosed APL who accepted two different maintenance treatments. After remission induction and consolidation chemotherapy according to their Sanz scores, patients received two different kinds of maintenance scheme. The first regimen was using ATRA, RIF, and standard dose of CT sequentially (ATRA/RIF/CT regimen, while the second one was using ATRA and low dose of chemotherapy with methotrexate (MTX plus 6-mercaptopurine (6-MP alternately (ATRA/CTlow regimen. The OS, DFS, relapse rate, minimal residual disease, and adverse reactions in two groups were monitored and evaluated. Results. ATRA/RIF/CT regimen could effectively reduce the chance of relapse in different risk stratification of patients, but there was no significant difference in 5-year DFS rate and OS rate between the two groups. Besides, the patients in the experimental group suffered less severe adverse reactions than those in the control group. Conclusions. The repeated sequential therapeutic regimen to APL with ATRA, RIF, and chemotherapy is worth popularizing for its high effectiveness and low toxicity.

  9. [A study on inclusion complexes of cyclodextrin with three anticancer xanthines by fluorescence].

    Science.gov (United States)

    Wei, Yan-li; Dong, Chuan

    2004-07-01

    The inclusion complexes of beta-Cyclodextrin (beta-CD) and HP-beta-Cyclodextrin (HP-beta-CD) with 6-Mercaptopurine (6-MP), Azathioprine (BAN) and 8-Azaguanine (Azan) were investigated by fluorescence. Various factors affecting the formation of inclusion complexes were discussed in detail including formation time and pH effect. The formation constants of their inclusion complexes were determined. The results indicated that their inclusion was affected significantly by laying time and pH. The formation time of beta-CD inclusion complexes is much longer than that of HP-beta-CD. The optimum pH is about pH = 7.7-12. Their maximum excitation wavelengths are all in the range of 276-285 nm and the maximum emission wavelengths are all in the range of 328-353 nm. The fluorescence signals are intensified with increasing concentration of CD. The stoichiometries of the inclusion complexes of CD with these three anticancer xanthines are all 1:1 and the formation constants are calculated.

  10. Raman spectroscopy towards clinical application: drug monitoring and pathogen identification.

    Science.gov (United States)

    Neugebauer, Ute; Rösch, Petra; Popp, Jürgen

    2015-12-01

    Raman spectroscopy is a label-free method that measures quickly and contactlessly, providing detailed information from the sample, and has proved to be an ideal tool for medical and life science research. In this review, recent advances of the technique towards drug monitoring and pathogen identification by the Jena Research Groups are reviewed. Surface-enhanced Raman spectroscopy (SERS) and ultraviolet resonance Raman spectroscopy in hollow-core optical fibres enable the detection of drugs at low concentrations as shown for the metabolites of the immunosuppressive drug 6-mercaptopurine as well as antimalarial agents. Furthermore, Raman spectroscopy can be used to characterise pathogenic bacteria in infectious diseases directly from body fluids, making time-consuming cultivation processes dispensable. Using the example of urinary tract infection, it is shown how bacteria can be identified from patients' urine samples within <1 h. The methods cover both single-cell analysis and dielectrophoretic capturing of bacteria in suspension. The latter method could also be used for fast (<3.5 h) identification of antibiotic resistance as shown exemplarily for vancomycin-resistant enterococci. Copyright © 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

  11. Adult Multisystem Langerhans Cell Histiocytosis Presenting with Central Diabetes Insipidus Successfully Treated with Chemotherapy

    Directory of Open Access Journals (Sweden)

    Jung-Eun Choi

    2014-09-01

    Full Text Available We report the rare case of an adult who was diagnosed with recurrent multisystem Langerhans cell histiocytosis (LCH involving the pituitary stalk and lung who present with central diabetes insipidus and was successfully treated with systemic steroids and chemotherapy. A 49-year-old man visited our hospital due to symptoms of polydipsia and polyuria that started 1 month prior. Two years prior to presentation, he underwent excision of right 6th and 7th rib lesions for the osteolytic lesion and chest pain, which were later confirmed to be LCH on pathology. After admission, the water deprivation test was done and the result indicated that he had central diabetes insipidus. Sella magnetic resonance imaging showed a mass on the pituitary stalk with loss of normal bright spot at the posterior lobe of the pituitary. Multiple patchy infiltrations were detected in both lung fields by computed tomography (CT. He was diagnosed with recurrent LCH and was subsequently treated with inhaled desmopressin, systemic steroids, vinblastine, and mercaptopurine. The pituitary mass disappeared after two months and both lungs were clear on chest CT after 11 months. Although clinical remission in multisystem LCH in adults is reportedly rare, our case of adult-onset multisystem LCH was treated successfully with systemic chemotherapy using prednisolone, vinblastine, and 6-mercaptopurine, which was well tolerated.

  12. Thiopurines in the Management of Crohn’s Disease: Safety and Efficacy Profile in Patients with Normal TPMT Activity—A Retrospective Study

    Directory of Open Access Journals (Sweden)

    Amine Benmassaoud

    2016-01-01

    Full Text Available Background and Aims. Thiopurines are used in the treatment of Crohn’s disease (CD and thiopurine S-methyltransferase (TPMT activity can guide thiopurine dosing to avoid adverse events. This retrospective study evaluated the safety and efficacy of starting thiopurines at low dose versus full dose in patients with CD and normal TPMT. Methods. This was a single center retrospective study including adult CD patients with normal TPMT levels (≥25 nmol/hr/g Hgb who were followed for 1 year. Patients started at full dose of azathioprine (2–2.5 mg/kg or 6-mercaptopurine (1–1.5 mg/kg were compared to patients started at low dose. Harvey-Bradshaw index, treatment failure, and drug-related adverse events were recorded. Results. Our study included 134 patients. Both groups had similar incidences of drug-related adverse events and discontinuation of therapy due to side effects. Fifty-six percent of all adverse events occurred within 31 days and 92% occurred within 3 months of therapy. Clinical response favored the full-dose group at 6 months (69% versus 27%, p=0.0542. Conclusions. Our study indicates that it is safe to start patients on full-dose thiopurine when they have a normal TPMT given its very similar toxicity profile to patients started on low dose. This may also positively impact efficacy.

  13. First experience with intracytoplasmic sperm injection for extreme oligozoospermia associated with Crohn‘s disease and 6—mercaptopurine chemotherapy

    Institute of Scientific and Technical Information of China (English)

    E.ScottSills; MichaelJ.Tucker

    2003-01-01

    Aim:To describe the reproductive outcome following intracytoplasmic sperm injection(ICSI)for male factor infertility associated with Crohn's disease and 6-mercaptopurine(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.

  14. Treatment of inflammatory bowel disease: A review of medical therapy

    Institute of Scientific and Technical Information of China (English)

    Patricia L Kozuch; Stephen B Hanauer

    2008-01-01

    Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory diseases of the gastrointestinal tract. While a cure remains elusive, both can be treated with medications that induce and maintain remission. With the recent advent of therapies that inhibit tumor necrosis factor (TNF) alpha the overlap in medical therapies for UC and CD has become greater. Although 5-ASA agents have been a mainstay in the treatment of both CD and UC, the data for their efficacy in patients with CD, particularly as maintenance therapy, are equivocal. Antibiotics may have a limited role in the treatment of colonic CD. Steroids continue to be the first choice to treat active disease not responsive to other more conservative therapy; nonsystemic steroids such as oral and rectal budesonide for ileal and right-sided CD and distal UC respectively are also effective in mild-rnederate disease. 6-mercaptopurine (6-MP) and its prodrug azathioprine are steroid-sparing immunomodulators effective in the maintenance of remission of both CD and UC, while methotrexate may be used in both induction and maintenance of CD. Infliximab and adalimumab are anti-TNF agents approved in the US and Europe for the treatment of Crohn's disease, and infliximab is also approved for the treatment of UC.

  15. Are we giving azathioprine too late? The case for early immunomodulation in inflammatory bowel disease

    Institute of Scientific and Technical Information of China (English)

    María Josefina Etchevers; Montserrat Aceituno; Miquel Sans

    2008-01-01

    Inflammatory bowel disease (IBD) includes two entities, Crohn's disease and ulcerative colitis. Both are chronic conditions with frequent complications and surgical procedures and a great impact on patient's quality of life. The thiopurine antimetabolites azathioprine and 6-mercaptopurine are widely used in IBD patients. Current indications include maintenance therapy, steroid-dependant disease, fistula closure, prevention of infliximab immunogenicity and prevention of Crohn's disease recurrence. Surprisingly, the wide use of immunosuppressants in the last decades has not decreased the need of surgery, probably because these treatments are introduced at too late stages in disease course. An earlier use of immunossupressants is now advocated by some authors. The rational includes: (1) failure to modify IBD natural history of present therapeutic approach, (2) demonstration that azathioprine can induce mucosal healing, a relevant prognostic factor for Crohn's disease and ulcerative colitis, and (3) demonstration that early immunossupression has a very positive impact on pediatric, recently diagnosed Crohn's disease patients. We are now awaiting the results of new studies, to clarify the contribution of azathioprine, as compared to infliximab (SONIC Study), and to demonstrate the usefulness of azathioprine in recently diagnosed adult Crohn's disease patients (AZTEC study).

  16. Using adaptive model predictive control to customize maintenance therapy chemotherapeutic dosing for childhood acute lymphoblastic leukemia.

    Science.gov (United States)

    Noble, Sarah L; Sherer, Eric; Hannemann, Robert E; Ramkrishna, Doraiswami; Vik, Terry; Rundell, Ann E

    2010-06-07

    Acute lymphoblastic leukemia (ALL) is a common childhood cancer in which nearly one-quarter of patients experience a disease relapse. However, it has been shown that individualizing therapy for childhood ALL patients by adjusting doses based on the blood concentration of active drug metabolite could significantly improve treatment outcome. An adaptive model predictive control (MPC) strategy is presented in which maintenance therapy for childhood ALL is personalized using routine patient measurements of red blood cell mean corpuscular volume as a surrogate for the active drug metabolite concentration. A clinically relevant mathematical model is developed and used to describe the patient response to the chemotherapeutic drug 6-mercaptopurine, with some model parameters being patient-specific. During the course of treatment, the patient-specific parameters are adaptively identified using recurrent complete blood count measurements, which sufficiently constrain the patient parameter uncertainty to support customized adjustments of the drug dose. While this work represents only a first step toward a quantitative tool for clinical use, the simulated treatment results indicate that the proposed mathematical model and adaptive MPC approach could serve as valuable resources to the oncologist toward creating a personalized treatment strategy that is both safe and effective.

  17. Shorter maintenance therapy in childhood Acute Lymphoblastic Leukemia. The experience of the prospective, randomized Brazilian GBTLI ALL-93 protocol.

    Directory of Open Access Journals (Sweden)

    Silvia Regina Brandalise

    2016-10-01

    Full Text Available Maintenance therapy is an important phase of the childhood ALL treatment, requiring 2-year long therapy adherence of the patients and families. Weekly methotrexate (MTX with daily 6-mercaptopurine (6MP constitutes the backbone of maintenance therapy. Reduction in the maintenance therapy could overweight problems related with poverty of children with ALL living in Limited-Income countries (LIC. Objective: To compare, prospectively, the EFS rates of children with ALL treated according to two maintenance regimens: 18 vs 24 months duration. Materials and Methods: From October 1993 to September 1999, 867 consecutive untreated ALL patients 10 years and high WBC at diagnosis. Overall death in remission rate was 6.85% (56 patients. Deaths during maintenance were 13 in group 1 and 12 in group 2, all due to infection. Over 15 years of follow-up, two patients both from Group 2 presented a second malignancy (Hodgkin’s disease and thyroid carcinoma after 8.3 and 11 years off therapy, respectively. Conclusion: Six-month reduction of maintenance therapy in ALL children treated according to the GBTLI ALL-93 protocol, provided the same overall outcome as 2-year duration regimen.

  18. Current treatment of ulcerative colitis

    Institute of Scientific and Technical Information of China (English)

    Johannes Meier; Andreas Sturm

    2011-01-01

    Ulcerative colitis (UC) is a chronic disease featuring recurrent inflammation of the colonic mucosa. The goal of medical treatment is to rapidly induce a steroid-free remission while at the same time preventing complications of the disease itself and its treatment. The choice of treatment depends on severity, localization and the course of the disease. For proctitis, topical therapy with 5-aminosalicylic acid (5-ASA) compounds is used. More extensive or severe disease should be treated with oral and local 5-ASA compounds and corticosteroids to induce remission. Patients who do not respond to this treatment require hospitalization. Intravenous steroids or, when refractory, calcineurin inhibitors (cyclosporine, tacrolimus), tumor necrosis factor-α antibodies (infliximab) or immunomodulators (azathioprine, 6-mercaptopurine) are then called for. Indications for emergency surgery include refractory toxic megacolon, perforation, and continuous severe colorectal bleeding. Close collaboration between gastroenterologist and surgeon is mandatory in order not to delay surgical therapy when needed. This article is intended to give a general, practice- orientated overview of the key issues in ulcerative colitis treatment. Recommendations are based on published consensus guidelines derived from national and international guidelines on the treatment of ulcerative colitis.

  19. [Nodular regenerative hyperplasia as a complication of thiopurine treatment in a patient with inflammatory bowel disease].

    Science.gov (United States)

    Cohen-Ezra, Oranit; Avni, Yona; Morgenstern, Sara; Ben-Ari, Ziv

    2012-12-01

    Immunomodulator therapy with thiopurine analogues azathioprine or 6-mercaptopurine is commonly prescribed for the treatment of organ transplantation, inflammatory bowel disease, autoimmune diseases and malignancies. Hepatotoxicity due to thiopurine analogues usually presents as an increase in serum transaminase levels. Toxicity is usually not severe, and a dose reduction is effective in most patients. Nodular regenerative hyperplasia (NRH) is a very rare but potentially severe complication of thiopurine-containing therapy. NRH is often asymptomatic, neither biochemical nor molecular markers are indicative for NRH. The suspicion rises when there are clinical symptoms of portal hypertension or increases in transaminases levels orthrombocytopenia. Liver biopsy is essential for definitive diagnosis. This is a case report of a 40-year-old male patient with Crohn's disease who developed increased serum levels of liver enzymes and thrombocytopenia following the administration of thiopurine. Although treatment with thiopurine was discontinued, he has further progressed and presented with acute variceal bleeding due to portal hypertension. The diagnosis of nodular regenerative hyperplasia was proven by a liver biopsy. In conclusion, NRH is a very rare but potentially severe complication of thiopurine-containing immunosuppressive therapy for IBD.

  20. Sinusoidal obstruction syndrome (veno-occlusive disease in a patient receiving bevacizumab for metastatic colorectal cancer: a case report

    Directory of Open Access Journals (Sweden)

    Agarwal Vijay

    2008-07-01

    Full Text Available Abstract Introduction We present the case of a patient with colon cancer who, while receiving bevacizumab, developed sinusoidal obstruction syndrome (veno-occlusive disease (SOSVOD. Certain antitumour agents such as 6-mercaptopurine and 6-thioguanine have also been reported to initiate hepatic SOSVOD in isolated cases. There have been no reports so far correlating bevacizumab with SOSVOD. Case presentation A 77-year-old man was being treated with oxaliplatin and a modified de Gramont regimen of 5-fluorouracil for metastatic colon cancer. Bevacizumab (7.5 mg/kg was added from the seventh cycle onwards. Protracted neutropenia and thrombocytopenia led to discontinuation of oxaliplatin after the ninth cycle. A computed tomography scan showed complete response and bevacizumab was continued for another 3 months, after which time the patient developed right hypochondrial pain, transudative ascites, splenomegaly and abnormal liver function tests. Upper gastrointestinal endoscopy showed oesophageal varices. Liver biopsy showed features considered to be consistent with SOSVOD. Bevacizumab was stopped and a policy of watchful waiting was adopted. He tolerated the acute damage to his liver and subsequently the ascites resolved and liver function tests normalised. Conclusion We need to be aware that bevacizumab can cause sinusoidal obstruction syndrome (veno-occlusive disease and that the occurrence of ascites should not be attributed to progressive disease without appropriate evaluation.

  1. Management of difficult inflammatory bowel disease: where are we now?

    Institute of Scientific and Technical Information of China (English)

    D.S. Rampton

    2000-01-01

    Management of inflammatory bowel disease includes not only drug, endoscopic and surgical therapy but alsopsychosocial support, dietary and specific nutritional measures: a multidisciplinary medical, surgical, nursingand dietetic approach is essential for all patients, particularly those with complex or refractory disease. Inthis paper, current treatment of acute severe ulcerative colitis and steroid-refractory or -dependent Crohn'sdisease is reviewed. Adjunctive intravenous cyclosporin is an alternative to urgent colectomy in steroid-refractory patients with acute severe ulcerative colitis, while the place of intravenous heparin for thisindication awaits clarification. Azathioprine or 6-mercaptopurine are useful options in chronically active,steroid-refractory or -dependent Crohn's disease, but may take up to 4 months to work. Methotrexate is amore recent immunomodulatory alternative. Of new therapies selectively aimed at specific pathophysiologicaltargets, the first to reach clinical application is anti-TNF-alpha antibody (infliximab) for refractory Crohn'sdisease: its benefits are promising, but experience with it is limited to date, its cost is high and there areuncertainties about long-term safety. In view of the increasing variety and complexity of management optionsin inflammatory bowel disease, whether apparently responsive or difficult to treat, patients must participatein decisions about which therapies they are to be given.

  2. Experimental and theoretical dipole moments of purines in their ground and lowest excited singlet states

    Science.gov (United States)

    Aaron, Jean-Jacques; Diabou Gaye, Mame; Párkányi, Cyril; Cho, Nam Sook; Von Szentpály, László

    1987-01-01

    The ground-state dipole moments of seven biologically important purines (purine, 6-chloropurine, 6-mercaptopurine, hypoxanthine, theobromine, theophylline and caffeine) were determined at 25°C in acetic acid (all the above compounds with the exception of purine) and in ethyl acetate (purine, theophylline and caffeine). Because of its low solubility, it was not possible to measure the dipole moment of uric acid. The first excited singlet-state dipole moments were obtained on the basis of the Bakhshiev and Chamma—Viallet equations using the variation of the Stokes shift with the solvent dielectric constant-refractive index term. The theoretical dipole moments for all the purines listed above and including uric acid were calculated by combining the use of the PPP (π-LCI-SCF-MO) method for the π-contribution to the overall dipole moment with the σ-contribution obtained as a vector sum of the σbond moments and group moments. The experimental and theoretical values were compared with the data available in the literature for some of the purines under study. For several purines, the calculations were carried out for different tautomeric forms. Excited singlet-state dipole moments are smaller than the ground-state values by 0.8 to 2.2 Debye units for all purines under study with the exception of 6-chloropurine. The effects of the structure upon the ground- and excited-state dipole moments of the purines are discussed.

  3. Efficient DNA interstrand crosslinking by 6-thioguanine and UVA radiation.

    Science.gov (United States)

    Brem, Reto; Daehn, Ilse; Karran, Peter

    2011-08-15

    Patients taking the immunosuppressant and anticancer thiopurines 6-mercaptopurine, azathioprine or 6-thioguanine (6-TG), develop skin cancer at a very high frequency. Their DNA contains 6-TG which absorbs ultraviolet A (UVA) radiation, and their skin is UVA hypersensitive, consistent with the formation of DNA photodamage. Here we demonstrate that UVA irradiation of 6-TG-containing DNA causes DNA interstrand crosslinking. In synthetic duplex oligodeoxynucleotides, the interstrand crosslinks (ICLs) can form between closely opposed 6-TG bases and, in a less favoured reaction, between 6-TG and normal bases on the opposite strand. In vivo, UVA irradiation of cultured cells containing 6-TG-substituted DNA also causes ICL formation and induces the chromosome aberrations that are characteristically associated with this type of DNA lesion. 6-TG/UVA activates the Fanconi anemia (FA) pathway via monoubiquitination of the FANCD2 protein. Cells defective in the FA pathway or other factors involved in ICL processing, such as XPF and DNA Polζ, are all hypersensitive to killing by 6-TG/UVA-consistent with a significant contribution of photochemical ICLs to the cytotoxicity of this treatment. Our findings suggest that sunlight-exposed skin of thiopurine treated patients may experience chronic photochemical DNA damage that requires constant intervention of the FA pathway.

  4. Genotyping NUDT15 can predict the dose reduction of 6-MP for children with acute lymphoblastic leukemia especially at a preschool age.

    Science.gov (United States)

    Suzuki, Hisato; Fukushima, Hiroko; Suzuki, Ryoko; Hosaka, Sho; Yamaki, Yuni; Kobayashi, Chie; Sakai, Aiko; Imagawa, Kazuo; Iwabuchi, Atsushi; Yoshimi, Ai; Nakao, Tomohei; Kato, Keisuke; Tsuchida, Masahiro; Kiyokawa, Nobutaka; Koike, Kazutoshi; Noguchi, Emiko; Fukushima, Takashi; Sumazaki, Ryo

    2016-09-01

    The pharmacokinetics among children has been altered dynamically. The difference between children and adults is caused by immaturity in things such as metabolic enzymes and transport proteins. The periods when these alterations happen vary from a few days to some years after birth. We hypothesized that the effect of gene polymorphisms associated with the dose of medicine could be influenced by age. In this study, we analyzed 51 patients with childhood acute lymphoblastic leukemia (ALL) retrospectively. We examined the associations between the polymorphism in NUDT15 and clinical data, especially the dose of 6-mercaptopurine (6-MP). Ten of the patients were heterozygous for the variant allele in NUDT15. In patients under 7 years old with NUDT15 variant allele, the average administered dose of 6-MP was lower than that for the patients homozygous for the wild-type allele (P=0.04). Genotyping of NUDT15 could be a beneficial to estimate the tolerated dose of 6-MP for patients with childhood ALL, especially at a preschool age in Japan. Furthermore, the analysis with stratification by age might be useful in pharmacogenomics among children.

  5. Structural determinants of glutathione transferases with azathioprine activity identified by DNA shuffling of alpha class members.

    Science.gov (United States)

    Kurtovic, Sanela; Modén, Olof; Shokeer, Abeer; Mannervik, Bengt

    2008-02-01

    A library of alpha class glutathione transferases (GSTs), composed of chimeric enzymes derived from human (A1-1, A2-2 and A3-3), bovine (A1-1) and rat (A2-2 and A3-3) cDNA sequences was constructed by the method of DNA shuffling. The GST variants were screened in bacterial lysates for activity with the immunosuppressive agent azathioprine, a prodrug that is transformed into its active form, 6-mercaptopurine, by reaction with the tripeptide glutathione catalyzed by GSTs. Important structural determinants for activity with azathioprine were recognized by means of primary structure analysis and activities of purified enzymes chosen from the screening. The amino acid sequences could be divided into 23 exchangeable segments on the basis of the primary structures of 45 chosen clones. Segments 2, 20, 21, and 22 were identified as primary determinants of the azathioprine activity representing two of the regions forming the substrate-binding H-site. Segments 21 and 22 are situated in the C-terminal helix characterizing alpha class GSTs, which is instrumental in their catalytic function. The study demonstrates the power of DNA shuffling in identifying segments of primary structure that are important for catalytic activity with a targeted substrate. GSTs in combination with azathioprine have potential as selectable markers for use in gene therapy. Knowledge of activity-determining segments in the structure is valuable in the protein engineering of glutathione transferase for enhanced or suppressed activity.

  6. Management of postoperative recurrence of Crohn's disease.

    Science.gov (United States)

    van Lent, Anja U; D'Haens, Geert R

    2013-01-01

    The course of Crohn's disease (CD) is unpredictable and potentially destructive. The percentage of patients requiring surgery at some stage in their disease accumulates to over 70%. After resection of the affected intestine, reappearance of CD occurs in the majority of patients. Prophylactic medical therapy to reduce the rate of postoperative recurrence has been proven to be effective, yet the incidence of recurrence remains high. Patient profiling (risk stratification) is important in this postoperative setting. High-risk patients (associated with e.g. smoking, the need of repetitive surgery and penetrating disease) require strong immunosuppressive treatment, which should be commenced immediately after surgery, when recurrent disease activity begins. Additionally, early screening endoscopy should be performed to monitor treatment effect. The efficacy of thiopurines is shown to be higher than mesalazine or imidazole antibiotics alone for preventing and ameliorating endoscopic recurrence of CD postoperatively; however, anti-tumor necrosis factors (anti-TNFs) are increasingly considered the most potent agents. In patients with a risk factor for early postoperative recurrence, the first line of treatment is 6-mercaptopurine, in combination with imidazole antibiotics if tolerated, followed by anti-TNFs. When lesions are found at colonoscopy, therapy should be upscaled. We propose a treatment algorithm to direct therapeutic management of CD postoperatively. © 2013 S. Karger AG, Basel.

  7. [Treatment of fistulizing Crohn's disease].

    Science.gov (United States)

    Tonkić, Ante; Borzan, Vladimir

    2013-04-01

    The treatment of fistulating Crohn's disease should include a combined medical and surgical approach and should be defined on an individual basis. Asymptomatic enteroenteric fistulas usually require no treatment, but internal fistulas (gastrocolic, duodenocolic, enterovesical) that cause severe or persistent symptoms require surgical intervention. While low asymptomatic anal-introital fistula may not need surgical treatment, in case of a symptomatic enterovaginal fistula surgery is usually required. There are no controlled-randomized trials to assess the effect of medical treatment for non-perianal fistulating Crohn's disease. The incidence of perianal fistulae varies according to the location of the disease, with its occurrence varying between 21-23%. The diagnostic approach should include an examination under anesthesia, endoscopy, and either MRI or EUS before the treatment begins. Asymptomatic simple perianal fistulas require no treatment. The presence of a perianal abscess should be ascertained and if present should be drained urgently. In case of a complex perianal disease, seton placement should also be recommended. Antibiotics (metronidazole and ciprofloxacine) are useful for treating complex perianal disease, however, when discontinued, most of the fistulas relapse. The current consensus suggests that azathioprine/6-mercaptopurine is the first line medical therapy for complex perianal disease, which is always given in combination with surgical therapy (seton, fistulotomy/fistulectomy). Anti TNF-alpha agents (infliximab and adalimumab) should be used as a second choice medical treatment. In refractory and extensive complex perianal disease a diverting stoma or proctectomy should be performed.

  8. Diagnosis and management of Crohn's disease.

    Science.gov (United States)

    Wilkins, Thad; Jarvis, Kathryn; Patel, Jigneshkumar

    2011-12-15

    Crohn's disease is a chronic inflammatory condition affecting the gastrointestinal tract at any point from the mouth to the rectum. Patients may experience diarrhea, abdominal pain, fever, weight loss, abdominal masses, and anemia. Extraintestinal manifestations of Crohn's disease include osteoporosis, inflammatory arthropathies, scleritis, nephrolithiasis, cholelithiasis, and erythema nodosum. Acute phase reactants, such as C-reactive protein level and erythrocyte sedimentation rate, are often increased with inflammation and may correlate with disease activity. Levels of vitamin B12, folate, albumin, prealbumin, and vitamin D can help assess nutritional status. Colonoscopy with ileoscopy, capsule endoscopy, computed tomography enterography, and small bowel follow-through are often used to diagnose Crohn's disease. Ultrasonography, computed axial tomography, scintigraphy, and magnetic resonance imaging can assess for extraintestinal manifestations or complications (e.g., abscess, perforation). Mesalamine products are often used for the medical management of mild to moderate colonic Crohn's disease. Antibiotics (e.g., metronidazole, fluoroquinolones) are often used for treatment. Patients with moderate to severe Crohn's disease are treated with corticosteroids, azathioprine, 6-mercaptopurine, or anti-tumor necrosis factor agents (e.g., infliximab, adalimumab). Severe disease may require emergent hospitalization and a multidisciplinary approach with a family physician, gastroenterologist, and surgeon.

  9. Characteristics and degradation of chitosan/cellulose acetate microspheres with different model drugs

    Institute of Scientific and Technical Information of China (English)

    Hui-yun ZHOU; Xi-guang CHEN

    2008-01-01

    In this study, chitosan/cellulose acetate micro-spheres (CCAM) were prepared by W/O/W emulsification and solvent evaporation as a drug delivery system. The microspheres were spherical, free-flowing and non-aggre-gated. The CCAM had good flow and suspension ability. The loading efficiency of different model drugs increased with the increasing hydrophobicity of the drug. The load-ing efficiency of 6-mercaptopurine (6-MP) was more than 30% whereas that of ranitidine hydrochloride (RT) or acetaminophen (ACP) was only 10%. The pH values of solution affected the swelling ability of CCAM and the relative humidity had little effect on the characteristics of CCAM when it was not more than 75%. The CCAM system had a good effect on the controlled release of dif-ferent model drugs. However, the release rate became slower with the increase of the hydrophobicity of drugs. The release rate of CCAM loaded with hydrophilic RT was almost 60% during 48 h and the release rate of CCAM loaded with hydrophobic drug of 6-MP was not more than 30%. In the meantime, the CCAM system was degradable in vitro and the degradation rate was faster in lysozyme solution than that in the medium of PBS. So the CCAM system was a degradable promising drug delivery system especially for hydrophobic drugs.

  10. Adult Multisystem Langerhans Cell Histiocytosis Presenting with Central Diabetes Insipidus Successfully Treated with Chemotherapy

    Science.gov (United States)

    Choi, Jung-Eun; Lee, Hae Ri; Ohn, Jung Hun; Moon, Min Kyong; Park, Juri; Lee, Seong Jin; Choi, Moon-Gi; Yoo, Hyung Joon; Kim, Jung Han

    2014-01-01

    We report the rare case of an adult who was diagnosed with recurrent multisystem Langerhans cell histiocytosis (LCH) involving the pituitary stalk and lung who present with central diabetes insipidus and was successfully treated with systemic steroids and chemotherapy. A 49-year-old man visited our hospital due to symptoms of polydipsia and polyuria that started 1 month prior. Two years prior to presentation, he underwent excision of right 6th and 7th rib lesions for the osteolytic lesion and chest pain, which were later confirmed to be LCH on pathology. After admission, the water deprivation test was done and the result indicated that he had central diabetes insipidus. Sella magnetic resonance imaging showed a mass on the pituitary stalk with loss of normal bright spot at the posterior lobe of the pituitary. Multiple patchy infiltrations were detected in both lung fields by computed tomography (CT). He was diagnosed with recurrent LCH and was subsequently treated with inhaled desmopressin, systemic steroids, vinblastine, and mercaptopurine. The pituitary mass disappeared after two months and both lungs were clear on chest CT after 11 months. Although clinical remission in multisystem LCH in adults is reportedly rare, our case of adult-onset multisystem LCH was treated successfully with systemic chemotherapy using prednisolone, vinblastine, and 6-mercaptopurine, which was well tolerated. PMID:25309800

  11. The contribution of pharmacogenetics to pharmacovigilance.

    Science.gov (United States)

    Bondon-Guitton, Emmanuelle; Despas, Fabien; Becquemont, Laurent

    2016-04-01

    Since the beginning of this century, information on pharmacogenetics appears in the summary of product characteristics (SPC) of drugs. Pharmacogenetic tests particularly concern the enzymes involved in the metabolism of drugs, among which P450 cytochromes. Some patients known as poor metabolisers eliminate some drugs more slowly, causing overdoses and adverse drug reactions (ADRs). The best-known examples are AVK and VKORC1-CYP2C9 or clopidogrel and CYP2C19. In the USA, the tests are recommended before the introduction of these drugs to prevent the occurrence of ADRs. Other tests are also commonly performed to address the toxicity of certain anticancer drugs (DPYD-capecitabine, UGT1A1-irinotecan, TPMT 6-mercaptopurine). Pharmacogenetic testing is also available to identify HLA loci that are very strongly associated with the occurrence of immuno-allergic reactions to a specific drug. The best-known example is HLA-B*5701, strongly associated with hypersensitivity to abacavir, and this test is now always prescribed before the instatement of this drug.

  12. [Our experiences in the treatment of acute leukemias].

    Science.gov (United States)

    Jelić, S; Dragović, M; Vidaković, B; Plecas, V

    1976-01-01

    This paper deals with observations concerning treatment of acute leukemia in the Department of haematology of The Clinical hospital of Belgrade during the period from 1970 to 1975, and with results of the treatment itself. During the last five years, 27 patients with different types of acute leukemia were treated. The type of acute leukemia was determined using cytological criteria of Levy and Lortholary and cytochemical criteria as described by Hayhoe. One thrid of the patients died during the first days of hospitalisation, before any effect of cytostatic treatment could be evaluated. The cause of death in those patients was septic shock, intracranial haemorrhage or cardiovascular colapsus; initial signs of those complications of acute leukemia were allready present before diagnosis. Those data point to the fact that diagnosis of acute leukemia is often made too late, when irreversible ocmplications of the disease are allready established. Patients over sixty, often "fragile" to aggresive cytostatic therapy, may enter complete and relatively long lasting remission with induction therapy cosisting of 6-mercaptopurine and methotrexate only. Allthough the number of cases was rather limited, the authors had rather disappointing results with the 06-LA-66 protocole in adult lymphoblastic leukemia. The first with COAP treatment protocole seem encouraging. Adequate cytostatic therapy was in several cases impossible, duo to the lack of adequate substitution therapy; such inadequate cytostatic therapy resulted in partial remissions with a rather poor quality survival. A beeter cooperation is needed between hospital centers and institutions which provide matherial for the substitution theapy.

  13. [Stem-cell leukoses in the adult age--a clinical study].

    Science.gov (United States)

    Trux, F; Fink, R; Wutke, K

    1977-10-01

    The cytochemical differentiation of 86 stem cell leucoses of adults resulted with 74% of the cases in a clear prevalence of PAS-negative forms at this age. PAS-positive leucoses were observed only in 11%. The survival time of the patients revealed a clear dependence of the degree of the remission achieved. Also for the cases of PAS-negative leucoses, which achieved a complete remission, it was not worse than the survival time of acute lymphoplastic leucoses. However, the remission coefficient of the PAS-negative leucoses was essentially below the value of lymphoblastic forms. Multiple cytostatic combinations reached the best remission rates. Above all the combination of ribidomycin, cytosine arabinosid (Alexan), 6-mercaptopurine (Mercaleukin), prednisolone and vincristine (Oncovin), called RAMPO-scheme by the authors, seemed to give much success according to the results of this study. The number of complete and good partial remissions was calculated with 62% for the ViDaP-scheme, with 51% for the COAP-scheme. For all cases of treatment the coefficient of remission was 54%.

  14. Treatment of adult acute lymphoblastic leukaemia.

    Science.gov (United States)

    Jacobs, P; Wood, L; Novitzky, N

    1990-01-01

    Eighty-five consecutive patients with acute lymphoblastic leukaemia (ALL), having a median age of 24 years (range 10-69 years), underwent induction and consolidation chemotherapy with weekly parenteral vincristine, Adriamycin, l-asparaginase and daily oral prednisone (VAAP), followed by standard (CNS) prophylaxis. Maintenance therapy was given for 3 years and consisted of daily 6-mercaptopurine, weekly methotrexate and monthly intrathecal therapy, with drug intensification comprising either vincristine, Adriamycin and l-asparaginase (VAA) or cyclophosphamide, vincristine, cytosine arabinoside and prednisone (COAP). Complete remission (CR) was obtained in 59 patients (69%) and only the French-American-British (FAB) L1 morphology was a significant predictive factor (P = 0.048). Twenty-three patients failed to achieve CR and of these 12 had primary drug resistance. Median follow-up is currently 260 weeks, median predicted survival of all patients is 58 weeks and for those who achieved CR it is 104 weeks. Median duration of CR is 70 weeks. Of the prognostic factors for survival, only FAB L1 subtype was significant. Bone marrow relapses occurred in 29 patients, and of these 9 (31%) achieved CR. There has been CNS relapse in two patients and both have died. Eleven patients continue in CR off therapy, with a median of 152 weeks. This regimen is effective, with acceptable toxicity, and a number of patients are potentially cured. The incidence of resistant and relapsing disease is an argument for further intensifying both induction and postinduction therapy.

  15. Study of Drug Metabolism by Xanthine Oxidase

    Directory of Open Access Journals (Sweden)

    Lizhou Sun

    2012-04-01

    Full Text Available In this work, we report the studies of drug metabolism by xanthine oxidase (XOD with electrochemical techniques. Firstly, a pair of stable, well-defined and quasi-reversible oxidation/reduction peaks is obtained with the formal potential at −413.1 mV (vs. SCE after embedding XOD in salmon sperm DNA membrane on the surface of pyrolytic graphite electrode. Then, a new steady peak can be observed at −730 mV (vs. SCE upon the addition of 6-mercaptopurine (6-MP to the electrochemical system, indicating the metabolism of 6-MP by XOD. Furthermore, the chronoamperometric response shows that the current of the catalytic peak located at −730 mV increases with addition of 6-MP in a concentration-dependent manner, and the increase of the chronoamperometric current can be inhibited by an XOD inhibitor, quercetin. Therefore, our results prove that XOD/DNA modified electrode can be efficiently used to study the metabolism of 6-MP, which may provide a convenient approach for in vitro studies on enzyme-catalyzed drug metabolism.

  16. A nurse-driven outpatient clinic for thiopurine-treated inflammatory bowel disease patients reduces physician visits and increases follow-up efficiency.

    Science.gov (United States)

    López, María; Dosal, Angelina; Villoria, Albert; Moreno, Laura; Calvet, Xavier

    2015-01-01

    Patients on thiopurine therapy need frequent monitoring to prevent drug adverse events. To describe the structure and main results of a nurse-driven outpatient clinic (NDOC) program for the follow-up of patients receiving treatment with thiopurine immunosuppressants, we retrospectively reviewed patients' clinical charts on thiopurine drugs, azathioprine (AZA), and 6-mercaptopurine. We evaluated the efficacy of the NDOC by comparing the number of physician visits and the adequacy of laboratory controls for each patient before and after inclusion in the program. From January 2006 to December 2008, 179 patients were included. Of these, 102 had received thiopurines for at least 1 year before the start of the NDOC. Mean age was 42 ± 15 years; 83 were female. In all, 137 of the 179 patients (76%) had Crohn disease. AZA was the most frequent drug used (97%). Mean time of follow-up was 2.03 ± 0.9 years. Implementation of this program decreased the number of physician visits per year-from 4.6 ± 1.9 to 2.4 ± 1.3 (p < .001)-and the number of periods longer than 4 months without laboratory control (from 68% to 45%; p = .01). Leucopenia episodes and complications did not differ significantly before and after the start of the NDOC. Nurse-driven follow-up of these patients reduces physician visits while improving tightness of the follow-up.

  17. Growth media simulating ileal and colonic environments affect the intracellular proteome and carbon fluxes of enterohemorrhagic Escherichia coli O157:H7 strain EDL933.

    Science.gov (United States)

    Polzin, Sabrina; Huber, Claudia; Eylert, Eva; Elsenhans, Ines; Eisenreich, Wolfgang; Schmidt, Herbert

    2013-06-01

    In this study, the intracellular proteome of Escherichia coli O157:H7 strain EDL933 was analyzed by two-dimensional gel electrophoresis and matrix-assisted laser desorption ionization-time-of-flight (MALDI-TOF) spectrometry after growth in simulated ileal environment media (SIEM) and simulated colonic environment media (SCEM) under aerobic and microaerobic conditions. Differentially expressed intracellular proteins were identified and allocated to functional protein groups. Moreover, metabolic fluxes were analyzed by isotopologue profiling with [U-(13)C(6)]glucose as a tracer. The results of this study show that EDL933 responds with differential expression of a complex network of proteins and metabolic pathways, reflecting the high metabolic adaptability of the strain. Growth in SIEM and SCEM is obviously facilitated by the upregulation of nucleotide biosynthesis pathway proteins and could be impaired by exposition to 50 µM 6-mercaptopurine under aerobic conditions. Notably, various stress and virulence factors, including Shiga toxin, were expressed without having contact with a human host.

  18. Acute thiopurine overdose: analysis of reports to a National Poison Centre 1995-2013.

    Directory of Open Access Journals (Sweden)

    Claudia Gregoriano

    Full Text Available Literature regarding acute human toxicity of thiopurines is limited to a handful of case reports. Our objectives were to describe all cases of overdose with thiopurines reported to the Swiss Toxicological Information Centre between 1995-2013. A retrospective analysis was performed to determine circumstances, magnitude, management and outcome of overdose with these substances. A total of 40 cases (14 paediatric were reported (azathioprine, n = 35; 6-mercaptopurine, n = 5. Of these, 25 were with suicidal intent, 12 were accidental and 3 were iatrogenic errors. The magnitude of overdose ranged from 1.5 to 43 (median 8 times the usual dose in adults. Twelve cases (30% had attributable symptoms. The majority of these were minor and included gastrointestinal complaints and liver function test and blood count abnormalities. Symptoms were experienced by patients who took at least 1.5-times their usual daily thiopurine dose. Overdoses over two or more consecutive days, even if of modest size, were less well tolerated. One case of azathioprine and allopurinol co-ingestion over consecutive days led to agranulocytosis. Decontamination measures were undertaken in 11 cases (10 activated charcoal, 1 gastric lavage and these developed fewer symptoms than untreated patients. This study shows that acute overdoses with thiopurines have a favourable outcome in the majority of cases and provides preliminary evidence that gastrointestinal decontamination with activated charcoal may reduce symptom development after overdose of these substances if patients present to medical services soon after ingestion.

  19. Acute thiopurine overdose: analysis of reports to a National Poison Centre 1995-2013.

    Science.gov (United States)

    Gregoriano, Claudia; Ceschi, Alessandro; Rauber-Lüthy, Christine; Kupferschmidt, Hugo; Banner, Nicholas R; Krähenbühl, Stephan; Taegtmeyer, Anne B

    2014-01-01

    Literature regarding acute human toxicity of thiopurines is limited to a handful of case reports. Our objectives were to describe all cases of overdose with thiopurines reported to the Swiss Toxicological Information Centre between 1995-2013. A retrospective analysis was performed to determine circumstances, magnitude, management and outcome of overdose with these substances. A total of 40 cases (14 paediatric) were reported (azathioprine, n = 35; 6-mercaptopurine, n = 5). Of these, 25 were with suicidal intent, 12 were accidental and 3 were iatrogenic errors. The magnitude of overdose ranged from 1.5 to 43 (median 8) times the usual dose in adults. Twelve cases (30%) had attributable symptoms. The majority of these were minor and included gastrointestinal complaints and liver function test and blood count abnormalities. Symptoms were experienced by patients who took at least 1.5-times their usual daily thiopurine dose. Overdoses over two or more consecutive days, even if of modest size, were less well tolerated. One case of azathioprine and allopurinol co-ingestion over consecutive days led to agranulocytosis. Decontamination measures were undertaken in 11 cases (10 activated charcoal, 1 gastric lavage) and these developed fewer symptoms than untreated patients. This study shows that acute overdoses with thiopurines have a favourable outcome in the majority of cases and provides preliminary evidence that gastrointestinal decontamination with activated charcoal may reduce symptom development after overdose of these substances if patients present to medical services soon after ingestion.

  20. Inhibitors and pathways of hepatocytic protein degradation.

    Science.gov (United States)

    Seglen, P O; Gordon, P B; Grinde, B; Solheim, A; Kovács, A L; Poli, A

    1981-01-01

    On the basis of experiments using amino acids and various inhibitors (lysosomotropic amines, leupeptin, chymostatin, vanadate, vinblastine, anoxia, methylaminopurines), five different modes of endogenous protein degradation in isolated rat hepatocytes can be distinguished. The two non-lysosomal (amine-resistant) mechanisms preferentially degrade relatively labile (short-lived) proteins: one of these mechanisms is energy-dependent and chymostatin-sensitive, the other is not. Of the three lysosomal (amine-sensitive) mechanisms, one--quantitatively minor--is amino acid-resistant and preferentially degrades labile proteins. The two amino acid-sensitive mechanisms each seen account for about one-half of the degradation of relatively stable (long-lived) proteins; one of them is suppressed by leucine and apparently corresponds to the formation of electron microscopically visible autophagosomes; the other may represent a different type of autophagy, inhibited by asparagine and glutamine. A new class of inhibitors, the purine derivatives (methylated 6-aminopurines, and 6-mercaptopurines) appear to specifically suppress autophagic/lysosomal protein degradation, and may help to further elucidate the mechanisms of autophagy.

  1. Pharmacogenetics in inflammatory bowel disease

    Institute of Scientific and Technical Information of China (English)

    Marie Pierik; Paul Rutgeerts; Robert Vlietinck; Severine Vermeire

    2006-01-01

    Pharmacogenetics is the study of the association between variability in drug response and (or) drug toxicity and polymorphisms in genes. The goal of this field of science is to adapt drugs to a patient's specific genetic background and therefore make them more efficacious and safe. In this article we describe the variants in genes that influence either the efficacy or toxicity of common drugs used in the treatment of inflammatory bowel diseases (IBD), ulcerative colitis (UC),and Crohn's disease (CD) including sulfasalazine and mesalazine, azathioprine (AZA) and 6-mercaptopurine (6-MP), methotrexate (MTX), glucocorticosteroids (CSs) and infliximab. Furthermore, difficulties with pharmacogenetic studies in general and more specifically in IBD are described. Although pharmacogenetics is a promising field that already contributed to a better understanding of some of the underlying mechanisms of action of drugs used in IBD, the only discovery translated until now into daily practice is the relation between thiopurine S-methyltransferase (TPMT) gene polymorphisms and hematological toxicity of thiopurine treatment. In the future it is necessary to organize studies in well characterized patient cohorts who have been uniformly treated and systematically evaluated in order to quantitate drug response more objectively. An effort should be made to collect genomic DNA from all patients enrolled in clinical drug trials after appropriate informed consent for pharmacogenetic studies.

  2. Plasma-induced signatures reveal an extracellular milieu possessing an immunoregulatory bias in treatment-naive paediatric inflammatory bowel disease.

    Science.gov (United States)

    Gurram, B; Salzman, N H; Kaldunski, M L; Jia, S; Li, B U K; Stephens, M; Sood, M R; Hessner, M J

    2016-04-01

    The inflammatory state associated with Crohn's disease (CD) and ulcerative colitis (UC) remains incompletely defined. To understand more clearly the extracellular milieu associated with inflammatory bowel disease (IBD), we employed a bioassay whereby plasma of treatment naive paediatric IBD patients (n = 22 CD, n = 15 UC) and unrelated healthy controls (uHC, n = 10) were used to induce transcriptional responses in a healthy leucocyte population. After culture, gene expression was measured comprehensively with microarrays and analysed. Relative to uHC, plasma of CD and UC patients induced distinct responses consisting, respectively, of 985 and 895 regulated transcripts [|log2 ratio| ≥ 0·5 (1·4-fold); false discovery rates (FDR) ≤ 0·01]. The CD:uHC and UC:uHC signatures shared a non-random, commonly regulated, intersection of 656 transcripts (χ(2)  = P uHC and T1D plasma. Multiplex enzyme-linked immunosorbent assay (ELISA) and receptor blockade studies confirmed transforming growth factor (TGF)-β and interleukin (IL)-10 as contributors to the IBD signature. Analysis of CD patient signatures detected a subset of transcripts associated with responsiveness to 6-mercaptopurine treatment. Through plasma-induced signature analysis, we have defined a unique, partially TGF-β/IL-10-dependent immunoregulatory signature associated with IBD that may prove useful in predicting therapeutic responsiveness.

  3. Review of Experience of a Statewide Poison Control Center With Pediatric Exposures to Oral Antineoplastic Drugs in the Nonmedical Setting.

    Science.gov (United States)

    Thornton, Stephen L; Liu, Jehnan; Soleymani, Kamyar; Romasco, Rebecca L; Farid, Hanieh; Clark, Richard F; Cantrell, F Lee

    2016-01-01

    The use of oral antineoplastic agents in nonmedical settings continues to increase. There are limited data available on pediatric exposures to these agents. We sought to identify characteristics of such exposures. We performed a retrospective review of database of a statewide poison system from 2000 to 2009 for all cases of pediatric exposures to oral antineoplastic agents, which took place in a nonmedical setting. Data collected include gender, age, agent of exposure, dose, drug concentration, reason for exposure, symptoms, outcomes, interventions, and length of hospital stay. There were a total of 328 patients. The mean average age was 4.1 years. Eighty-nine percentage (n = 293) was unintentional. Exposures to 21 different antineoplastic agents were identified. Methotrexate (n = 91) and 6-mercaptopurine (n = 47) were the most common agents encountered. Two hundred ninety-nine (91%) cases had no symptoms reported. When reported, gastrointestinal symptoms (n = 17) and central nervous system sedation (n = 6) were most common. One case of pancytopenia was reported. No deaths were reported in this series. Sixty-seven percent (n = 220) were managed at home, whereas 19 (6%) were admitted to a health care facility. Cases were followed by the poison control center for 0.34 days (SD = 1.40). In this study, exposures to oral antineoplastics were primarily unintentional, asymptomatic, and managed at home. Study limitations include possible reporting bias, inability to objectively confirm exposures, and limited duration of monitoring by the poison control center. In this retrospective review, no significant morbidity or mortality was reported from pediatric exposures to oral antineoplastic drugs in the nonmedical setting.

  4. CLINICAL FEATURES AND CLINICAL OUTCOME OF ACUTE PROMYELOCYTIC LEUKEMIA PATIENTS TREATED AT CAIRO NATIONAL CANCER INSTITUTE IN EGYPT

    Directory of Open Access Journals (Sweden)

    Tamer M Fouad

    2011-01-01

    Full Text Available

    The current study reports the clinical features and treatment outcome of 67 patients with acute promyelocytic leukemia (APL presented to National Cancer Institute (NCI-Cairo, in Egypt from January 2007 to January 2011. The median follow-up time was 36 months. All patients were treated with the simultaneous administration of all-trans retinoic acid (ATRA and anthracyclin. The treatment protocol was modified due to resource limitations at the NCI-Cairo by replacing of idarubicin with doxorubicin in most of the cases and the inclusion of cytarbine during the consolidation phase only in pediatric patients. All patients who achieved molecular complete remission (CRm after consolidation received two-year maintenance treatment with low dose chemotherapy composed of 6 mercaptopurine, methotrexate and intermittent ATRA courses. The median age at presentation was 29 years. There was a slight male predominance (53%.  Bleeding was the most common presenting symptom (79%. Most patients had an intermediate risk Sanz score (49% and 34% had a high risk score.  All patients achieved molecular CR at end of consolidation therapy with a median duration of 100 days. The main therapeutic complications during the induction phase were febrile neutropenia (42%, bleeding (18% and differentiation syndrome (11%. Five patients died at diagnosis due to bleeding, three died during induction chemotherapy due to febrile neutropenia (n=2 and bleeding (n=1 and one patient died during consolidation therapy due to febrile neutropenia.  The 3-year OS was 89% and relapse rate was 3%. Adapting standard AIDA treatment protocols to limited resources by reducing dose-intensity during treatment consolidation, using ATRA in the consolidation phase and alternative anthracyclin (doxorubicin may be a valid treatment option in developing countries. In spite of the increased incidence of high and intermediate risk score APL in our sample, we reported an acceptable CR rate

  5. CLINICAL FEATURES AND CLINICAL OUTCOME OF ACUTE PROMYELOCYTIC LEUKEMIA PATIENTS TREATED AT CAIRO NATIONAL CANCER INSTITUTE IN EGYPT

    Directory of Open Access Journals (Sweden)

    Ola Khorshid

    2011-12-01

    Full Text Available The current study reports the clinical features and treatment outcome of 67 patients with acute promyelocytic leukemia (APL presented to National Cancer Institute (NCI-Cairo, in Egypt from January 2007 to January 2011. The median follow-up time was 36 months. All patients were treated with the simultaneous administration of all-trans retinoic acid (ATRA and anthracyclin. The treatment protocol was modified due to resource limitations at the NCI-Cairo by replacing of idarubicin with doxorubicin in most of the cases and the inclusion of cytarbine during the consolidation phase only in pediatric patients. All patients who achieved molecular complete remission (CRm after consolidation received two-year maintenance treatment with low dose chemotherapy composed of 6 mercaptopurine, methotrexate and intermittent ATRA courses. The median age at presentation was 29 years. There was a slight male predominance (53%.  Bleeding was the most common presenting symptom (79%. Most patients had an intermediate risk Sanz score (49% and 34% had a high risk score.  All patients achieved molecular CR at end of consolidation therapy with a median duration of 100 days. The main therapeutic complications during the induction phase were febrile neutropenia (42%, bleeding (18% and differentiation syndrome (11%. Five patients died at diagnosis due to bleeding, three died during induction chemotherapy due to febrile neutropenia (n=2 and bleeding (n=1 and one patient died during consolidation therapy due to febrile neutropenia.  The 3-year OS was 89% and relapse rate was 3%. Adapting standard AIDA treatment protocols to limited resources by reducing dose-intensity during treatment consolidation, using ATRA in the consolidation phase and alternative anthracyclin (doxorubicin may be a valid treatment option in developing countries. In spite of the increased incidence of high and intermediate risk score APL in our sample, we reported an acceptable CR rate, toxicity and OS.

  6. Metals and metal compounds in cancer treatment.

    Science.gov (United States)

    Desoize, Bernard

    2004-01-01

    Metals and metal compounds have been used in medicine for several thousands of years. In this review we summarized the anti-cancer activities of the ten most active metals: arsenic, antimony, bismuth, gold, vanadium, iron, rhodium, titanium, gallium and platinum. The first reviewed metal, arsenic, presents the anomaly of displaying anti-cancer and oncogenic properties simultaneously. Some antimony derivatives, such as Sb2O3, salt (tartrate) and organic compounds, show interesting results. Bismuth directly affects Helicobacter pylori and gastric lymphoma; the effects of bismuth complexes of 6-mercaptopurine are promising. Gold(I) and (III) compounds show anti-tumour activities, although toxicity remains high. Research into the potential use of gold derivatives is still ongoing. Several derivatives of vanadium show anti-proliferative activity, but their toxicity must be overcome. Several pieces of evidence indicate that iron deprivation could be an excellent therapeutic approach; furthermore, it is synergistic with classic anti-cancer drugs. Rhodium belongs to the same group as platinum and it also presents interesting activity, but with the same nephrotoxicity. Several rhodium compounds have entered phase I clinical trials. In contrast to the platinum complexes, titanium derivatives showed no evidence of nephrotoxicity or myelotoxicity; titanocene dichloride is undergoing clinical trial. The anti-proliferative effect of gallium could be related to its competition with the iron atom; in addition a derivative appears to reverse the multidrug resistance. The last metal reviewed, platinum, has given some of the very best anti-cancer drugs. Four derivatives are used today in the clinic; their mechanism of action and of resistance are described.

  7. NUDT15, FTO, and RUNX1 genetic variants and thiopurine intolerance among Japanese patients with inflammatory bowel diseases.

    Science.gov (United States)

    Sato, Toshiyuki; Takagawa, Tetsuya; Kakuta, Yoichi; Nishio, Akihiro; Kawai, Mikio; Kamikozuru, Koji; Yokoyama, Yoko; Kita, Yuko; Miyazaki, Takako; Iimuro, Masaki; Hida, Nobuyuki; Hori, Kazutoshi; Ikeuchi, Hiroki; Nakamura, Shiro

    2017-07-01

    Recent genome-wide analyses have provided strong evidence concerning adverse events caused by thiopurine drugs such as azathioprine (AZA) and 6-mercaptopurine. The strong associations identified between NUDT15 p.Arg139Cys and thiopurine-induced leukopenia and severe hair loss have been studied and confirmed over the last 2 years. However, other coding variants, including NUDT15 p.Val18_Val19insGlyVal, NUDT15 p.Val18Ile, and FTO p.Ala134Thr, and a noncoding variation in RUNX1 (rs2834826) remain to be examined in detail in this respect. Therefore, we investigated the correlation between these adverse events and the 5 recently identified variants mentioned above among Japanese patients with inflammatory bowel diseases (IBD). One hundred sixty thiopurine-treated patients with IBD were enrolled. Genotyping was performed using TaqMan SNP Genotyping Assays or Sanger sequencing. None of the 5 variants were associated with gastrointestinal intolerance to AZA. However, NUDT15 p.Arg139Cys was significantly associated with the interval between initiation and discontinuation of AZA among patients with gastrointestinal intolerance. This variant was strongly associated with early (<8 weeks) and late (≥8 weeks) leukopenia and severe hair loss. Moreover, it correlated with the interval between initiation of thiopurine therapy and leukopenia occurrence, and average thiopurine dose. NUDT15 p.Val18_Val19insGlyVal, NUDT15 p.Val18Ile, FTO p.Ala134Thr, and RUNX1 rs2834826 exhibited no significant relationship with the adverse events examined. Of the 5 variants investigated, NUDT15 p.Arg139Cys had the strongest impact on thiopurine-induced leukopenia and severe hair loss; therefore, its genotyping should be prioritized over that of other variants in efforts to predict these adverse events in Japanese patients with IBD.

  8. Microprocessor in controlled transdermal drug delivery of anti-cancer drugs.

    Science.gov (United States)

    Chandrashekar, N S; Shobha Rani, R H

    2009-12-01

    Microprocessor controlled transdermal delivery of anticancer drugs 5-Fluorouracil (5-FU) and 6-Mercaptopurine (6-MP) was developed and in vitro evaluation was done. Drugs were loaded based on the pharmacokinetics parameters. In vitro diffusion studies were carried at different current density (0.0, 0.1, 0.22, 0.50 mA/cm2). The patches were evaluated for the drug content, thickness, weight, folding endurance, flatness, thumb tack test and adhesive properties all were well with in the specification of transdermal patches with elegant and transparent in appearance. In vitro permeation studies through human cadaver skin showed, passive delivery (0.0 mA/cm2) of 6-MP was low. As the current density was progressively increased, the flux also increased. the flux also increased with 0.1 mA/cm2 for 15-20 min, but it was less than desired flux, 0.2 mA/cm2 for 30 min showed better flux than 0.1 mA/cm2 current, but lag time was more than 4 h, 0.5 mA/cm2 current for more than 1 h, flux was >159 microg/cm2 h which was desired flux for 6-MP. 5-FU flux reached the minimum effective concentration (MEC) of 54 microg/cm2 h with 0.5 mA/cm2 current for 30-45 min, drug concentration were within the therapeutic window in post-current phase. We concluded from Ohm's Law that as the resistance decreases, current increases. Skin resistance decrease with increase in time and current, increase in the drug permeation. Interestingly, for all investigated current densities, as soon as the current was switched off, 5-FU and 6-MP flux decreased fairly, but the controlled drug delivery can be achieved by switching the current for required period of time.

  9. Microscopic colitis.

    Science.gov (United States)

    Ianiro, Gianluca; Cammarota, Giovanni; Valerio, Luca; Annicchiarico, Brigida Eleonora; Milani, Alessandro; Siciliano, Massimo; Gasbarrini, Antonio

    2012-11-21

    Microscopic colitis may be defined as a clinical syndrome, of unknown etiology, consisting of chronic watery diarrhea, with no alterations in the large bowel at the endoscopic and radiologic evaluation. Therefore, a definitive diagnosis is only possible by histological analysis. The epidemiological impact of this disease has become increasingly clear in the last years, with most data coming from Western countries. Microscopic colitis includes two histological subtypes [collagenous colitis (CC) and lymphocytic colitis (LC)] with no differences in clinical presentation and management. Collagenous colitis is characterized by a thickening of the subepithelial collagen layer that is absent in LC. The main feature of LC is an increase of the density of intra-epithelial lymphocytes in the surface epithelium. A number of pathogenetic theories have been proposed over the years, involving the role of luminal agents, autoimmunity, eosinophils, genetics (human leukocyte antigen), biliary acids, infections, alterations of pericryptal fibroblasts, and drug intake; drugs like ticlopidine, carbamazepine or ranitidine are especially associated with the development of LC, while CC is more frequently linked to cimetidine, non-steroidal antiinflammatory drugs and lansoprazole. Microscopic colitis typically presents as chronic or intermittent watery diarrhea, that may be accompanied by symptoms such as abdominal pain, weight loss and incontinence. Recent evidence has added new pharmacological options for the treatment of microscopic colitis: the role of steroidal therapy, especially oral budesonide, has gained relevance, as well as immunosuppressive agents such as azathioprine and 6-mercaptopurine. The use of anti-tumor necrosis factor-α agents, infliximab and adalimumab, constitutes a new, interesting tool for the treatment of microscopic colitis, but larger, adequately designed studies are needed to confirm existing data.

  10. Effects of Immunosuppressants on Immune Response to Vaccine in Inflammatory Bowel Disease

    Directory of Open Access Journals (Sweden)

    Yuan Cao

    2015-01-01

    Full Text Available Objective: To evaluate the response rate to vaccination in different treatment groups (nonimmunosuppressants and immunosuppressants. Data Sources: We completed an online systematic search using PubMed to identify all articles published in English between January 1990 and December 2013 assessing the effect of the response rate to vaccination in different treatment groups (with and without immunomodulators. The following terms were used: "inflammatory bowel disease (IBD" OR "Crohn′s disease" OR "ulcerative colitis" AND ("vaccination" OR "vaccine" AND ("corticosteroids" OR "mercaptopurine" OR "azathioprine" OR "methotrexate [MTX]" AND "immunomodulators." Study Selection: The inclusion criteria of articles were that the studies: (1 Randomized controlled trials which included patients with a diagnosis of IBD (established by standard clinical, radiographic, endoscopic, and histologic criteria; (2 exposed patients received immunomodulators for maintenance (weight-appropriate doses of 6-mercaptopurine/azathioprine or within 3 months of stopping, 15 mg or more MTX per week or within 3 months of stopping; (3 exposed patients received nonimmunomodulators (no therapy, antibiotics only, mesalazine only, biological agent only such as infliximab, adalimumab, certolizumab or natalizumab or within 3 months of stopping one of these agents. The exclusion criteria of articles were that the studies: (1 History of hepatitis B virus (HBV, influenza or streptococcus pneumoniae infection; (2 patients who had previously been vaccinated against HBV, influenza or streptococcus pneumoniae; (3 any medical condition known to cause immunosuppression (e.g. chronic renal failure and human immunodeficiency virus infection; (4 individuals with positive hepatitis markers or liver cirrhosis; (5 patients with a known allergy to eggs or other components of the vaccines and (6 pregnancy. Results: Patients treated with immunomodulators were associated with lower response rates to

  11. Microscopic colitis

    Institute of Scientific and Technical Information of China (English)

    Gianluca Ianiro; Giovanni Cammarota; Luca Valerio; Brigida Eleonora Annicchiarico; Alessandro Milani; Massimo Siciliano; Antonio Gasbarrini

    2012-01-01

    Microscopic colitis may be defined as a clinical syndrome,of unknown etiology,consisting of chronic watery diarrhea,with no alterations in the large bowel at the endoscopic and radiologic evaluation.Therefore,a definitive diagnosis is only possible by histological analysis.The epidemiological impact of this disease has become increasingly clear in the last years,with most data coming from Western countries.Microscopic colitis includes two histological subtypes [collagenous colitis (CC) and lymphocytic colitis (LC)] with no differences in clinical presentation and management.Collagenous colitis is characterized by a thickening of the subepithelial collagen layer that is absent in LC.The main feature of LC is an increase of the density of intra-epitll lial lymphocytes in the surface epithelium.A number of pathogenetic theories have been proposed over the years,involving the role of luminal agents,autoimmunity,eosinophils,genetics (human leukocyte antigen),biliary acids,infections,alterations of pericryptal fibroblasts,and drug intake; drugs like ticlopidine,carbamazepine or ranitidine are especially associated with the development of LC,while CC is more frequently linked to cimetidine,non-steroidal antiinflammatory drugs and lansoprazole.Microscopic colitis typically presents as chronic or intermittent watery diarrhea,that may be accompanied by symptoms such as abdominal pain,weight loss and incontinence.Recent evidence has added new pharmacological options for the treatment of microscopic colitis:the role of steroidal therapy,especially oral budesonide,has gained relevance,as well as immunosuppressive agents such as azathioprine and 6-mercaptopurine.The use of anti-tumor necrosis factor-α agents,infliximab and adalimumab,constitutes a new,interesting tool for the treatment of microscopic colitis,but larger,adequately designed studies are needed to confirm existing data.

  12. Recent Advances in Autoimmune Pancreatitis.

    Science.gov (United States)

    Hart, Phil A; Zen, Yoh; Chari, Suresh T

    2015-07-01

    Autoimmune pancreatitis (AIP) is a form of chronic pancreatitis that is characterized clinically by frequent presentation with obstructive jaundice, histologically by a dense lymphoplasmacytic infiltrate with fibrosis, and therapeutically by a dramatic response to corticosteroid therapy. Two distinct diseases, type 1 and type 2 AIP, share these features. However, these 2 diseases have unique pancreatic histopathologic patterns and differ significantly in their demographic profiles, clinical presentation, and natural history. Recognizing the popular and long-standing association of the term "AIP" with what is now called "type 1 AIP," we suggest using "AIP" solely for type 1 AIP and to acknowledge its own distinct disease status by using "idiopathic duct-centric chronic pancreatitis" (IDCP) for type 2 AIP. AIP is the pancreatic manifestation of immunoglobulin G4-related disease (IgG4-RD). The etiopathogenesis of AIP and IgG4-RD is largely unknown. However, the remarkable effectiveness of B-cell depletion therapy with rituximab in patients with AIP and IgG4-RD highlights the crucial role of B cells in its pathogenesis. IDCP is less commonly recognized, and little is known about its pathogenesis. IDCP has no biomarker but is associated with inflammatory bowel disease in ~25% of patients. Recently, the international consensus diagnostic criteria for AIP identified combinations of features that are diagnostic of both diseases. Both AIP and IDCP are corticosteroid responsive; however, relapses are common in AIP and rare in IDCP. Therefore, maintenance therapy with either an immunomodulator (eg, azathioprine, 6-mercaptopurine, or mycophenolate mofetil) or rituximab is often necessary for patients with AIP. Long-term survival is excellent for both patients with AIP and patients with IDCP.

  13. Republished: recent advances in autoimmune pancreatitis: type 1 and type 2.

    Science.gov (United States)

    Kamisawa, Terumi; Chari, Suresh T; Lerch, Markus M; Kim, Myung-Hwan; Gress, Thomas M; Shimosegawa, Tooru

    2014-01-01

    Autoimmune pancreatitis (AIP) is a form of chronic pancreatitis characterised clinically by frequent presentation with obstructive jaundice, histologically by a lymphoplasmacytic infiltrate with fibrosis, and therapeutically by a dramatic response to steroids. When so defined, AIP can be sub-classified into two subtypes, 1 and 2. Recent international consensus diagnostic criteria for AIP have been developed for diagnosis of both forms of AIP. Type 1 AIP is the pancreatic manifestation of a multiorgan disease, recently named IgG4-related disease. Little is known about the pathogenesis of either form of AIP. Despite frequent association of type 1 AIP with elevated serum IgG4 levels and infiltration with IgG4-positive plasma cells, it is unlikely that IgG4 plays a pathogenic role in AIP. Type 1 AIP responds to steroids, but there needs to be consensus on treatment regimens for induction and therapeutic end points. Relapses are common, but can be reduced by long-term use of low-dose steroids. Recent reports suggest that immunomodulators (azathioprine, 6-mercaptopurine and mycophenolate mofetil), as well biological agents (the antibody to CD20, rituximab) may have a role in maintaining remission in relapsing type 1 AIP. Future studies should clarify the best management options for treatment of relapses and maintenance of remission. Type 2 AIP is a pancreas-specific disorder not associated with IgG4. It presents in younger individuals equally with obstructive jaundice and pancreatitis. The inflammatory process responds to steroid therapy; relapses are uncommon. The clinical spectrum and long-term outcomes of medically treated type 2 AIP are still being evaluated.

  14. Recent advances in autoimmune pancreatitis: type 1 and type 2.

    Science.gov (United States)

    Kamisawa, Terumi; Chari, Suresh T; Lerch, Markus M; Kim, Myung-Hwan; Gress, Thomas M; Shimosegawa, Tooru

    2013-09-01

    Autoimmune pancreatitis (AIP) is a form of chronic pancreatitis characterised clinically by frequent presentation with obstructive jaundice, histologically by a lymphoplasmacytic infiltrate with fibrosis, and therapeutically by a dramatic response to steroids. When so defined, AIP can be sub-classified into two subtypes, 1 and 2. Recent international consensus diagnostic criteria for AIP have been developed for diagnosis of both forms of AIP. Type 1 AIP is the pancreatic manifestation of a multiorgan disease, recently named IgG4-related disease. Little is known about the pathogenesis of either form of AIP. Despite frequent association of type 1 AIP with elevated serum IgG4 levels and infiltration with IgG4-positive plasma cells, it is unlikely that IgG4 plays a pathogenic role in AIP. Type 1 AIP responds to steroids, but there needs to be consensus on treatment regimens for induction and therapeutic end points. Relapses are common, but can be reduced by long-term use of low-dose steroids. Recent reports suggest that immunomodulators (azathioprine, 6-mercaptopurine and mycophenolate mofetil), as well biological agents (the antibody to CD20, rituximab) may have a role in maintaining remission in relapsing type 1 AIP. Future studies should clarify the best management options for treatment of relapses and maintenance of remission. Type 2 AIP is a pancreas-specific disorder not associated with IgG4. It presents in younger individuals equally with obstructive jaundice and pancreatitis. The inflammatory process responds to steroid therapy; relapses are uncommon. The clinical spectrum and long-term outcomes of medically treated type 2 AIP are still being evaluated.

  15. Metabolite monitoring to guide thiopurine therapy in systemic autoimmune diseases.

    Science.gov (United States)

    Chapdelaine, Aurélie; Mansour, Anne-Marie; Troyanov, Yves; Williamson, David R; Doré, Maxime

    2017-01-27

    6-Thioguanine nucleotide (6-TGN) is the active metabolite of thiopurine drugs azathioprine and 6-mercaptopurine. 6-Methylmercaptopurine (6-MMP) is an inactive and potentially hepatotoxic metabolite. A subgroup of patients (shunters) preferentially produce 6-MMP instead of 6-TGN, therefore displaying thiopurine resistance and risk for hepatotoxicity. Outside inflammatory bowel disease literature, few data exist regarding individualized thiopurine therapy based on metabolite monitoring. This study sought to describe metabolite monitoring in patients receiving weight-based thiopurine for systemic autoimmune diseases. Patients were enrolled using a laboratory database, and data were retrospectively collected. The correlation between the highest thiopurine dose (mg/kg) and the 6-TGN concentration (pmol/8 × 10(8) erythrocytes) was estimated with Pearson's correlation coefficient. Seventy-one patients with various systemic autoimmune conditions were enrolled. The correlation between the thiopurine dose and the 6-TGN level was weak for the overall patient sample (r = 0.201, p = 0.092) and for the subgroup of non-shunters (r = 0.278, p = 0.053). Subjects with 6-MMP levels >5700 pmol/8 × 10(8) erythrocytes had more hepatic cytolysis compared to subjects with 6-MMP 5700. Eleven non-shunters had hepatotoxicity, one of which had 6-MMP >5700. Thiopurine metabolite monitoring shows wide variability in 6-TGN levels among patients treated with weight-based thiopurine for systemic autoimmune diseases. Thirty-one percent of the patients in our series fulfilled the shunter definition. Thiopurine metabolite monitoring and dose adjustment to improve maintenance of remission and avoid hepatotoxicity should be studied prospectively.

  16. NUDT15 Variants Cause Hematopoietic Toxicity with Low 6-TGN Levels in Children with Acute Lymphoblastic Leukemia.

    Science.gov (United States)

    Yi, Eun Sang; Choi, Young Bae; Choi, Rihwa; Lee, Na Hee; Lee, Ji Won; Yoo, Keon Hee; Sung, Ki Woong; Lee, Soo-Youn; Koo, Hong Hoe

    2017-09-13

    We aimed to identify the impact of NUDT15 variants on thiopurine intolerance and 6-thioguanine nucleotide (6-TGN) levels in Korean children with acute lymphoblastic leukemia (ALL). Genotyping of NUDT15 was tested in 258 patients with ALL registered at Samsung Medical Center. Patients were classified into normal-activity (wild-type), intermediate-activity (heterozygous variant), and low-activity groups (homozygous or compound heterozygous variant). Clinical and laboratory features during the first year of maintenance therapy were investigated. A total of 182 patients were included in the final analysis. There were five (2.7%), 46 (25.3%), and 131 (72.0%) patients in low-, intermediate-, and normal-activity groups, respectively. The lowest 6-mercaptopurine (6-MP) dose (mg/m2/day) was administered to the low-activity group (low-activity group 7.5 vs. intermediate-activity group 24.4 vs. normal-activity group 31.1, p < 0.01) from three months to a year after beginning maintenance therapy. The low-activity group experienced the longest duration of therapy interruption during the first year (low-activity group 169 days vs. intermediate-activity group 30 days vs. normal-activity group 16 days, p < 0.01). They also showed the lowest blood cell counts and had a longer duration of leukopenia (low-activity group 131 days vs. intermediate-activity group 92 days vs. normal-activity group 59 days, p < 0.01). 6-TGN level and its ratio to 6-MP dose were lowest in the low-activity group. NUDT15 variants cause hematopoietic toxicity with low 6-TGN levels. NUDT15 genotyping should be conducted before administering thiopurine, and dose adjustments require caution regardless of 6-TGN levels.

  17. Infliximab for the Treatment of Crohn'S Disease: Review and Indications for Clinical Use in Canada

    Directory of Open Access Journals (Sweden)

    Remo Panaccione

    2001-01-01

    Full Text Available Crohn's disease is a chronic inflammatory disorder of the gastrointestinal tract. It may affect any portion of the gastrointestinal tract from the mouth to the anus. Symptoms typically include cramping abdominal pain, diarrhea (which may be bloody and nausea. As the severity of the illness worsens, patients may experience constant abdominal pain, vomiting, weight loss and fever. From the perspective of the patient, disease symptoms significantly impair quality of life, and interfere with their work environment and activities of daily living. Unfortunately, there is no cure for Crohn's disease. Patients experience a chronic, relapsing course characterized by recurrent flares of their disease. Conventional medical treatment of Crohn's disease includes the use of non-specific anti-inflammatory drugs (5-aminosalicylic acid agents, prednisone, budesonide, immunosuppressives (6-mercaptopurine, azathioprine, methotrexate and antibiotics. A variable onset of action, incomplete response rates and a significant risk of adverse effects characterize current therapies. Although surgery is frequently used to treat complications or medically refractory disease, postoperative recurrence is a common problem. Infliximab, a murine chimeric monoclonal antibody directed toward tumour necrosis factor-alpha, is a highly effective treatment of active Crohn's disease. In randomized, placebo-controlled clinical trials, 33% of patients treated with infliximab 5 mg/kg achieved remission (Crohn's Disease Activity Index score less than 150, compared with only 4% of those receiving placebo (P<0.001. Additionally, infliximab is the only drug therapy shown to be effective for the treatment of fistulizing Crohn's disease. In studies done to date, infliximab appears to be well tolerated and has a favourable side effect profile.

  18. Organ irradiation and combination chemotherapy in treatment of acute lymphocytic leukaemia in children.

    Science.gov (United States)

    Lanzkowsky, P; Shende, A; Aral, I; Saluja, G

    1975-01-01

    Lanzkowsky, P., Shende, A., Aral, I., Saluja, G. (1975). Archives of Disease in Childhood, 50, 685. Organ irradiation and combination chemotherapy in treatment of acute lymphocytic leukaemia in children. A total of 30 consecutive children with acute lymphocytic leukaemia (ALL) were treated from June 1971 until December 1974. Remission was induced with the use of vincristine and prednisone. After induction of remission, cranial irradiation and intrathecal methotrexate were given. Then the liver, spleen, and kidney were irradiated and 6-mercaptopurine, cyclophosphamide, and methotrexate were administered during the maintenance phase. Pulsed doses of vincristine and prednisone were administered at 10- to 12-week intervals. The patients were subdivided into two groups based on their initial white blood cell (WBC) counts: a standard risk group with an initial WBC count of less than 25 000/mm3 (25 X 10(9)/1) and a high risk group with an initial WBC count greater than 25 000/mm3 (25 X 10(9)/1). Of the 30 children entered in this study one standard risk patient died in the induction phase before attaining remission. Analysis of the results is therefore based on the remaining 29 patients, 22 standard risk and 7 high risk patients, who attained complete remission. Survival rates in continuous remission were found to be 43% of the high risk group, 88% for the standard risk group, and 77% for the combined group. Analysis of the data indicates that this therapy is unsatisfactory in high risk ALL. The results to date of this therapy for standard risk are sufficiently encouraging to continue its use in this subgroup of patients. PMID:1059384

  19. Preparation, characterization, and in vitro drug release behavior of glutathione-sensitive long-circulation micelles based on polyethylene glycol prodrug.

    Science.gov (United States)

    Shi, Liyan; Ding, Kaikai; Sun, Xin; Zhang, Ling; Zeng, Tian; Yin, Yihua; Zheng, Hua

    2016-01-01

    In this paper, a kind of glutathione-sensitive polymeric micelles was prepared through assembling in aqueous solution of an amphiphilic polymeric prodrug which was synthesized by linkage of 6-mercaptopurine (6-MP) and polyethylene glycol monomethyl ether using propiolic acid as a connecting arm. The glutathione (GSH)-sensitive strategy is based on a Michael addition-elimination reaction, that is the amphiphilic polymeric prodrug which contains α, β-unsaturated carbonyl group acts as a Michael acceptor to receive the attack of nucleophile - glutathione, and undergoes elimination reaction to release the original drug. Transmission electron microscope observation showed that the polymeric micelles (PMs) had a spherical-like morphology with a mean diameter of 28 ± 3.2 nm. The dynamic light scattering investigation data exhibited that the size and distribution changes of PMs are negligible after being placed for 15 days. In vitro drug release study indicated that only less than 13% of 6-MP was released from the micelles under GSH stimulation at micromolar level, while 34.5, 53.7, and 77.8% accumulative release rates were achieved under GSH stimulation at millimolar level (1, 2 and 10 mM), respectively. The cell inhibition rate of PM solution against HL-60 cells carried out by MTT method reached 85%. The cellular uptake and the intracellular drug release of PMs in HL-60 cells were observed through determining the intracellular 6-MP content by UV-vis spectrophotometer. In vitro macrophage uptake study showed a low phagocytosis rate, indicating the long-circulation ability of the PMs.

  20. Adenovirus replication as an in vitro probe for drug sensitivity in human tumors.

    Science.gov (United States)

    Parsons, P G; Maynard, K R; Little, J H; McLeod, G R

    1986-04-01

    The feasibility of using adenovirus 5 as an in vitro probe for chemosensitivity in short-term cultures of human tumors was evaluated using human melanoma cell lines and primary cultures of melanoma biopsies. A convenient immunoperoxidase method was developed for quantitating viral replication 2 days after infection. Two different approaches were explored: the host cell reactivation assay (HCR) using drug-treated virus; and the viral capacity assay using drug-treated cells. The HCR assay detected sensitivity to 5-(3-methyl-1-triazeno)imidazole-4-carboxamide (MTIC) in Mer- (methyl excision repair deficient) cell lines as decreased ability of the cells to replicate MTIC-treated virus. This test should be applicable to DNA-damaging agents and repair-deficient tumors. Adenovirus replicated readily in nonproliferating primary cultures of melanoma biopsies; application of the HCR assays to this material identified one Mer- sample of 11 tested. Herpes viruses were not suitable for use in HCR because herpes simplex virus type 1 failed to distinguish Mer- from Mer+ melanoma cells; and nonproductive infection of MTIC-sensitive lymphoid cells with Epstein-Barr virus yielded an MTIC-resistant cell line. The second assay (viral capacity) involved determination of the inhibition of replication of untreated virus in treated cells. This approach correctly predicted sensitivity to hydroxyurea and deoxyadenosine in melanoma cell lines when compared with clonogenic survival assay. Viral capacity was also inhibited by cytosine arabinoside, fluorouracil, vincristine, adriamycin, 6-mercaptopurine and ionising radiation, and may therefore be useful for detecting sensitivity to a wide range of antitumor agents.

  1. Diagnosis and treatment of fistulising Crohn's disease.

    Science.gov (United States)

    Hvas, Christian Lodberg; Dahlerup, Jens Frederik; Jacobsen, Bent Ascanius; Ljungmann, Ken; Qvist, Niels; Staun, Michael; Tøttrup, Anders

    2011-10-01

    A fistula is defined as a pathological connection between the intestine and an inner (bladder or other intestine) or outer (vagina or skin) epithelial surface. Fistulas are discovered in up to 25% of all Crohn's disease patients during long-term follow-up examinations. Most are perianal fistulas, and these may be classified as simple or complex. The initial investigation of perianal fistulas includes imaging (MRI of the pelvis and rectum), examination under anaesthesia (EUA) with digital imaging, endoscopy, probing and anal ultrasound. Non-perianal fistulas require contrast imaging and/or CT/MRI for complete anatomical definition. Any abscess should be drained, and the disease extent throughout the entire gastrointestinal tract should be evaluated. Treatment goals for perianal fistulas include reduced fistula secretion or none, evaluated by clinical examination; the absence of abscesses; and patient satisfaction. MR imaging is required to demonstrate definitive fistula closure. Fistulotomy is considered for simple perianal fistulas. In complex perianal fistulas, antibiotics and azathioprine or 6-mercaptopurine, which are often combined with a loose seton, constitute the first-line medical therapy. In cases with persistent secretion, infliximab at 5 mg/kg is given at weeks 0, 2, and 6 and subsequently every 8 weeks. Adalimumab may improve fistula response in both infliximab-naïve patients and following infliximab treatment failure. Local therapy with fibrin glue or fistula plugs is rarely effective. Definitive surgical closure of perianal fistulas using an advancement flap may be attempted, but this procedure is associated with a high risk of relapse. Colostomy and proctectomy are the ultimate surgical treatment options for fistulas. Intestinal resection is almost always needed for the closure of symptomatic non-perianal fistulas.

  2. Treatment of acute lymphoblastic leukaemia (ALL).

    Science.gov (United States)

    Jacobs, P; Wood, L

    1992-08-01

    Forty-six consecutive patients with acute lymphoblastic leukaemia (ALL), having a median age of 23 years (range 14 to 64), underwent induction and consolidation chemotherapy with weekly parenteral vincristine, adriamycin, l-asparaginase and daily oral prednisone (VAAP), followed by standard central nervous system (CNS) prophylaxis. Maintenance therapy was given for 3 years and consisted of daily 6-mercaptopurine, weekly methotrexate, and monthly intrathecal chemotherapy, with drug intensification comprising either vincristine, adriamycin and l-asparaginase (VAA) or cyclophosphamide, vincristine, cytosine arabinoside and prednisone (COAP). Complete remission (CR) was achieved in 36 patients (78%) and only the FAB L1 morphology was a significant predictive factor (Chi-squared = 3.91: p < 0.05). Eight of the 10 non-responders had significant drug resistance and 3 deaths were associated with marrow hypoplasia. Median follow-up is 52 months. Median duration of CR is 28 months, median survival of all patients is 16 months, and for those who achieved CR is 44 months. There was no difference between the two maintenance arms. Significant prognostic factors for survival are French-American-British (FAB) subtype, in which the L1 is better than L2 (p = 0.05), and age (p = 0.035). Nineteen patients have experienced medullary relapse and 7 (37%) achieved subsequent CR; this is durable in a single patient who underwent allogeneic bone marrow transplantation. Eight patients (17%) had CNS disease at diagnosis; 5 achieved CR and 1 is alive and disease-free at 65+ months. There has been 1 CNS relapse. These results demonstrate that prolonged remissions and survival can be achieved with this protocol and many patients possibly cured. The level of toxicity is acceptable and the pattern of induction failure indicates that a margin exists for intensifying chemotherapy and thereby possibly further improving results.

  3. Crohn's disease and acute pancreatitis. A review of literature.

    Science.gov (United States)

    Jasdanwala, Sarfaraz; Babyatsky, Mark

    2015-03-20

    Crohn's disease, a transmural inflammatory bowel disease, has many well-known extra-intestinal manifestations and complications. Although acute pancreatitis has a higher incidence in patients with Crohn's disease as compared to the general population, acute pancreatitis is still relatively uncommon in patients with Crohn's disease. Patients with Crohn's disease are at an approximately fourfold higher risk than the general population to develop acute pancreatitis. The risk of developing acute pancreatitis is higher in females as compared to males. Acute pancreatitis can occur at any age with higher incidence reported in patients in their 20s and between 40-50 years of age. The severity and prognosis of acute pancreatitis in patients with Crohn's disease is the same as in general population. Acute pancreatitis can occur before onset of intestinal Crohn's disease, this presentation being more common in children than adults. It can also occur as the presenting symptom. However, most commonly it occurs after intestinal symptoms have manifest with a mean time interval between the initial presentation and development of acute pancreatitis being 2 years. There are several etiological factors contributing to acute pancreatitis in patients with Crohn's disease. It is not clear whether acute pancreatitis is a direct extra-intestinal manifestation of Crohn's disease; however, majority of the cases of acute pancreatitis in patients with Crohn's disease are due to GS and medications. Drugs used for the treatment of Crohn's disease that have been reported to cause acute pancreatitis include 5-ASA agents, azathioprine and 6 mercaptopurine, metornidazole and corticosteroids. Recent evidence has emerged correlating both type 1 and 2 autoimmune pancreatitis with Crohn's disease. Understanding the association between the two disease entities is key to effectively manage patients with Crohn's disease and acute pancreatitis.

  4. Managing refractory Crohn's disease: challenges and solutions

    Directory of Open Access Journals (Sweden)

    Tanida S

    2015-04-01

    Full Text Available Satoshi Tanida, Keiji Ozeki, Tsutomu Mizoshita, Hironobu Tsukamoto, Takahito Katano, Hiromi Kataoka, Takeshi Kamiya, Takashi Joh Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Aichi Prefecture, Japan Abstract: The goals of treatment for active Crohn's disease (CD are to achieve clinical remission and improve quality of life. Conventional therapeutics for moderate-to-severe CD include 5-aminosalicylic acid, corticosteroids, purine analogs, azathioprine, and 6-mercaptopurine. Patients who fail to respond to conventional therapy are treated with tumor necrosis factor (TNF-α inhibitors such as infliximab and adalimumab, but their efficacy is limited due to primary nonresponse or loss of response. It is suggested that this requires switch to another TNF-α inhibitor, a combination therapy with TNF-α blockade plus azathioprine, or granulocyte and monocyte adsorptive apheresis, and that other therapeutic options having different mechanisms of action, such as blockade of inflammatory cytokines or adhesion molecules, are needed. Natalizumab and vedolizumab are neutralizing antibodies directed against integrin a4 and a4ß7, respectively. Ustekinumab is a neutralizing antibody directed against the receptors for interleukin-12 and interleukin-23. Here, we provide an overview of therapeutic treatments that are effective and currently available for CD patients, as well as some that likely will be available in the near future. We also discuss the advantages of managing patients with refractory CD using a combination of TNF-α inhibitors plus azathioprine or intensive monocyte adsorptive apheresis. Keywords: adalimumab, granulocyte and monocyte adsorptive apheresis, combination therapy, complete remission

  5. Recent advances in the management of distal ulcerative colitis

    Institute of Scientific and Technical Information of China (English)

    Ioannis; E; Koutroubakis

    2010-01-01

    The most frequent localization of ulcerative colitis(UC) is the distal colon.In treating patients with active distal UC,efficacy and targeting of the drug to the distal colon are key priorities.Oral and rectal 5-aminosalicylic acid(5-ASA) preparations represent the first line therapy of mild-to-moderate distal UC for both induction and maintenance treatment.It has been reported that many UC patients are not adherent to therapy and that noncompliant patients had a 5-fold risk of experiencing a relapse.These findings led to the introduction of oncedaily oral regimens of 5-ASA as better therapeutic options in clinical practice due to improved adherence.New formulations of mesalazine,including the multimatrix delivery system,and mesalazine granules,which allow once-daily administration,have been developed.They have been demonstrated to be efficacious in inducing and maintaining remission in mild-to-moderate distal UC in large clinical trials.However,existing data for distal UC are rather insufficient to make a comparison between new and classical 5-ASA formulations.It seems that the new formulations are at least as effective as classical oral 5-ASA formulations.Other treatment options,in the case that 5-ASA therapy is not effective,include systemic corticosteroids,thiopurines(azathioprine or 6-mercaptopurine),cyclosporine,infliximab and surgery.The combination of a prompt diagnostic work-up,a correct therapeutic approach and an appropriate follow-up schedule is important in the management of patients with distal UC.This approach can shorten the duration of symptoms,induce a prolonged remission,improve patient’s quality of life,and optimize the use of health resources.

  6. Effects of Immunosuppressants on Immune Response to Vaccine in Inflammatory Bowel Disease

    Institute of Scientific and Technical Information of China (English)

    Yuan Cao; Di Zhao; An-Tao Xu; Jun Shen; Zhi-Hua Ran

    2015-01-01

    Objective:To evaluate the response rate to vaccination in different treatment groups (nonimmunosuppressants and immunosuppressants).Data Sources:We completed an online systematic search using PubMed to identify all articles published in English between January 1990 and December 2013 assessing the effect of the response rate to vaccination in different treatment groups (with and without immunomodulators).The following terms were used:"inflammatory bowel disease (IBD)" OR "Cmhn's disease" OR "ulcerative colitis"AND ("vaccination" OR "vaccine") AND ("corticosteroids" OR "mercaptopurine" OR "azathioprine" OR "methotrexate [MTX]") AND "immunomodulators."Study Selection:The inclusion criteria of articles were that the studies:(1) Randomized controlled trials which included patients with a diagnosis of IBD (established by standard clinical,radiographic,endoscopic,and histologic criteria); (2) exposed patients received immunomodulators for maintenance (weight-appropriate doses of 6-mercaptopurine/azathioprine or within 3 months of stopping,15 mg or more MTX per week or within 3 months of stopping; (3) exposed patients received nonimmunomodulators (no therapy,antibiotics only,mesalazine only,biological agent only such as infliximab,adalimumab,certolizumab or natalizumab or within 3 months of stopping one of these agents).The exclusion criteria of articles were that the studies:(1) History of hepatitis B virus (HBV),influenza or streptococcus pneumoniae infection; (2) patients who had previously been vaccinated against HBV,influenza or streptococcus pneumoniae; (3) any medical condition known to cause immunosuppression (e.g.chronic renal failure and human immunodeficiency virus infection); (4) individuals with positive hepatitis markers or liver cirrhosis; (5) patients with a known allergy to eggs or other components of the vaccines and (6) pregnancy.Results:Patients treated with immunomodulators were associated with lower response rates to vaccination

  7. Mercaptopurine/Methotrexate Maintenance Therapy of Childhood Acute Lymphoblastic Leukemia: Clinical Facts and Fiction

    Science.gov (United States)

    Nielsen, Stine N.; Frandsen, Thomas L.; Nersting, Jacob

    2014-01-01

    The antileukemic mechanisms of 6-mercaptopurine (6MP) and methotrexate (MTX) maintenance therapy are poorly understood, but the benefits of several years of myelosuppressive maintenance therapy for acute lymphoblastic leukemia are well proven. Currently, there is no international consensus on drug dosing. Because of significant interindividual and intraindividual variations in drug disposition and pharmacodynamics, vigorous dose adjustments are needed to obtain a target degree of myelosuppression. As the normal white blood cell counts vary by patients’ ages and ethnicity, and also within age groups, identical white blood cell levels for 2 patients may not reflect the same treatment intensity. Measurements of intracellular levels of cytotoxic metabolites of 6MP and MTX can identify nonadherent patients, but therapeutic target levels remains to be established. A rise in serum aminotransferase levels during maintenance therapy is common and often related to high levels of methylated 6MP metabolites. However, except for episodes of hypoglycemia, serious liver dysfunction is rare, the risk of permanent liver damage is low, and aminotransferase levels usually normalize within a few weeks after discontinuation of therapy. 6MP and MTX dose increments should lead to either leukopenia or a rise in aminotransferases, and if neither is experienced, poor treatment adherence should be considered. The many genetic polymorphisms that determine 6MP and MTX disposition, efficacy, and toxicity have precluded implementation of pharmacogenomics into treatment, the sole exception being dramatic 6MP dose reductions in patients who are homozygous deficient for thiopurine methyltransferase, the enzyme that methylates 6MP and several of its metabolites. In conclusion, maintenance therapy is as important as the more intensive and toxic earlier treatment phases, and often more challenging. Ongoing research address the applicability of drug metabolite measurements for dose adjustments

  8. Model-Based Individualized Treatment of Chemotherapeutics: Bayesian Population Modeling and Dose Optimization.

    Directory of Open Access Journals (Sweden)

    Devaraj Jayachandran

    Full Text Available 6-Mercaptopurine (6-MP is one of the key drugs in the treatment of many pediatric cancers, auto immune diseases and inflammatory bowel disease. 6-MP is a prodrug, converted to an active metabolite 6-thioguanine nucleotide (6-TGN through enzymatic reaction involving thiopurine methyltransferase (TPMT. Pharmacogenomic variation observed in the TPMT enzyme produces a significant variation in drug response among the patient population. Despite 6-MP's widespread use and observed variation in treatment response, efforts at quantitative optimization of dose regimens for individual patients are limited. In addition, research efforts devoted on pharmacogenomics to predict clinical responses are proving far from ideal. In this work, we present a Bayesian population modeling approach to develop a pharmacological model for 6-MP metabolism in humans. In the face of scarcity of data in clinical settings, a global sensitivity analysis based model reduction approach is used to minimize the parameter space. For accurate estimation of sensitive parameters, robust optimal experimental design based on D-optimality criteria was exploited. With the patient-specific model, a model predictive control algorithm is used to optimize the dose scheduling with the objective of maintaining the 6-TGN concentration within its therapeutic window. More importantly, for the first time, we show how the incorporation of information from different levels of biological chain-of response (i.e. gene expression-enzyme phenotype-drug phenotype plays a critical role in determining the uncertainty in predicting therapeutic target. The model and the control approach can be utilized in the clinical setting to individualize 6-MP dosing based on the patient's ability to metabolize the drug instead of the traditional standard-dose-for-all approach.

  9. Model-Based Individualized Treatment of Chemotherapeutics: Bayesian Population Modeling and Dose Optimization.

    Science.gov (United States)

    Jayachandran, Devaraj; Laínez-Aguirre, José; Rundell, Ann; Vik, Terry; Hannemann, Robert; Reklaitis, Gintaras; Ramkrishna, Doraiswami

    2015-01-01

    6-Mercaptopurine (6-MP) is one of the key drugs in the treatment of many pediatric cancers, auto immune diseases and inflammatory bowel disease. 6-MP is a prodrug, converted to an active metabolite 6-thioguanine nucleotide (6-TGN) through enzymatic reaction involving thiopurine methyltransferase (TPMT). Pharmacogenomic variation observed in the TPMT enzyme produces a significant variation in drug response among the patient population. Despite 6-MP's widespread use and observed variation in treatment response, efforts at quantitative optimization of dose regimens for individual patients are limited. In addition, research efforts devoted on pharmacogenomics to predict clinical responses are proving far from ideal. In this work, we present a Bayesian population modeling approach to develop a pharmacological model for 6-MP metabolism in humans. In the face of scarcity of data in clinical settings, a global sensitivity analysis based model reduction approach is used to minimize the parameter space. For accurate estimation of sensitive parameters, robust optimal experimental design based on D-optimality criteria was exploited. With the patient-specific model, a model predictive control algorithm is used to optimize the dose scheduling with the objective of maintaining the 6-TGN concentration within its therapeutic window. More importantly, for the first time, we show how the incorporation of information from different levels of biological chain-of response (i.e. gene expression-enzyme phenotype-drug phenotype) plays a critical role in determining the uncertainty in predicting therapeutic target. The model and the control approach can be utilized in the clinical setting to individualize 6-MP dosing based on the patient's ability to metabolize the drug instead of the traditional standard-dose-for-all approach.

  10. Monitoração terapêutica da azatioprina: uma revisão Therapeutic drug monitoring of azathioprine: a review

    Directory of Open Access Journals (Sweden)

    Maurílio Pacheco Neto

    2008-06-01

    Full Text Available Os nucleotídeos de tioguanina (6-TGN, metabólitos ativos da azatioprina (AZA e da 6-mercaptopurina (6-MP, atuam como antagonistas das purinas, inibindo as sínteses de DNA, RNA e a protéica, e induzindo à citotoxicidade/imunossupressão. A enzima geneticamente determinada, tiopurina metiltransferase (TPMT, está envolvida no metabolismo desses agentes e, hipoteticamente, determina a resposta clínica às tiopurinas. A baixa atividade dessa enzima diminui a metilação das tiopurinas, resultando em potencial sobredose, enquanto altos níveis de TPMT levam à superprodução do metabólito tóxico 6-metilmercaptopurina (6-MMP e à não-efetividade terapêutica da AZA e da 6-MP. Várias mutações no gene da TPMT têm sido identificadas e correlacionadas com fenótipos de baixa atividade. Neste artigo, também se discute a monitoração terapêutica desses fármacos por meio da medida dos níveis de 6-TGN intra-eritrocitários, os quais se correlacionam com imunossupressão e mielotoxicidade. Já a 6-MMP está diretamente relacionada com hepatotoxicidade. Esses ensaios estão associados ao uso de doses adequadas dessa droga, resultando num melhor controle da doença e menor uso de corticosteróides.Thioguanine nucleotides (6-TGN, active metabolites of azathioprine (AZA and 6-mercaptopurine (6-MP, act as purine antagonists, inhibiting DNA, RNA, and protein synthesis and inducing cytotoxicity and immunosuppression. The genetically determined thiopurine methyltransferase enzyme (TPMT is involved in the metabolism of these agents and, theoretically, determines the clinical response to thiopurines. Low activity of this enzyme decreases the methylation of thiopurines, what results in potential overdosing, whereas high TPMT status leads to overproduction of toxic metabolite 6-methilmercaptopurine (6-MMP and ineffectiveness of AZA and 6-MP. Several mutations in the TPMT gene have been identified and correlated with low activity phenotypes. In this

  11. The importance of thiopurine methyltransferase activity for the use of azathioprine in transplant recipients.

    Science.gov (United States)

    Chocair, P R; Duley, J A; Simmonds, H A; Cameron, J S

    1992-05-01

    The immunosuppressive efficacy of azathioprine is related to its rapid metabolism in vivo to 6-mercaptopurine (6MP), with subsequent conversion to thioguanine nucleotides by an anabolic route involving hypoxanthine-guanine phosphoribosyltransferase. Two alternative catabolic routes exist: oxidation to 6-thiouric acid via xanthine oxidase and methylation to 6-methylmercaptopurine via the enzyme thiopurine methyltransferase (TPMT). Catabolism via either route would restrict formation of the active metabolites. We analyzed TPMT activity in erythrocyte lysates of 25 controls, 25 uremic patients on dialysis, and 68 transplanted patients. Median activity was lower in controls (31.0 pmol/hr/mg Hb, range 16.2-43.0) and transplanted patients receiving only cyclosporine and prednisolone (31.7 pmol/hr/mg Hb, range 12.7-43.5) than in the azathioprine treated group, (36.1 pmol/hr/mg Hb, range 16.1-71.3), or the uremic group on dialysis, (35.5 pmol/hr/mg Hb, range 18.6-62.6) suggesting that both azathioprine and uremia induce the enzyme, but CsA does not. Only 3 patients demonstrated total intolerance to azathioprine, 2 of whom had very low TPMT activity (zero and 12.7 pmol/hr/mg Hb). The intolerance of the third patient, despite high TPMT activity, was attributed to concomitant cotrimoxazole therapy. Patients with intermediate activity (15-26 pmol/hr/mg Hb) could tolerate azathioprine well. Of 29 cadaver recipients given only azathioprine plus prednisolone, 24 with a better clinical outcome had a significantly lower activity (33.1 pmol/hr/mg Hb, range 16.1-46.1) than 5 with reduced allograft function (42.5 pmol/hr/mg Hb, range 33.8-51.5). TPMT activity in these 24 patients was also significantly lower than the general group of azathioprine-treated recipients. This inverse association between TPMT activity and allograft function was again found among 30 patients receiving triple therapy (azathioprine, CsA, prednisolone). Self-selection of the best recipients for azathioprine

  12. A national survey on the patterns of treatment of inflammatory bowel disease in Canada

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    Best Allan

    2003-06-01

    Full Text Available Abstract Background There is a general lack of information on the care of inflammatory bowel disease (IBD in a broad, geographically diverse, non-clinic population. The purposes of this study were (1 to compare a sample drawn from the membership of a national Crohn's and Colitis Foundation to published clinic-based and population-based IBD samples, (2 to describe current patterns of health care use, and (3 to determine if unexpected variations exist in how and by whom IBD is treated. Methods Mailed survey of 4453 members of the Crohn's and Colitis Foundation of Canada. The questionnaire, in members stated language of preference, included items on demographic and disease characteristics, general health behaviors and current and past IBD treatment. Each member received an initial and one reminder mailing. Results Questionnaires were returned by 1787, 913, and 128 people with Crohn's disease, ulcerative colitis and indeterminate colitis, respectively. At least one operation had been performed on 1159 Crohn's disease patients, with risk increasing with duration of disease. Regional variation in surgical rates in ulcerative colitis patients was identified. 6-Mercaptopurine/Azathioprine was used by 24% of patients with Crohn's disease and 12% of patients with ulcerative colitis (95% CI for the difference: 8.9% – 15%. In patients with Crohn's disease, use was not associated with gender, income or region of residence but was associated with age and markers of disease activity. Infliximab was used by 112 respondents (4%, the majority of whom had Crohn's disease. Variations in infliximab use based on region of residence and income were not seen. Sixty-eight percent of respondents indicated that they depended most on a gastroenterologist for their IBD care. There was significant regional variation in this. However, satisfaction with primary physician did not depend on physician type (for example, gastroenterologist versus general practitioner. Conclusion

  13. Risk-directed therapy for childhood acute lymphoblastic leukemia. Results of the Associazione Italiana Ematologia Oncologia Pediatrica '82 studies.

    Science.gov (United States)

    Vecchi, V; Aricò, M; Basso, G; Ceci, A; Madon, E; Mandelli, F; Masera, G; Massimo, L; Pession, A; Zanesco, L

    1993-10-15

    In 1982, the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) started its third-generation study, aiming to improve previous results obtained by AIEOP '79 study and to deliver a standardized treatment to most Italian children with acute lymphoblastic leukemia (ALL). We treated 902 children (older than 1 year and younger than 15 years of age) with newly diagnosed ALL in multicenter studies of risk-directed therapy (111 low risk [LR] from Study 8201; 570 average risk [AR] from Study 8202; and 117 and 104 high risk [HR] from Studies 8303 and 8503, respectively). Induction therapy was composed of vincristine, prednisone, and asparaginase for LR or AR patients and these agents plus daunorubicin, (Study 8503) or vincristine, prednisone, cytarabine, and intermediate-dose methotrexate (Study 8303) for HR patients. Central nervous system (CNS) preventive therapy consisted of intrathecal methotrexate only (LR), intrathecal methotrexate plus 18 Gy cranial irradiation (AR and HR Study 8503), or high-dose (HD) cytarabine (HR Study 8303). Reinduction therapy was vincristine/prednisone/daunorubicin for AR patients with cyclophosphamide added for HR patients in Study 8303 and HD asparaginase in Study 8503. LR patients did not receive intensification therapy. Continuation therapy comprised 6-mercaptopurine plus methotrexate and monthly pulses with vincristine plus prednisone for all patients, except for HR patients in Study 8303 who also received teniposide plus cytarabine. Weekly HD asparaginase was also given in Study 8503. Duration of treatment was 24 months for Studies 8201 and 8202, 15 months for Study 8303, and 22 months for Study 8503. The overall complete remission (CR) rate was 94.7% (97.3% for LR, 94.9% for AR, and 93.2% for HR). Overall 7-year event-free survival (EFS) was 53.6% (standard error [SE], 1.8). EFS was 60.8% in LR (SE, 4.7), 60.6% in AR at 7 years (SE, 4.7), and 18.5% in Study 8303 (HR) at 5 years (SE, 3.8). Because of the poor result in HR

  14. Factors affecting recurrence after surgery for Crohn's disease

    Institute of Scientific and Technical Information of China (English)

    Takayuki Yamamoto

    2005-01-01

    Although in Crohn's disease post-operative recurrence is common, the determinants of disease recurrence remain speculative. The aim of this study was to examine factors affecting post-operative recurrence of Crohn's disease. A Medline-based literature review was carried out. The following factors were investigated: age at onset of disease, sex, family history of Crohn's disease,smoking, duration of Crohn's disease before surgery,prophylactic medical treatment (corticosteroids, 5-amino salicylic acid [5-ASA] and immunosuppressants),anatomical site of involvement, indication for surgery (perforating or non-perforating disease), length of resected bowel, anast-omotic technique, presence of granuloma in the specimen, involvement of disease at the resection margin, blood transfusions and postoperative complications. Smoking significantly increases the risk of recurrence (risk is approximately twice as high), especially in women and heavy smokers. Quitting smoking reduces the post-operative recurrence rate. A number of studies have shown a higher risk when the duration of the disease before surgery was short. There were, however, different definitions of 'short' among the studies. Prophylactic cortic-osteroids therapy is not effective in reducing the post-operative recurrence. A number of randomized controlled trials offered evidence of the efficacy of 5-ASA (mesalazine) in reducing post-operative recurrence. Recently, the thera-peutic efficacy of immunosuppressive drugs (azathioprine and 6-mercaptopurine) in the prevention of post-operative recurrence has been investigated and several studies have reported that these drugs might help prevent the recurrence. Further clinical trials would be necessary to evaluate the prophylactic efficacy of immunosuppressants.Several studies showed a higher recurrence rate in patients with perforating disease than in those with non-perforating disease. However, evidence for differing recurrence rates in perforating and non

  15. Accelerated infliximab infusions for inflammatory bowel disease improve effectiveness

    Institute of Scientific and Technical Information of China (English)

    John; McConnell; Simona; Parvulescu-Codrea; Brian; Behm; Beth; Hill; Elizabeth; Dunkle; Karen; Finke; Kathryn; Snyder; Anne; Tuskey; Debbie; Cox; Beth; Woodward

    2012-01-01

    AIM:To study the safety and effectiveness associated with accelerated infliximab infusion protocols in patients with inflammatory bowel disease(IBD).METHODS:Original protocols and infusion rates were developed for the administration of infliximab over 90-min and 60-min.Then the IBD patients on stable maintenance infliximab therapy were offered accelerated infusions.To be eligible for the study,patients needed a minimum of four prior infusions.An initial infusion of 90-min was given to each patient;those tolerating the accelerated infusion were transitioned to a 60-min infusion protocol at their next and all subsequent visits.Any patient having significant infusion reactions would be reverted to the standard 120-min protocol.A change in a patient’s dose mandated a single 120-min infusion before accelerated infusions could be administered again.RESULTS:The University of Virginia Medical Center’s Institutional Review Board approved this study.Fifty IBD patients treated with infliximab 5mg/kg,7.5mg/kg and 10mg/kg were offered accelerated infusions.Forty-six patients consented to participate in the study.Nineteen(41.3%) were female,five(10.9%) were African American and nine(19.6%) had ulcerative colitis.The mean age was 42.6 years old.Patients under age 18 were excluded.Ten patients used immunosuppressive drugs concurrently out of which six were taking azathioprine,three were taking 6-mercaptopurine and one was taking methotrexate.One of the 46 study patients used corticosteroid therapy for his IBD.Seventeen of the patients used prophylactic medications prior to receiving infusions;six patients received corticosteroids as pre-medication.Four patients had a history of distant transfusion reactions to infliximab.These reactions included shortness of breath,chest tightness,flushing,pruritus and urticaria.These patients all took prophylactic medications before receiving infusions.46 patients(27 males and 19 females) received a total of fifty 90-min infusions and ninety

  16. Analysis a case of elderly newly diagnosed acute promyelocytic leukemia and a review of the literature%初发急性早幼粒细胞性白血病老年患者诊治全过程1例报告及文献复习

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    王传馥; 张洪娣; 潘祖玉; 俞卓伟

    2013-01-01

    Objective To observe the efficacy of all-trans retinoic acid (ATRA) and IV arsenic trioxide (ATO) plus chemotherapy regimens for a elderly patient with acute promyelocytic leukemia (APL). Methods a 71-year-old man with newly diagnosed APL, for induction, oral ATRA 60mg/d, and intravenous ATO 10mg/d, starting on day 1 and continuing until CR; idarubicin (IDA) and cytarabine (Ara-C) was added to induction treatment. Achieved hematologic and medullary complete remission( hCR and mCR), the patient treated with 3 consolidation courses. Course1: homoharringtonine 2mg/d, days1-5 combined with Ara-C 100mg/d, days1-5. Course2、 3: IDA10mg/d, daysl-3 combined with Ara-C 100mg/d, days1-3. The patients in molecular CR after 3 consolidation courses, bone marrow (BM) samples were assayed by quantitative RT-PCR for PML-RARA fusion transcripts is negative. Followed by nine courses maintenance therapy, each course of treatment for 3 months, a total of 27 months. Nine courses divided in two stages to carry on, the first stage include five courses (sequential regimen, m1: intravenous ATOl0mg/d, days1-10; m2: oralATRA 30mg/d, days1-30; m3: intravenous Methotrexate (MTX) 5mg, qw×4w) and the second stage include four courses (sequential regimen, ml: oral ATRA 30mg/d, days1-30; m2: oral MTX 15mg, qw×4w; m3: oral 6-mercaptopurine (6-MP) 50mg/d, days1-14). Results The 71-year-old patient with APL (moderate risk) administered ATRA, Ⅳ ATO and chemotherapy in combination was achieved molecular CR and continuing molecular CR more than 52 months. During the therapy, the patient suffered from the adverse events included pneumonia, hydrothorax, hepatic disfunction, herpes zoster, atrial premature beats and fibrillation atrial, etc. Treatment should be timely, and should pay more attention to support measures. For patients aged >70 years, the doses should be appropriately reduced. Conclusion Ederly patient with APL may be tolerant to ATRA combined with ATO plus chemotherapy, and obtain the

  17. Preferential inhibition of xanthine oxidase by 2-amino-6-hydroxy-8-mercaptopurine and 2-amino-6-purine thiol

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    Mukhopadhyay Anup

    2007-05-01

    Full Text Available Abstract Background The anticancer drug, 6-mercaptopurine (6MP is subjected to metabolic clearance through xanthine oxidase (XOD mediated hydroxylation, producing 6-thiouric acid (6TUA, which is excreted in urine. This reduces the effective amount of drug available for therapeutic efficacy. Co-administration of allopurinol, a suicide inhibitor of XOD, which blocks the hydroxylation of 6MP inadvertently enhances the 6MP blood level, counters this reduction. However, allopurinol also blocks the hydroxylation of hypoxanthine, xanthine (released from dead cancer cells leading to their accumulation in the body causing biochemical complications such as xanthine nephropathy. This necessitates the use of a preferential XOD inhibitor that selectively inhibits 6MP transformation, but leaves xanthine metabolism unaffected. Results Here, we have characterized two such unique inhibitors namely, 2-amino-6-hydroxy-8-mercaptopurine (AHMP and 2-amino-6-purinethiol (APT on the basis of IC50 values, residual activity in bi-substrate simulative reaction and the kinetic parameters like Km, Ki, kcat. The IC50 values of AHMP for xanthine and 6MP as substrate are 17.71 ± 0.29 μM and 0.54 ± 0.01 μM, respectively and the IC50 values of APT for xanthine and 6MP as substrates are 16.38 ± 0.21 μM and 2.57 ± 0.08 μM, respectively. The Ki values of XOD using AHMP as inhibitor with xanthine and 6MP as substrate are 5.78 ± 0.48 μM and 0.96 ± 0.01 μM, respectively. The Ki values of XOD using APT as inhibitor with xanthine and 6MP as substrate are 6.61 ± 0.28 μM and 1.30 ± 0.09 μM. The corresponding Km values of XOD using xanthine and 6MP as substrate are 2.65 ± 0.02 μM and 6.01 ± 0.03 μM, respectively. The results suggest that the efficiency of substrate binding to XOD and its subsequent catalytic hydroxylation is much superior for xanthine in comparison to 6MP. In addition, the efficiency of the inhibitor binding to XOD is much more superior when 6MP is the

  18. Inflammatory bowel diseases (IBD) - critical discussion of etiology, pathogenesis, diagnostics, and therapy; Chronisch entzuendliche Darmerkrankungen - Kritische Diskussion von Aetiologie, Pathogenese, Diagnostik und Therapie

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    Ochsenkuehn, T.; Sackmann, M.; Goeke, B. [Medizinische Klinik II, Klinikum der Universitaet Muenchen-Grosshadern (Germany)

    2003-01-01

    Aims Crohn's disease and ulcerative colitis are the most frequent inflammatory bowel diseases (IBD) with a prevalence of approximately one out of 500.Cytokine research opened new and potent treatment options and thus stimulated clinical and basic research.However, the IBD still remain a challenge for patients and physicians,demanding close cooperation between gastroenterologists,radiologists and surgeons.The basic understanding of IBD,which is necessary for efficient diagnostic and therapeutic concepts is reviewed. Based upon recent publications and our clinical experience we discuss aspects of etiology,pathogenesis,diagnostics,and therapy of Crohn's disease and ulcerative colitis. A genetically influenced, exaggerated and sustained immune response against the own gut flora seems to be one of the most important factors in the pathogenesis of IBD.Not less important are environmental influences.For instance, cigarette smoking had been judged to have some negative influence on the natural course of Crohn's disease.Now,however, recent studies show that smoking is even a significant independent risk factor in the pathogenesis of IBD. Since IBD and especially Crohn's disease can effect the whole body, detailed analysis of inflammatory organ involvement is necessary before therapy.For instance, the MRIenteroclysis technique adds a necessary diagnostic tool for the exploration of those parts of the small bowel that cannot been reached by routine endoscopy like the upper ileum and the lower jejunum. In terms of therapy, a change of paradigms can be observed: patients will no longer be treated only when symptoms arise, but will early be integrated into a therapeutic concept, which is determined by site and extent of the disease and adapted to the abilities and needs of the patient.Furthermore,immunosuppressive agents like azathioprine and 6-mercaptopurine will establish as central concept in the medical treatment of IBD.Discussion IBD-therapy should