Improved pharmacokinetics of mercaptopurine afforded by a thermally robust hemihydrate.

Science.gov (United States)

Kersten, Kortney M; Matzger, Adam J

2016-04-18

Structural and thermal data were obtained for a novel hemihydrate of 6-mercaptopurine. The hemihydrate shows increased solubility and bioavailability when compared to the monohydrate form, better stability against conversion in aqueous media than the anhydrate form, and a dehydration temperature of 240 °C, the highest of any known hydrate crystal.

Individualized 6-mercaptopurine increments in consolidation treatment of childhood acute lymphoblastic leukemia

DEFF Research Database (Denmark)

Tulstrup, Morten; Frandsen, Thomas L; Abrahamsson, Jonas

2018-01-01

increments of additional 25 mg/m2 /day beginning on days 50 and/or 71 unless dose-limiting myelosuppression had occurred. RESULTS: In the experimental arm, 166 patients (42%) received one dose increment, and 62 (16%) received two. Fifty-seven of 387 (15%) patients in the experimental arm were MRD positive...... minimal residual disease (MRD) positivity and event-free survival. METHODS: 392 patients were randomized to experimental and 396 to standard therapy. Patients allocated to standard therapy received oral 6-mercaptopurine (25 mg/m2 /day) from days 30 to 85, while the experimental arm received stepwise...... at end of consolidation vs 77 of 389 (20%) in the control arm (P = .08). Five-year probability of event-free survival was 0.89 (95% CI: 0.85-0.93) in the experimental arm vs 0.93 (0.90-0.96) in the control arm (P = .13). The median accumulated length of 6-mercaptopurine treatment interruptions was 7 (IQR...

Effect of tautomerism on Au-6-mercaptopurine nanocluster stability

Science.gov (United States)

Rashidpour, Neda; Kashid, Vikas; Shah, Vaishali

2013-02-01

We have investigated the stability of conjugated nanoparticles of Au-6-Mercaptopurine (6-MP) using ab initio density functional theory. We have studied the conjugation of the 6 tautomers of 6-MP via the different atomic sites with the gold nanoparticles. Our results show that the least stable tautomer has the strongest adsorption with the Au nanoparticles whereas the most stable tautomer has the weakest adsorption. We will discuss our results to explain the experimentally observed increased plasma half life time of the conjugated drug in vitro.

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

DEFF Research Database (Denmark)

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...

Effect of the anticarcinogenic drug 6-mercaptopurine on mineral metabolism

International Nuclear Information System (INIS)

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 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

Intracellular metabolites of mercaptopurine in children with lymphoblastic leukaemia: a possible indicator of non-compliance?

Science.gov (United States)

Lennard, L; Welch, J; Lilleyman, J S

1995-10-01

As part of a programme assessing the pharmacokinetics of oral thiopurines given for lymphoblastic leukaemia, we assayed intracellular metabolites of mercaptopurine in children from all over the United Kingdom who were given a standard dose of the drug. The metabolites we measured, thioguanine nucleotides and methylmercaptopurines, are products of two competing metabolic pathways and would be expected to show an inverse correlation. A total of 327 children from 17 centres in the UK were studied. All were on the same therapeutic schedule of mercaptopurine. All had been on an unattenuated full protocol-directed dose (at least 75 mg m-2) for a minimum of 7 days before assay. There was a very wide variation in the concentration of the two metabolites measured; the thioguanine nucleotides ranged from 0 to 1255 pmol per 8 x 10(8) red cells (median 289, lower quartile 210, upper quartile 377) and the methylmercaptopurine metabolites ranged from 0 to 46.3 nmol per 8 x 10(8) red cells (median 5.18, lower quartile 2.31, upper quartile 11.59). The anticipated negative correlation was not apparent, but the ratio between the two was not randomly distributed. No child had both metabolite concentrations in the upper quartiles, but in 32 (10%) children the concentration of both metabolites was in the lower quartile. Of the 32, only one metabolite was detected in four and none at all in six. The most likely explanation for these findings is that a minority of children with lymphoblastic leukaemia fail to take oral mercaptopurine either totally or intermittently. The extent of the problem is unknown, but we suspect it may be clinically important in at least 10% of patients.

Analysis of 6-mercaptopurine in human plasma with a high-performance liquid chromatographic method including post-column derivatization and fluorimetric detection.

Science.gov (United States)

Jonkers, R E; Oosterhuis, B; ten Berge, R J; van Boxtel, C J

1982-12-10

A relatively simple assay with improved reliability and sensitivity for measuring levels of 6-mercaptopurine in human plasma is presented. After extraction of the compound and the added internal standard with phenyl mercury acetate, samples were separated by ion-pair reversed-phase high-performance liquid chromatography. On-line the analytes were oxidized to fluorescent products and detected in a flow-fluorimeter. The within-day coefficient of variation was 3.8% at a concentration of 25 ng/ml. The lower detection limit was 2 ng/ml when 1.0 ml of plasma was used. Mercaptopurine concentration versus time curves of two subjects after a single oral dose of azathioprine are shown.

Assessment of Mercaptopurine (6MP) Metabolites and 6MP Metabolic Key-Enzymes in Childhood Acute Lymphoblastic Leukemia

NARCIS (Netherlands)

Wojtuszkiewicz, A.; Barcelos, A.; Dubbelman, B.; Abreu, R.A. de; Brouwer, C.; Bökkerink, J.P.M.; Haas, V. de; Groot-Kruseman, H. de; Jansen, G.; Kaspers, G.L.; Cloos, J.; Peters, G.J.

2014-01-01

Pediatric acute lymphoblastic leukemia (ALL) is treated with combination chemotherapy including mercaptopurine (6MP) as an important component. Upon its uptake, 6MP undergoes a complex metabolism involving many enzymes and active products. The prognostic value of all the factors engaged in this

The quantitative determination of metabolites of 6-mercaptopurine in biological materials. VI. Evidence for posttranscriptional modification of 6-thioguanosine residues in RNA from L5178Y cells treated with 6-mercaptopurine.

Science.gov (United States)

Breter, H J

1985-05-24

Mammalian cells incorporate 6-thioguanosine into their nucleic acids when grown in the presence of 6-mercaptopurine. 35S-labeled total RNA was prepared from L5178Y murine lymphoma cells grown in vitro in the presence of 6-[35S]mercaptopurine. Base analyses of this RNA suggested that 6-thioguanosine residues in RNA molecules undergo posttranscriptional modification. Thus, enzymatic peak-shifting analyses using anion-exchange high-performance liquid chromatography were applied to the hydrolysis products released from total RNA preparations by digestion with nuclease P1 or nuclease P1 plus nucleotide pyrophosphatase. At least eight 35S-labeled, phosphatase-sensitive compounds structurally different from [35S]6thioGMP were found in nuclease P1 digests. Four of these compounds were susceptible to cleavage with nucleotide pyrophosphatase, thus indicating that they contained phosphoric acid anhydride bonds. Individual RNA species were not separately examined, the radiochromatographic data, however, which were obtained from digests of total RNA preparations, present evidence that 6-thioguanosine 5'-diphosphate and 6-thioguanosine 5'-triphosphate exist as 5'-terminal starting nucleotides (in tRNA and rRNA) and that 6-thioguanosine becomes incorporated into the highly modified dinucleoside triphosphate structures (caps) which commonly block the 5'-termini of eukaryotic poly(A)+ mRNA-molecules.

Mercaptopurine metabolite levels are predictors of bone marrow toxicity following high-dose methotrexate therapy of childhood acute lymphoblastic leukaemia

DEFF Research Database (Denmark)

Vang, Sophia Ingeborg; Schmiegelow, Kjeld; Frandsen, Thomas

2015-01-01

High-dose methotrexate (HD-MTX) courses with concurrent oral low-dose MTX/6-mercaptopurine (6MP) for childhood acute lymphoblastic leukaemia (ALL) are often followed by neutro- and thrombocytopenia necessitating treatment interruptions. Plasma MTX during HD-MTX therapy guides folinic acid rescue ...

Complex formation of hypoxanthine and 6-mercaptopurine with Cd(II) ion

International Nuclear Information System (INIS)

Perello, L.; Borras, J.; Soto, L.; Gordo, F.J.; Gordo, J.C.

1984-01-01

Reaction of Cd(II) ion with hypoxanthine (H 2 Y) and with 6-mercaptopurine (H 2 MP) in dioxane-water (50%) leads to the formation of CdY x 2H 2 O and Cd(HMP) 2 x 2H 2 O, respectively. In methanolic medium Cd(II) and H 2 MP give Cd(MP) x H 2 O. These compounds have been characterized by chemical analysis, IR spectra and thermogravimetric analysis. The stability constant of CdY complex at 25 +- 0.1 0 C and 1M ionic strength with NaClO 4 in dioxane-water medium is logβ = 10.25 +- 0.05. (Author)

Intracellular metabolites of mercaptopurine in children with lymphoblastic leukaemia: a possible indicator of non-compliance?

OpenAIRE

Lennard, L.; Welch, J.; Lilleyman, J. S.

1995-01-01

As part of a programme assessing the pharmacokinetics of oral thiopurines given for lymphoblastic leukaemia, we assayed intracellular metabolites of mercaptopurine in children from all over the United Kingdom who were given a standard dose of the drug. The metabolites we measured, thioguanine nucleotides and methylmercaptopurines, are products of two competing metabolic pathways and would be expected to show an inverse correlation. A total of 327 children from 17 centres in the UK were studie...

Complex formation of hypoxanthine and 6-mercaptopurine with Cd(II) ion

Energy Technology Data Exchange (ETDEWEB)

Perello, L.; Borras, J.; Soto, L.; Gordo, F.J.; Gordo, J.C. (Valencia Univ. (Spain))

1984-01-01

Reaction of Cd(II) ion with hypoxanthine (H/sub 2/Y) and with 6-mercaptopurine (H/sub 2/MP) in dioxane-water (50%) leads to the formation of CdY x 2H/sub 2/O and Cd(HMP)/sub 2/ x 2H/sub 2/O, respectively. In methanolic medium Cd(II) and H/sub 2/MP give Cd(MP) x H/sub 2/O. These compounds have been characterized by chemical analysis, IR spectra and thermogravimetric analysis. The stability constant of CdY complex at 25 +- 0.1/sup 0/C and 1M ionic strength with NaClO/sub 4/ in dioxane-water medium is log..beta.. = 10.25 +- 0.05.

Ordinary differential equations and Boolean networks in application to modelling of 6-mercaptopurine metabolism.

Science.gov (United States)

Lavrova, Anastasia I; Postnikov, Eugene B; Zyubin, Andrey Yu; Babak, Svetlana V

2017-04-01

We consider two approaches to modelling the cell metabolism of 6-mercaptopurine, one of the important chemotherapy drugs used for treating acute lymphocytic leukaemia: kinetic ordinary differential equations, and Boolean networks supplied with one controlling node, which takes continual values. We analyse their interplay with respect to taking into account ATP concentration as a key parameter of switching between different pathways. It is shown that the Boolean networks, which allow avoiding the complexity of general kinetic modelling, preserve the possibility of reproducing the principal switching mechanism.

Analysis of 6-mercaptopurine in human plasma with a high-performance liquid chromatographic method including post-column derivatization and fluorimetric detection

NARCIS (Netherlands)

Jonkers, R. E.; Oosterhuis, B.; ten Berge, R. J.; van Boxtel, C. J.

1982-01-01

A relatively simple assay with improved reliability and sensitivity for measuring levels of 6-mercaptopurine in human plasma is presented. After extraction of the compound and the added internal standard with phenyl mercury acetate, samples were separated by ion-pair reversed-phase high-performance

Assessing Compliance With Mercaptopurine Treatment in Younger Patients With Acute Lymphoblastic Leukemia in First Remission | Division of Cancer Prevention

Science.gov (United States)

This randomized phase III trial studies compliance to a mercaptopurine treatment intervention compared to standard of care in younger patients with acute lymphoblastic leukemia in remission. Assessing ways to help patients who have acute lymphoblastic leukemia to take their medications as prescribed may help them in taking their medications more consistently and may improve

Electrocatalytic activity of electropolymerized cobalt tetraaminophthalocyanine film modified electrode towards 6-mercaptopurine and 2-mercaptobenzimidazole

OpenAIRE

Fan, Jie-Ping; Zhang, Xiao-Min; Ying, Min

2010-01-01

The electrocatalytic activity of electropolymerized cobalt tetraaminophthalocyanine (poly-CoTAPc) film modified on the glassy carbon electrode (GCE) towards 6-mercaptopurine (6MP) and 2-Mercaptobenzimidazole (MBI) was studied. Comparing with the case at the unmodified GCE, the poly-CoTAPc film decreased the overpotential of oxidation of 6MP (1.0 x 10-3 mol L-1) and MBI (1.0 x 10-3 mol L-1) by 335 and 189 mV, respectively, and increased the peak current by about 3 and 2 times, respectively, wh...

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

Directory of Open Access Journals (Sweden)

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.

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.

Release behavior and toxicity profiles towards leukemia (WEHI-3B) cell lines of 6-mercaptopurine-PEG-coated magnetite nanoparticles delivery system.

Science.gov (United States)

Dorniani, Dena; Kura, Aminu Umar; Hussein-Al-Ali, Samer Hasan; bin Hussein, Mohd Zobir; Fakurazi, Sharida; Shaari, Abdul Halim; Ahmad, Zalinah

2014-01-01

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.

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

DEFF Research Database (Denmark)

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...... the remaining patients (P = 0·03). This study shows individualized toxicity-titrated 6MP dosing during consolidation is feasible without increased risk of toxicity....

Stabilization of gold nanoparticles by 6-mercaptopurine monolayers. Effects of the solvent properties.

Science.gov (United States)

Viudez, Alfonso J; Madueño, Rafael; Pineda, Teresa; Blázquez, Manuel

2006-09-14

6-Mercaptopurine-coated gold nanoparticles (6MP-AuNPs) have been prepared by modification of the nanoparticle surface with 6MP upon displacement of the protective layer of citrate anions. The modification has been studied by UV-vis and FTIR spectroscopies. A study of the stability of these 6MP-AuNPs in aqueous solutions as a function of ionic strength and pH has shown the importance of the charges on the stabilization. The protonation of N9 of the 6MP molecules brings about a sudden flocculation phenomenon. However, the flocculation is reversible upon changing the pH to values where the molecules become newly charged. Evidence of the competence between the interaction of capping solvent molecules and the attractive forces between particles is also shown in this paper.

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

OpenAIRE

Dorniani, Dena; Kura, Aminu Umar; Hussein-Al-Ali, Samer Hasan; Hussein, Mohd Zobir bin; Fakurazi, Sharida; Shaari, Abdul Halim; Ahmad, Zalinah

2014-01-01

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 th...

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

DEFF Research Database (Denmark)

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 evaluated in the target population. Preclinical and clinical evaluations were performed according to a Pediatric Investigation Plan, in order to apply for a Pediatric Use Marketing Authorization. METHODS: The pre-clinical study assessed the maximum tolerated dosage-volume and evaluated local mucosal...... to 50mg registered tablets were evaluated in a random order on two consecutive days. Seven blood samples over 9h were obtained each day to determine 6-MP pharmacokinetic parameters, including Tmax, Cmax, AUC0-9 and AUC0-∞. A questionnaire adapted to children testing Loulla palatability and preference...

Concanavalin-A conjugated fine-multiple emulsion loaded with 6-mercaptopurine.

Science.gov (United States)

Khopade, A J; Jain, N K

2000-01-01

Fine-multiple (water-in-oil-in-water) emulsions were prepared by two-step emulsification using sonication. They were coated with concanavalin-A (Con-A) by three methods. The one involving covalent coupling of Con-A to the multiple emulsion incorporated anchor was better compared with lipid derivatized Con-A anchoring or the glutaraldehyde-based cross-linking method, as shown by the faster rate of dextran-induced aggregation. The selected multiple emulsions were characterized by physical properties such as droplet size, encapsulation efficiency, and zeta potential. Stability parameters such as droplet size, creaming, leakage, and aggregation as a function of relative turbidity were monitored over a 1-month period, which revealed good stability of the formulations. The release profile of 6-mercaptopurine followed zero-order kinetics. Pharmacokinetic studies showed an increase in half-life and bioavailability from multiple emulsion formulations administered intravenously. There was prolonged retention of drug in various tissues of rats when treated with Con-A-coated multiple emulsion as compared with uncoated one. Our study demonstrates the suitability of fine-multiple emulsion for intravenous administration and the potential for prolonged retention of drugs and targeting in biological systems.

Determination of 6-mercaptopurine and azathioprine in plasma by high-performance liquid chromatography.

Science.gov (United States)

Ding, T L; Benet, L Z

1979-07-21

Using 1-ml plasma samples, levels of 6-mercaptopurine (6MP) as low as 5 ng/ml and azathioprine (AZA) as low as 40 ng/ml can be detected using a high-performance liquid chromatography reversed-phase column procedure following extraction. Both compounds were stable in frozen plasma for seven weeks. AZA stability in blood was temperature dependent; the half-lives of AZA breakdown to 6MP at 37 degrees were 28 and 46 min in blood drawn from two rhesus monkeys. Plasma levels of 6MP were measured in a rhesus monkey following 6MP (1.47 mg/kg) and AZA (3 mg/kg) intravenous administration. 6MP levels were also measured in three renal transplant patients on daily 50- and 100-mg AZA doses. Peak levels (45-75 ng/ml) were reached within an hour and 6MP levels were detected for up to 7 h.

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.

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

International Nuclear Information System (INIS)

Ganeshkumar, Moorthy; Sastry, Thotapalli Parvathaleswara; Sathish Kumar, Muniram; Dinesh, Murugan Girija; Kannappan, Sudalyandi; Suguna, Lonchin

2012-01-01

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 50 ) was much lower in N-Au-Mp-Fa than in free Mp and N-Au-Mp.

6-Mercaptopurine attenuates tumor necrosis factor-? production in microglia through Nur77-mediated transrepression and PI3K/Akt/mTOR signaling-mediated translational regulation

OpenAIRE

Huang, Hsin-Yi; Chang, Hui-Fen; Tsai, Ming-Jen; Chen, Jhih-Si; Wang, Mei-Jen

2016-01-01

Background The pathogenesis of several neurodegenerative diseases often involves the microglial activation and associated inflammatory processes. Activated microglia release pro-inflammatory factors that may be neurotoxic. 6-Mercaptopurine (6-MP) is a well-established immunosuppressive drug. Common understanding of their immunosuppressive properties is largely limited to peripheral immune cells. However, the effect of 6-MP in the central nervous system, especially in microglia in the context ...

Effect of 6-mercaptopurine on 65Zn distribution in the pregnant rat

International Nuclear Information System (INIS)

Amemiya, K.; Hurley, L.S.; Keen, C.L.

1989-01-01

The effect of 6-mercaptopurine (6-MP) on the distribution of gavaged 65 Zn in maternal and embryonic tissues of Sprague-Dawley rats was examined 24 hr after injection of the drug on day 13 of pregnancy. 6-MP injection resulted in a significantly higher retention of counts of 65 Zn in maternal liver and lower counts in maternal plasma, uterus, placenta, and embryo than in controls. Compared to controls, gel chromatography of maternal liver from 6-MP injected dams showed higher counts associated with a protein peak of molecular weight 6,000-8,000, the approximate molecular weight of the zinc-binding protein metallothionein. These results support the idea that the zinc deficiency, which is observed in day 21 fetuses from dams injected with 6-MP during midgestation, may be the result of a drug-induced sequestering of zinc into maternal liver followed by a decrease in maternal plasma zinc and subsequent reduction in fetal zinc uptake. We suggest that this 6-MP-associated redistribution of zinc into maternal liver may be due to induction of maternal metallothionein synthesis by the drug

Photochemical sensitization by azathioprine and its metabolites. Part 3. A direct EPR and spin-trapping study of light-induced free radicals from 6-mercaptopurine and its oxidation products.

Science.gov (United States)

Moore, D E; Sik, R H; Bilski, P; Chignell, C F; Reszka, K J

1994-12-01

Sunlight has been implicated in the high incidence of skin cancer found in patients receiving 6-mercaptopurine (PSH) in the form of its pro-drug azathioprine. In this study we have used EPR spectroscopy in conjunction with the spin-trapping technique to determine whether PSH and its metabolic or photochemical oxidation products generate highly reactive free radicals upon UV irradiation. When an aqueous anaerobic solution (pH 5 or 9) of PSH (pKa = 7.7) and either 2-methyl-2-nitrosopropane (MNP) or nitromethane (NM) were irradiated (lambda > 300 nm) with a Xe arc lamp, the corresponding purine-6-thiyl (PS.) radical adduct and the reduced form of the spin trap (MNP/H. or CH3NO2.-) were observed. However, no radical adducts were detected when PSH and 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) were irradiated (lambda = 320 nm) in oxygen-free buffer. These findings suggest that PSH does not photoionize but that instead MNP and NM are reduced by direct electron transfer from excited state PSH, 1.3(PSH)*. In aerobic solution, oxygen can act as an electron acceptor and the O2.- and PS. radicals are formed and trapped by DMPO. 6-Mercaptopurine did photoionize when irradiated with a Nd:YAG laser at 355 nm as evidenced by the appearance of the DMPO/H.(eq- + H+) adduct, which decreased in intensity in the presence of N2O. 1.3(6-Mercaptopurine)* oxidized ascorbate, formate and reduced glutathione to the corresponding ascorbyl, CO2.- or glutathiyl radicals. The photochemical behavior of 6-thioxanthine and 6-thiouric acid was similar to PSH. However, the excited states of these metabolic oxidation products exhibited stronger reducing properties than 1.3(PSH)*.(ABSTRACT TRUNCATED AT 250 WORDS)

Raman mapping and in situ SERS spectroelectrochemical studies of 6-mercaptopurine SAMs on the gold electrode.

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Yang, Haifeng; Liu, Yanli; Liu, Zhimin; Yang, Yu; Jiang, Jianhui; Zhang, Zongrang; Shen, Guoli; Yu, Ruqin

2005-02-24

The self-assembled monolayers (SAMs) of 6-mercaptopurine (6MP) were formed at the roughened polycrystalline gold surfaces in acid and alkaline media. The time-dependent Raman mapping spectral analysis in conjunction with the quantum calculations for the vibrational modes using ab initio BLYP/6-31G method suggested that both of the resulted 6MP SAMs adopted the same adsorption mode through the S atom of pyrimidine moiety and the N7 atom of the imidazole moiety anchoring the gold surface in a vertical way. The in situ surface-enhanced Raman scattering spectroelectrochemical experiment was conducted to examine the stability of the SAMs at various bias potentials. It was found that the detaching process of the 6MP SAMs from the surface involved one electron reduction as the voltage was applied at ca. 0.7 V vs a standard calomel electrode.

A combined molecular dynamics simulation and quantum mechanics study on mercaptopurine interaction with the cucurbit [6,7] urils: Analysis of electronic structure

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Zaboli, Maryam; Raissi, Heidar

2018-01-01

In the current study, the probability of complex formation between mercaptopurine drug with cucurbit[6]urils and cucurbit[7]urils has been investigated. The calculations for geometry optimization of complexes have been carried out by means of DFT (B3LYP), DFT-D (B3LYP-D) and M06-2X methods. The Atoms In Molecules (AIM), Natural Bond Orbital (NBO), NMR, the density of states (DOSs) and frontier molecular orbital (MO) analyses have been done on the inclusion complexes. In addition, the UV-Vis spectra of the first eight states have been obtained by CAM-B3LYP/TD-DFT calculation. The obtained results of the complexation process reveal that CB[7]-DRG complexes are more favorable than that of CB[6]-DRG interactions. Furthermore, our theoretical results show that configurations III and I are the most stable configurations related to the CB[6]/DRG and CB[7]/DRG interactions, respectively. The positive ∇2ρ(r) and HC values at the bond critical points indicate that exist the weak H-bonds between CB[6] and CB[7] with H atoms of the drug molecule. The obtained negative binding energy values of CB[7]-DRG interaction in solution phase show the stability of these complexes in the aqueous medium. Also, all of the observed parameters of molecular dynamics simulation such as the number of contacts, hydrogen bonding, center-of-mass distance and van der Waals energy values confirm the encapsulation of mercaptopurine molecule inside the cucurbit[7]urils cavity at about 3.2 ns.

Loading cisplatin onto 6-mercaptopurine covalently modified MSNS: a nanomedicine strategy to improve the outcome of cisplatin therapy

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Lv X

2016-12-01

Full Text Available Xiaojie Lv,1 Ming Zhao,1,2 Yuiji Wang,1 Xi Hu,1 Jianhui Wu,1 Xueyun Jiang,1 Shan Li,1 Chunying Cui,1 Shiqi Peng1 1Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, College of Pharmaceutical Sciences, Capital Medical University, Beijing, People’s Republic of China; 2Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan Abstract: In the treatment of cancer patients, cisplatin (CDDP exhibits serious cardiac and renal toxicities, while classical combinations related to CDDP are unable to solve these problems and may result in worse prognosis. Alternately, this study covalently conjugated 6-mercaptopurine (6MP onto the surface of mercapto-modified mesoporous silica nanoparticles (MSNS to form MSNS-6MP and loaded CDDP into the holes on the surface of MSNS-6MP to form MSNS-6MP/CDDP, a tumor-targeting nano-releasing regime for CDDP and 6MP specifically. In the S180 mouse model, the anti-tumor activity and overall survival of MSNS-6MP/CDDP (50 mg·kg-1·day-1, corresponding to 1 mg·kg-1·day-1 of 6MP and 5 mg·kg-1·day-1 of CDDP were significantly higher than those of CDDP alone (5 mg·kg-1·day-1 or CDDP (5 mg·kg-1·day-1 plus 6MP (1 mg·kg-1·day-1. The assays of serum alanine aminotransferase, aspartate aminotransferase and creatinine, as well as the images of myocardium and kidney histology, support that MSNS-6MP/CDDP is able to completely eliminate liver, kidney and heart toxicities induced by CDDP alone or CDDP plus 6MP. Keywords: 6-mercaptopurine, cisplatin, mesoporous silica nanoparticles, cancer therapy, nanomedicine

A SERS protocol as a potential tool to access 6-mercaptopurine release accelerated by glutathione-S-transferase.

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Wang, Ying; Sun, Jie; Yang, Qingran; Lu, Wenbo; Li, Yan; Dong, Jian; Qian, Weiping

2015-11-21

The developed method for monitoring GST, an important drug metabolic enzyme, could greatly facilitate researches on relative biological fields. In this work, we have developed a SERS technique to monitor the absorbance behaviour of 6-mercaptopurine (6-MP) and its glutathione-S-transferase (GST)-accelerated glutathione (GSH)-triggered release behaviour on the surface of gold nanoflowers (GNFs), using the GNFs as excellent SERS substrates. The SERS signal was used as an indicator of absorbance or release of 6-MP on the gold surface. We found that GST can accelerate GSH-triggered release behaviour of 6-MP from the gold surface. We speculated that GST catalyzes nucleophilic GSH to competitively bind with the electrophilic substance 6-MP. Experimental results have proved that the presented SERS protocol can be utilized as an effective tool for accessing the release of anticancer drugs.

A combined molecular dynamics simulation and quantum mechanics study on mercaptopurine interaction with the cucurbit [6,7] urils: Analysis of electronic structure.

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Zaboli, Maryam; Raissi, Heidar

2018-01-05

In the current study, the probability of complex formation between mercaptopurine drug with cucurbit[6]urils and cucurbit[7]urils has been investigated. The calculations for geometry optimization of complexes have been carried out by means of DFT (B3LYP), DFT-D (B3LYP-D) and M06-2X methods. The Atoms In Molecules (AIM), Natural Bond Orbital (NBO), NMR, the density of states (DOSs) and frontier molecular orbital (MO) analyses have been done on the inclusion complexes. In addition, the UV-Vis spectra of the first eight states have been obtained by CAM-B3LYP/TD-DFT calculation. The obtained results of the complexation process reveal that CB[7]-DRG complexes are more favorable than that of CB[6]-DRG interactions. Furthermore, our theoretical results show that configurations III and I are the most stable configurations related to the CB[6]/DRG and CB[7]/DRG interactions, respectively. The positive ∇ 2 ρ (r) and HC values at the bond critical points indicate that exist the weak H-bonds between CB[6] and CB[7] with H atoms of the drug molecule. The obtained negative binding energy values of CB[7]-DRG interaction in solution phase show the stability of these complexes in the aqueous medium. Also, all of the observed parameters of molecular dynamics simulation such as the number of contacts, hydrogen bonding, center-of-mass distance and van der Waals energy values confirm the encapsulation of mercaptopurine molecule inside the cucurbit[7]urils cavity at about 3.2ns. Copyright © 2017 Elsevier B.V. All rights reserved.

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

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...... 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...

Improvement of aqueous solubility and rectal absorption of 6-mercaptopurine by addition of sodium benzoate.

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Takeichi, Y; Kimura, T

1994-10-01

The solubility of 6-mercaptopurine (6-MP) in water increased as the concentration of sodium benzoate or sodium hippurate in the solution increased. The solubility of 6-MP in 20% (w/v) sodium benzoate or sodium hippurate solution was about 6-fold larger than that of 6-MP alone. The stability constant of the soluble complex of 6-MP with sodium benzoate was estimated to be 2-8 M-1 from (1) phase-solubility study and (2) analysis of chemical shifts observed in 1H-NMR. Partition of 6-MP from the saturated solution to n-octanol was also greatly increased by the addition of sodium benzoate or sodium hippurate, the degree being less in the latter. Administration of 6-MP with 20% (w/v) sodium benzoate to rat rectum resulted in enhanced absorption and the area under the plasma concentration-time curve was comparable to that obtained by intravenous administration (bioavailability = 100%), while the bioavailability after intrarectal administration of 6-MP with 20% (w/v) sodium hippurate was only 9%. The reason for the difference was discussed.

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. Copyright © 2014 Elsevier B.V. All rights reserved.

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

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Prüfer, Jasmin; Schuchardt, Mirjam; Tölle, Markus; Prüfer, Nicole; Höhne, Matthias; Zidek, Walter; van der Giet, Markus

2014-01-01

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.

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.

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

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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....

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.

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

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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...... therapy (P=0.04) were both related to an increased risk of an event (overall P value of the Cox model: 0.003), whereas neither sex, age at diagnosis, administration of central nervous system irradiation, nor presence of a day 15 bone marrow with > or =25% versus

Construction of 6-thioguanine and 6-mercaptopurine carriers based on βcyclodextrins and gold nanoparticles.

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Sierpe, R; Noyong, Michael; Simon, Ulrich; Aguayo, D; Huerta, J; Kogan, Marcelo J; Yutronic, N

2017-12-01

As a novel strategy to overcome some of the therapeutic disadvantages of 6-thioguanine (TG) and 6-mercaptopurine (MP), we propose the inclusion of these drugs in βcyclodextrin (βCD) to form the complexes βCD-TG and βCD-MP, followed by subsequent interaction with gold nanoparticles (AuNPs), generating the ternary systems: βCD-TG-AuNPs and βCD-MP-AuNPs. This modification increased their solubility and improved their stability, betting by a site-specific transport due to their nanometric dimensions, among other advantages. The formation of the complexes was confirmed using powder X-ray diffraction, thermogravimetric analysis and one and two-dimensional NMR. A theoretical study using DFT and molecular modelling was conducted to obtain the more stable tautomeric species of TG and MP in solution and confirm the proposed inclusion geometries. The deposition of AuNPs onto βCD-TG and βCD-MP via sputtering was confirmed by UV-vis spectroscopy. Subsequently, the ternary systems were characterized by TEM, FE-SEM and EDX to directly observe the deposited AuNPs and evaluate their sizes, size dispersion, and composition. Finally, the in vitro permeability of the ternary systems was studied using parallel artificial membrane permeability assay (PAMPA). Copyright © 2017 Elsevier Ltd. All rights reserved.

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

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Levinsen, Mette; Rosthøj, Susanne; Nygaard, Ulrikka

2015-01-01

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......,749 HD-MTX courses to 411 children with acute lymphoblastic leukemia on maintenance therapy. Results: The degree of myelosuppression following HD-MTX was similar for patients with TPMTIA and patients with high TPMT activity (TPMTHA), when HD-MTX started with same blood counts and 6MP doses. However...

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

Optimization of Time Controlled 6-mercaptopurine Delivery for Site- Specific Targeting to Colon Diseases.

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Hude, Rahul U; Jagdale, Swati C

2016-01-01

6-MP has short elimination time (Mercaptopurine (6-MP) for treatment of colon diseases. Compression coating technique was used. 32 full factorial design was designed for optimization of the outer coat for the core tablet. For outer coat amount of Eudragit RS 100 and hydroxypropyl methylcellulose (HPMC K100) were employed as independent variables each at three levels while responses evaluated were swelling index and bursting time. Direct compression method was used for tablets formulation. 80% w/w of microcrystalline cellulose and 20% w/w of croscarmellose sodium were found to be optimum concentration for the core tablet. The outer coat of optimized batch (ED) contains 21.05% w/w Eudragit RS 100 and 78.95% w/w HPMC K100 of total polymer weight. In-vitro dissolution study indicated that combination of polymer retards the drug release in gastric region and releases ≥95% of drug in colonic region after ≥7 h. Whereas in case of in-vivo placebo x-ray imaging study had shown that the tablet reaches colonic part after 5±0.5 h providing the proof of arrival in the colon. Stability study indicated that the optimized formulation were physically and chemically stable. Present research work concluded that compression coating by Eudragit RS 100 and HPMC K100 to 6-MP core provides potential colon targeted system with advantages of reduced gastric exposure and enhanced bioavailability. Formulation can be considered as potential and promising candidate for the treatment of colon diseases.

Orientation of 6-mercaptopurine SAMs at the silver electrode as studied by Raman mapping and in situ SERS.

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Chu, Hui; Yang, Haifeng; Huan, Shuangyan; Shen, Guoli; Yu, Ruqin

2006-03-23

Self-assembled monolayers (SAMs) of 6-mercaptopurine (6MP) on a silver electrode in acid and alkaline media were investigated by a combination protocol of the SERS technique with Raman mapping, and it was found that the adsorption mode of 6MP SAMs changed with the pH value of the environment. Quantum calculations for the vibrational mode were performed by the BLYP/6-31G method. 6MP was adsorbed on the silver electrode with a tilted orientation via S, N1, and N7 atoms in acid medium, while the SAMs adopted head-on adsorption modes with the S atom and the N1 atom anchoring the silver surface in alkaline medium. However, 6MP SAMs turned to the same upright orientation on the electrode through the S and N7 atoms when either acid or basic solution was removed. Stability of 6MP SAMs was observed by in situ SERS spectroelectrochemical measurements. The results reveal that the desorption potentials of 6MP SAMs formed under acid and alkaline conditions from the Ag electrode were at ca. -1.3 V and -1.6 V vs SCE, respectively.

Expert opinion: experience with 6-mercaptopurine in the treatment of inflammatory bowel disease.

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Korelitz, Burton I

2013-05-28

Arbitrarily, modern day treatment of inflammatory bowel disease begins with the introduction of immunosuppressives for ulcerative colitis. Clinical improvement with sulfasalazine had been meaningful but modest. Treatment with adrenocorticotropic hormone and corticosteroids led to clinical responses never before realized but it took much too long to recognize that they were not capable of maintaining remission, that adverse reactions were subtle but potentially devastating and that some other agent would be necessary to capitalize on their transient advantage. This of course was true in the treatment of Crohn's disease as well. Not much was ever made of the role of sulfasalazine for Crohn's disease, but with the severing of the diazobond and the elimination of the sulphur component, the 5-aminosalacylic acid (5-ASA) products clearly led to clinical improvement, especially in cases of Crohn's colitis and those with ileitis where the 5-ASA product was released in the terminal ileum and more proximal in the small bowel as well as in ulcerative colitis. The induction of remission was first demonstrated by 6-mercaptopurine (6-MP) with case reports and uncontrolled trials in patients with ulcerative colitis, but its placebo controlled trial for Crohn's disease firmly established its role in inducing remission. No subsequent trial has confirmed its similar role for ulcerative colitis, but nevertheless clinicians know well that 6-MP works at least as well and probably more effectively for ulcerative colitis than for Crohn's disease. What changes have taken place utilizing 6-MP in the management of inflammatory bowel disease since its introduction in the 1960's and 1970's and its trial for Crohn's disease published in the New England Journal of Medicine in 1980?

6-mercaptopurine and daunorubicin double drug liposomes-preparation, drug-drug interaction and characterization.

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Agrawal, Vineet; Paul, Manash K; Mukhopadhyay, Anup K

2005-01-01

This article addresses and investigates the dual incorporation of daunorubicin (DR) and 6-mercaptopurine (6-MP) in liposomes for better chemotherapy. These drugs are potential candidates for interaction due to the quinone (H acceptor) and hydroxyl (H donor) groups on DR and 6-MP, respectively. Interactions between the two drugs in solution were monitored by UV/Vis and fluorescence spectroscopy. Interaction between the two drugs inside the liposomes was evaluated by HPLC (for 6-MP) and by fluorescence spectroscopy (for daunorubicin) after phospholipase-mediated liposome lysis. Our results provide evidence for the lack of interaction between the two drugs in solution and in liposomes. The entrapment efficiencies of 6-MP in the neutral Phosphatidyl choline (PC):Cholesterol (Chol):: 2:1 and anionic PC:Chol:Cardiolipin (CL) :: 4:5:1 single and double drug liposomes were found to be 0.4% and 1.5% (on average), respectively. The entrapment efficiencies of DR in the neutral and anionic double drug liposomes were found to be 55% and 31%, respectively. The corresponding entrapment of daunorubicin in the single drug liposomes was found to be 62% on average. Our thin layer chromatography (TLC) and transmission electron microscopy (TEM) results suggest stability of lipid and liposomes, thus pointing plausible existence of double drug liposomes. Cytotoxicity experiments were performed by using both single drug and double drug liposomes. By comparing the results of phase contrast and fluorescence microscopy, it was observed that the double drug liposomes were internalized in the jurkat and Hut78 (highly resistant cell line) leukemia cells as viewed by the fluorescence of daunorubicin. The cytotoxicity was dose dependent and had shown a synergistic effect when double drug liposome was used.

Phagocytosis and Epithelial Cell Invasion by Crohn’s Disease-Associated Adherent-Invasive Escherichia coli Are Inhibited by the Anti-inflammatory Drug 6-Mercaptopurine

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Federica Migliore

2018-05-01

Full Text Available Adherent-invasive Escherichia coli (AIEC strains are overrepresented in the dysbiotic microbiota of Crohn’s disease (CD patients, and contribute to the onset of the chronic inflammation typical of the disease. However, the effects of anti-inflammatory drugs used for CD treatment on AIEC virulence have not yet been investigated. In this report, we show that exposure of AIEC LF82 strain to amino-6-mercaptopurine (6-MP riboside, one of the most widely used anti-inflammatory drugs in CD, impairs its ability to adhere to, and consequently to invade, human epithelial cells. Notably, phagocytosis of LF82 treated with 6-MP by human macrophages is also reduced, suggesting that 6-MP affects AIEC cell surface determinants involved both in interaction with epithelial cells and in uptake by macrophages. Since a main target of 6-MP in bacterial cells is the inhibition of the important signal molecule c-di-GMP, we also tested whether perturbations in cAMP, another major signaling pathway in E. coli, might have similar effects on interactions with human cells. To this aim, we grew LF82 in the presence of glucose, which leads to inhibition of cAMP synthesis. Growth in glucose-supplemented medium resulted in a reduction in AIEC adhesion to epithelial cells and uptake by macrophages. Consistent with these results, both 6-MP and glucose can affect expression of cell adhesion-related genes, such as the csg genes, encoding thin aggregative fimbriae (curli. In addition, glucose strongly inhibits expression of the fim operon, encoding type 1 pili, a known AIEC determinant for adhesion to human cells. To further investigate whether 6-MP can indeed inhibit c-di-GMP signaling in AIEC, we performed biofilm and motility assays and determination of extracellular polysaccharides. 6-MP clearly affected biofilm formation and cellulose production, but also, unexpectedly, reduced cell motility, itself an important virulence factor for AIEC. Our results provide strong evidence

A search for the optimal duration of treatment with 6-mercaptopurine for ulcerative colitis.

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Lobel, Efrat Z; Korelitz, Burton I; Xuereb, Mark A; Panagopoulos, Georgia

2004-03-01

6-mercaptopurine has proven to be effective in the treatment and maintenance of remission of ulcerative colitis (UC). The optimal duration of treatment with 6-MP is unknown. The intention of this study was to determine the best duration of treatment with 6-MP in terms of maintenance efficacy once remission has been achieved. We reviewed the records from the inflammatory bowel disease (IBD) center at Lenox Hill Hospital and one large IBD practice in New York City of 334 patients treated with 6-MP for UC. These patients were followed from 4 months to 28.7 yr. Sixty-one patients were treated with 6-MP for at least 6 months and had at least a 3-month disease-free interval off steroids while on the medication. These patients were divided into two groups: Group 1 continued 6-MP and group 2 discontinued the drug at various times for reasons other than relapse. Time to relapse was calculated for both groups. A Kaplan-Meier survival analysis was employed and differences between the two groups were analyzed using the log-rank test. The median time to relapse in group 2 was 24 wk and in group 1 was 58 wk (p products, dose of 6-MP during remission, duration of UC, and duration of treatment with 6-MP before remission was achieved. Discontinuation of treatment with 6-MP while UC is in remission leads to a higher relapse rate than maintenance on 6-MP. Therefore, we favor the indefinite treatment with 6-MP in most patients.

Human thiopurine methyltransferase pharmacogenetics: effect of phenotype on sensitivity of cultured lymphocytes to 6-mercaptopurine

International Nuclear Information System (INIS)

Van Loon, J.; Weinshilboum, R.

1986-01-01

Thiopurine methyltransferase (EC 2.1.1.67, TPMT) catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine (6-MP). TPMT activity in human lymphocytes and other tissues is controlled by a common genetic polymorphism. These experiments were designed to study the relationship between TPMT phenotype and the effect of 6-MP on 3 H-thymidine ( 3 H-TdR) incorporation into phytohemaglutinin (PHA) stimulated human peripheral blood lymphocytes. Lymphocytes were obtained from the blood of nine subjects, three subjects with each TPMT phenotype. 6-MP dose response curves were performed at optimal (10 μg/ml) and suboptimal (1 μg/ml) concentrations of PHA. ED50 values for 6-MP with lymphocytes from subjects who genetically lacked TPMT activity were higher than ED50 values for lymphocytes from subjects with genetically intermediate or high TPMT activity. However, ED50 values decreased as level of stimulation increased. Therefore, the effects of 6-MP were studied at a series of PHA concentrations that ranged from 0.1 μg/ml to 10 μg/ml. Lymphocytes from subjects who lacked TPMT activity had significantly higher K/sub ii/ values (1.37 +/- 0.340 μM; mean +/- SEM) for inhibition of 3 H-TdR incorporation by 6-MP than did lymphocytes from subjects with intermediate or high TPMT activity (0.529 +/- 0.068 μM and 0.327 +/- 0.064 μM, respectively, P < .05 for both comparisons)

Human thiopurine methyltransferase pharmacogenetics: effect of phenotype on sensitivity of cultured lymphocytes to 6-mercaptopurine

Energy Technology Data Exchange (ETDEWEB)

Van Loon, J.; Weinshilboum, R.

1986-03-05

Thiopurine methyltransferase (EC 2.1.1.67, TPMT) catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine (6-MP). TPMT activity in human lymphocytes and other tissues is controlled by a common genetic polymorphism. These experiments were designed to study the relationship between TPMT phenotype and the effect of 6-MP on /sup 3/H-thymidine (/sup 3/H-TdR) incorporation into phytohemaglutinin (PHA) stimulated human peripheral blood lymphocytes. Lymphocytes were obtained from the blood of nine subjects, three subjects with each TPMT phenotype. 6-MP dose response curves were performed at optimal (10 ..mu..g/ml) and suboptimal (1 ..mu..g/ml) concentrations of PHA. ED50 values for 6-MP with lymphocytes from subjects who genetically lacked TPMT activity were higher than ED50 values for lymphocytes from subjects with genetically intermediate or high TPMT activity. However, ED50 values decreased as level of stimulation increased. Therefore, the effects of 6-MP were studied at a series of PHA concentrations that ranged from 0.1 ..mu..g/ml to 10 ..mu..g/ml. Lymphocytes from subjects who lacked TPMT activity had significantly higher K/sub ii/ values (1.37 +/- 0.340 ..mu..M; mean +/- SEM) for inhibition of /sup 3/H-TdR incorporation by 6-MP than did lymphocytes from subjects with intermediate or high TPMT activity (0.529 +/- 0.068 ..mu..M and 0.327 +/- 0.064 ..mu..M, respectively, P < .05 for both comparisons).

XRD, vibrational spectra and quantum chemical studies of an anticancer drug: 6-Mercaptopurine.

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

2015-07-05

The single crystal of the hydrated anticancer drug, 6-Mercaptopurine (6-MP), has been grown by slow evaporation technique under room temperature. The structure was determined by single crystal X-ray diffraction. The vibrational spectral analysis was carried out using Laser Raman and FT-IR spectroscopy in the range of 3300-100 and 4000-400 cm(-1). The single crystal X-ray studies shows that the crystal packing is dominated by N-H⋯O and O-H⋯N classical hydrogen bonds leading to a hydrogen bonded ensemble. This classical hydrogen bonds were further connected through O-H⋯S hydrogen bond to form two primary ring R4(4)(16) and R4(4)(12) motifs. These two primary ring motifs are interlinked with each other to build a ladder like structure. These ladders are connected through N-H⋯N hydrogen bond along c-axis of the unit cell through chain C(5) motifs. Further, the strength of the hydrogen bonds is studied through vibrational spectral measurements. The shifting of bands due to the intermolecular interactions was also analyzed in the solid crystalline state. Geometrical optimizations of the drug molecule were done by Density Functional Theory (DFT) using the B3LYP function and Hartree-Fock (HF) level with 6-311++G(d,p) basis set. The optimized molecular geometry and computed vibrational spectra are compared with experimental results which show significant agreement. The natural bond orbital (NBO) analysis was carried out to interpret hyperconjugative interaction and intramolecular charge transfer (ICT). The chemical hardness, electro-negativity and chemical potential of the molecule are carried out by HOMO-LUMO plot. In which, the frontier orbitals has lower band gap value indicating the possible pharmaceutical activity of the molecule. Copyright © 2015 Elsevier B.V. All rights reserved.

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; Breitkreutz, Joerg; Nelken, Brigitte; Schrappe, Martin; Stanulla, Martin; Thomas, Caroline; Bertrand, Yves; Leverger, Guy; Baruchel, André; Schmiegelow, Kjeld; Jacqz-Aigrain, Evelyne

2016-02-15

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 evaluated in the target population. Preclinical and clinical evaluations were performed according to a Pediatric Investigation Plan, in order to apply for a Pediatric Use Marketing Authorization. The pre-clinical study assessed the maximum tolerated dosage-volume and evaluated local mucosal toxicity of 28 daily administrations in treated compared to controls gold hamsters. The multi-centre clinical study was single-dose, open-label, crossover trial, conducted in 15 ALL children during maintenance therapy. The bioavailability and palatability of a single 50mg fixed dose of Loulla compared to 50mg registered tablets were evaluated in a random order on two consecutive days. Seven blood samples over 9h were obtained each day to determine 6-MP pharmacokinetic parameters, including Tmax, Cmax, AUC0-9 and AUC0-∞. A questionnaire adapted to children testing Loulla palatability and preference for either Loulla or the usual 6-MP tablet was completed. Occurrence of adverse events was determined at study visits by vital sign measurements, patient's spontaneous reporting, investigator's questioning and clinical examination. The preclinical study in gold hamsters showed that dosage-volume of 75 mg/kg/day was well tolerated. The relative bioavailability of liquid Loulla formulation compared to the reference presentation is 76% for AUC0-9 and AUC0-∞ and 80% for Cmax. The taste of Loulla and the mouth feeling after ingestion compare favorably to the tablet. No adverse event occurred. Pharmacokinetic, palatability and safety data support the use of Loulla in children. Copyright © 2015 Elsevier B.V. All rights reserved.

Late-onset Rise of 6-MMP Metabolites in IBD Patients on Azathioprine or Mercaptopurine.

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Munnig-Schmidt, Erik; Zhang, Mei; Mulder, Chris J; Barclay, Murray L

2018-03-19

The thiopurines azathioprine and mercaptopurine remain pivotal maintenance treatments in inflammatory bowel disease (IBD); however, up to 15%-20% of patients preferentially produce the hepatotoxic metabolite 6-methylmercaptopurine (6MMP) at the expense of the therapeutic 6-thioguanine nucleotides (6TGN). This metabolic shunting usually begins within 3 months of therapy. We noted patients developing shunting many months or years after starting treatment and aimed to determine how often this late shunting occurs and whether this could be explained by patient factors or concomitant medications. The New Zealand database of thiopurine metabolite results from 2002 to 2016 (19085 6TGN/6MMP pairs from 7130 patients) was interrogated to identify patients developing a 6MMP/6TGN ratio >20 after at least 4 months treatment. Dosing history, concomitant therapy, and comorbidity data were assessed. Fifteen percent of database patients developed preferential 6-MMP production, and of these, 29 patients had late-onset shunting with sufficient data available for validation. This extrapolates to 90 patients in total, representing 1.7% of IBD patients on thiopurines, or 10% of all those with preferential 6-MMP production. Time from starting therapy to shunting was 5 months to 10.4 years (median, 21 months). Eleven patients had abnormal liver function when shunting was recognized, all with 6MMP >5900 pmol/8 × 108 red blood cells. No common factors were found to explain the late onset. Some IBD patients develop preferential 6MMP production many months or years after commencing therapy. This is important when considering frequency of metabolite monitoring, failure of therapy, or abnormal liver function. 10.1093/ibd/izx081_video1izx081.video15746667546001.

Promotion of SH-SY5Y Cell Growth by Gold Nanoparticles Modified with 6-Mercaptopurine and a Neuron-Penetrating Peptide

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Xiao, Yaruo; Zhang, Enqi; Fu, Ailing

2017-12-01

Much effort has been devoted to the discovery of effective biomaterials for nerve regeneration. Here, we reported a novel application of gold nanoparticles (AuNPs) modified with 6-mercaptopurine (6MP) and a neuron-penetrating peptide (RDP) as a neurophic agent to promote proliferation and neurite growth of human neuroblastoma (SH-SY5Y) cells. When the cells were treated with 6MP-AuNPs-RDP conjugates, they showed higher metabolic activity than the control. Moreover, SH-SY5Y cells were transplanted onto the surface coated with 6MP-AuNPs-RDP to examine the effect of neurite development. It can be concluded that 6MP-AuNPs-RDP attached to the cell surface and then internalized into cells, leading to a significant increase of neurite growth. Even though 6MP-AuNPs-RDP-treated cells were recovered from frozen storage, the cells still maintained constant growth, indicating that the cells have excellent tolerance to 6MP-AuNPs-RDP. The results suggested that the 6MP-AuNPs-RDP had promising potential to be developed as a neurophic nanomaterial for neuronal growth.

Methylation of 6-mercaptopurine and 6-thioguanine by thiopurine S-methyltransferase. A comparison of activity in red blood cell samples of 199 blood donors.

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Kröplin, T; Iven, H

2000-07-01

To compare 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) as substrates for the methylation reaction catalysed by the enzyme thiopurine S-methyltransferase (TPMT). TPMT activity in haemolysed red blood cells of healthy blood donors was determined twice, using the same experimental setting and equal molar concentrations of 6-TG and 6-MP as substrates. After extraction, the reaction products 6-methyl-TG and 6-methyl-MP were quantified using specific high-performance liquid chromatography procedures. The medians of the TPMT activities from 199 blood donors were 54.4 nmol 6-MTG g(-1)Hb h(-1) when measured with 6-TG as the substrate and 35.8 nmol 6-MMP g(-1) Hb h(-1) when measured with 6-MP. The correlation coefficient for the 199 pairs of values was 0.8695. On average, TPMT activity was 34% lower with 6-MP as substrate than with 6-TG as substrate.

Amperometric determination of 6-mercaptopurine on functionalized multi-wall carbon nanotubes modified electrode by liquid chromatography coupled with microdialysis and its application to pharmacokinetics in rabbit.

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Cao, Xu-Ni; Lin, Li; Zhou, Yu-Yan; Shi, Guo-Yue; Zhang, Wen; Yamamoto, Katsunobu; Jin, Li-Tong

2003-07-27

In this paper, multi-wall carbon nanotubes functionalized with carboxylic groups modified electrode (MWNT-COOH CME) was fabricated. This chemically modified electrode (CME) can be used as the working electrode in the liquid chromatography for the determination of 6-mercaptopurine (6-MP). The results indicate that the CME exhibits efficiently electrocatalytic oxidation for 6-MP with relatively high sensitivity, stability and long-life. The peak currents of 6-MP are linear to its concentrations ranging from 4.0 x 10(-7) to 1.0 x 10(-4) mol l(-1) with the calculated detection limit (S/N=3) of 2.0 x 10(-7) mol l(-1). Coupled with microdialysis, the method has been successfully applied to the pharmacokinetic study of 6-MP in rabbit blood. This method provides a fast, sensible and simple technique for the pharmacokinetic study of 6-MP in vivo.

Probes of eukaryotic DNA-dependent RNA polymerase II-I. Binding of 9-beta-D-arabinofuranosyl-6-mercaptopurine to the elongation subsite.

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Cho, J M; Kimball, A P

1982-08-15

9-beta-D-Arabinofuranosyl-6-mercaptopurine (ara-6-MP) was used to affinity-label wheat germ DNA-dependent RNA polymerase II (or B) (nucleosidetriphosphate:RNA nucleotidyltransferase, EC 2.7.7.6). This nucleoside analogue was found to be a competitive inhibitor with respect to [3H]UMP incorporation. Natural substrates protected the enzyme from inactivation by ara-6-MP when the enzyme was preincubated with excess concentrations of substrates, suggesting that the inhibitor binds at the elongation subsite. The inhibitor bound the catalytic center of the enzyme with a stoichiometry of 0.6:1. The sulfhydryl reagent, dithiothreitol, reversed the inhibition by ara-6-MP, suggesting that the 6-thiol group of the inhibitor was interacting closely with an essential cysteine residue in the catalytic center of the enzyme. Chromatographic analysis of the pronase-digestion products of the RNA polymerase II-ara-6-MP complex also showed that ara-6-MP had bound a cysteine residue. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the denatured [6-35S]ara-6-MP-labeled RNA polymerase II revealed that over 80% of the radioactivity was associated with the IIb subunit of the enzyme.

The ten-year single-center experience with 6-mercaptopurine in the treatment of inflammatory bowel disease.

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Glazier, Kenneth D; Palance, Adam L; Griffel, Louis H; Das, Kiron M

2005-01-01

To report the 10-year experience of a single center in treating patients with refractory inflammatory bowel disease (IBD) with relatively lower dose of 6-mercaptopurine (6-MP). The charts of 285 patients with IBD (Crohn's disease 160 and ulcerative colitis 125) receiving 6-MP were reviewed. Clinical response, subsequent breakthrough while taking 6-MP, and relapse rates when 6-MP was discontinued and side effects were assessed. Ninety-three percent of the patients were taking 50 to 75 mg/day of 6-MP. Complete remission was achieved in 62%, partial remission in 14.5%, and failure to achieve remission in 23.5% of the patients. Of complete responders, 27.5% had breakthrough while continuing 6-MP. Nine percent of those that achieved a complete remission experienced a relapse after 6-MP was discontinued. Side effects included leukopenia (11.2%), abnormal liver function tests (3.8%), various infections, including pneumonia (3.1%), pancreatitis (2.5%), nausea (2.1%), headache (2.8%), fever (1.4%), hair loss (1%), and rash (0.7%). Two cancers occurred while taking 6-MP: melanoma on the finger and a fatal colonic lymphoma. Four patients continued 6-MP throughout pregnancies and had normal outcomes. In our experience 6-MP is relatively safe and appears to be as effective at a lower dosage (0.84 mg/kg per day) compared with the recommended higher dosage (1-1.5 mg/kg per day), when leukopenia was more frequent. Serious side effects, although rare, need to be monitored.

6-mercaptopurine (6-MP) entrapped stealth liposomes for improvement of leukemic treatment without hepatotoxicity and nephrotoxicity.

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Umrethia, Manish; Ghosh, Pradip Kumar; Majithya, Rita; Murthy, R S R

2007-03-01

6-mercaptopurine (6-MP) is a purine analogue used in childhood leukemia. Because of the oral bioavailability of 6-MP is low and highly variable, the aim of this study was to develop a new parenteral formulation that can prolong the biological half-life of the drug, improve its therapeutic efficacy, and its associated reduce side effects. Conventional and stealth 6-MP liposomes were prepared by a thin film hydration technique followed by a high-pressure homogenization process and characterized for percent entrapment efficiency (%EE), particle size, and stability in human plasma. Pharmacokinetic, tissue distribution, and biochemical analysis were performed after intravenous (IV) administration of all formulations of 6-MP on rats. The conventional liposomes were found less stable than stealth liposomes in human plasma at 37 degrees C. Stealth liposomes exhibited high peak plasma concentration (C(max)), and long circulating capacity in blood and biological half-life. The uptake of stealth liposomes by the liver and spleen and accumulation in the kidney were significantly less than that of conventional liposomes and the free drug. Serum urea, creatinine, GOT (Glutamic Oxaloacetic Transaminase), and GPT (Glutamic Pyruvic Transaminase) increased significantly in rats given an IV injection of conventional liposomes and the free drug, but not in those administered with the same dose of stealth liposomes. Stealth liposomes may help to increase therapeutic efficacy of 6-MP and to reduce total amount of dose as well as frequency of the dose. It also may reduce the possibility of the risk of toxicity to the liver and kidney generally associated with free 6-MP.

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

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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

Quantitation of intracellular metabolites of [35S]-6-mercaptopurine in L5178Y cells grown in time-course incubates.

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Breter, H J; Zahn, R K

1979-09-01

6-Mercaptopurine (6MP) metabolism was quantitatively determined in L5178Y murine lymphoma. Cells grown in time-course incubates with [35S]-6MP were extracted with cold perchloric acid, and the buffered extracts were subjected to high-performance liquid cation-exchange chromatography prior to and after hydrolysis with alkaline phosphatase. Free sulfate, 6-thiouric acid, 6-thioxanthosine, 6-thioguanosine, 6-thioinosine, free 6MP, and 6-methylthioinosine were separated from each other; identified in the radiochromatograms by elution volume, UV spectroscopic data, and enzymatic peak-shifting analyses with purine nucleoside phosphorylase; and quantitatively determined by means of 35S radioactivity. Gross intracellular 35S concentrations remained constant at 5 x 10(-5) M after 1 hr of incubation. 6MP metabolism in L5178Y cells was distinguished into an early phase (to 1 hr of incubation) in which 6MP was predominantly catabolized to 6-thiouric acid and free sulfate, into an intermediate phase (to 8 hr) in which substantial amounts of free 6MP and of ribonucleotides of 6-thioxanthosine and 6-thioguanosine were present while the concentrations of nonnucleotide oxidation products sharply decreased, and into a late phase (to 24 hr) in which the ribonucleotides of 6MP, of 6-thioguanosine and, in particular, of 6-methylthioinosine were the most abundant metabolites.

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.

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

OpenAIRE

Mohammed Hassan Mohammed et al

2012-01-01

6-[(5-pyridine-yl-1, 2, 3, 4-oxadiazole-2-yl)dithiol]-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 ...

Determination of microgramme amounts of osmium and ruthenium based on inhibition of the iodine-azide reaction by their complexes with 6-mercaptopurine

International Nuclear Information System (INIS)

Matusiewicz, H.; Kurzawa, Z.

1976-01-01

A new kinetic method of the determination of microamounts of osmium and ruthenium has been developed. The reaction between sodum azide and iodine induced by 6-mercaptopurine (6-MP) was used for this purpose. Under suitable experimental conditions the induction coefficient of 6-MP amounts to 1750+-40. The formed complexes of the metals are stable in the medium containing an excess of azide ions and do not induce the iodine-azide reaction. The method consists in the determination of the 6-MP not bound to the metal. The amount of osmium or ruthenium is then determined from linear relations. Before the determination osmium and ruthenium must be separated from other cations and from each other by distillation as volatile tetroxides. The iodine-azide method is simple, sensitive and does not require any apparatus. The range of the determination is 0.1-5.0 μg in 5 cm 3 of the solution of Os(8) and 0.5-5.0 μg for Ru(8). The error of the determination is +-6.4% and +- 6.1% for osmium and ruthenium, respectively. The time of the determination is 30 minutes not taking into account 2-hour waiting time necessary for the formation of the complexes. (author)

Assessment of mercaptopurine (6MP) metabolites and 6MP metabolic key-enzymes in childhood acute lymphoblastic leukemia.

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Wojtuszkiewicz, Anna; Barcelos, Ana; Dubbelman, Boas; De Abreu, Ronney; Brouwer, Connie; Bökkerink, Jos P; de Haas, Valerie; de Groot-Kruseman, Hester; Jansen, Gerrit; Kaspers, Gertjan L; Cloos, Jacqueline; Peters, G J

2014-01-01

Pediatric acute lymphoblastic leukemia (ALL) is treated with combination chemotherapy including mercaptopurine (6MP) as an important component. Upon its uptake, 6MP undergoes a complex metabolism involving many enzymes and active products. The prognostic value of all the factors engaged in this pathway still remains unclear. This study attempted to determine which components of 6MP metabolism in leukemic blasts and red blood cells are important for 6MP's sensitivity and toxicity. In addition, changes in the enzymatic activities and metabolite levels during the treatment were analyzed. In a cohort (N=236) of pediatric ALL patients enrolled in the Dutch ALL-9 protocol, we studied the enzymes inosine-5'-monophosphate dehydrogenase (IMPDH), thiopurine S-methyltransferase (TPMT), hypoxanthine guanine phosphoribosyl transferase (HGPRT), and purine nucleoside phosphorylase (PNP) as well as thioguanine nucleotides (TGN) and methylthioinosine nucleotides (meTINs). Activities of selected enzymes and levels of 6MP derivatives were measured at various time points during the course of therapy. The data obtained and the toxicity related parameters available for these patients were correlated with each other. We found several interesting relations, including high concentrations of two active forms of 6MP--TGN and meTIN--showing a trend toward association with better in vitro antileukemic effect of 6MP. High concentrations of TGN and elevated activity of HGPRT were found to be significantly associated with grade III/IV leucopenia. However, a lot of data of enzymatic activities and metabolite concentrations as well as clinical toxicity were missing, thereby limiting the number of assessed relations. Therefore, although a complex study of 6MP metabolism in ALL patients is feasible, it warrants more robust and strict data collection in order to be able to draw more reliable conclusions.

Reaction of a chemotherapeutic agent, 6-mercaptopurine, with a direct-acting, electrophilic carcinogen, benzo[a]pyrene-7,8-diol 9,10-epoxide.

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MacLeod, M C; Stewart, E; Daylong, A; Lew, L K; Evans, F E

1991-01-01

The chemotherapeutic agent 6-mercaptopurine (6-MP) has been shown to react covalently with the ultimate carcinogenic metabolite of benzo[a]pyrene, 7-r,8-t-dihydroxy-9-t,10-t-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE), in aqueous solution, forming a single adduct. NMR studies of the HPLC-purified product were consistent with its identification as 10(S)-(6'-mercaptopurinyl)-7,8,9-trihydroxy-7,8,9,10- tetrahydrobenzo[a]pyrene. Reaction kinetics were analyzed by using both HPLC separation of the products formed and a spectrophotometric assay for adduct formation. A simple model in which direct reaction between 6-MP and BPDE takes place without formation of a physical complex was found to adequately predict the dependence of product ratios on 6-MP concentration. Variations in the observed rate constant for this reaction with changes in temperature, pH, and buffer concentration were determined and compared to the effects of these variables on the observed rate constant for BPDE hydrolysis. In each case, the processes were affected quite differently, suggesting that different rate-determining steps are involved. The data suggest that the reaction mechanism involves SN2 attack of the anion of 6-MP, formed by ionization of the sulfhydryl group, on carbon 10 of BPDE, resulting in a trans-9,10 reaction product.

Study of the interaction of 6-mercaptopurine with protein by microdialysis coupled with LC and electrochemical detection based on functionalized multi-wall carbon nanotubes modified electrode.

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Cao, Xu-Ni; Lin, Li; Zhou, Yu-Yan; Zhang, Wen; Shi, Guo-Yue; Yamamoto, Katsunobu; Jin, Li-Tong

2003-07-14

Microdialysis sampling coupled with liquid chromatography and electrochemical detection (LC-ECD) was developed and applied to study the interaction of 6-Mercaptopurine (6-MP) with bovine serum albumin (BSA). In the LC-ECD, the multi-wall carbon nanotubes fuctionalized with carboxylic groups modified electrode (MWNT-COOH CME) was used as the working electrode for the determination of 6-MP. The results indicated that this chemically modified electrode (CME) exhibited efficiently electrocatalytic oxidation for 6-MP with relatively high sensitivity, stability and long-life. The peak currents of 6-MP were linear to its concentrations ranging from 4.0 x 10(-7) to 1.0 x 10(-4) mol l(-1) with the calculated detection limit (S/N = 3) of 2.0 x 10(-7) mol l(-1). The method had been successfully applied to assess the association constant (K) and the number of the binding sites (n) on a BSA molecular, which calculated by Scatchard equation, were 3.97 x 10(3) mol(-1) l and 1.51, respectively. This method provided a fast, sensible and simple technique for the study of drug-protein interactions.

Effects of 6-mercaptopurine treatment on sperm production and reproductive performance: a study in male mice.

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Ligumsky, Moshe; Badaan, Shadi; Lewis, Hadassa; Meirow, Dror

2005-04-01

Azathioprine and 6-mercaptopurine interact in purine metabolism and DNA synthesis, thus their potential mutagenic effects have been of concern in the management of inflammatory bowel disease (IBD), especially in patients of childbearing age. Although several clinical studies have indicated their safety in both reproduction and pregnancy, in a recent large epidemiological study concerns were raised about their adverse effects in pregnant patients with IBD, and experimental or basic data on this subject are limited. The aim of this study was to investigate sperm production, sperm quality, and reproductive outcome following prolonged 6-MP administration to male mice. Highly inbred Balb/c adult male mice were used. 6-MP at doses of 2, 5, and 8 mg/kg (n = 9 for each group) was given daily for 51 days and the treatment group was compared with controls. After 45 days of treatment, the mice were mated with females. Following 13 days of pregnancy, the products of conception were evaluated and live fetuses were examined for gross malformations. Sperm production and morphology were examined after 51 days of 6-MP administration. Treatment with 6-MP at all doses did not affect sperm morphology and sperm production in the testicular tubules, as compared with controls (70% normal sperm). However, pregnancy rates were inversely related to escalating doses of 6-MP: 55%, 41%, 28%, and 16% for control, 2, 5, and 8 mg/kg groups, respectively. Resorption rates (abortions) were 21% in the control group as compared with 45-50% in all the treatment groups, but the incidence of major congenital malformations was not increased. Long-term 6-MP treatment in male mice did not impair sperm production and sperm morphology. However, a significantly high rate of embryonic resorption indicated occult sperm damage. Thus, normal sperm analysis does not necessarily imply that sperm damage at genetic level did not occur. It is difficult to extrapolate from these results to the clinical use of 6-MP

6-Mercaptopurine, an activator of Nur77, enhances transcriptional activity of HIF-1alpha resulting in new vessel formation.

Science.gov (United States)

Yoo, Y-G; Na, T-Y; Yang, W-K; Kim, H-J; Lee, I-K; Kong, G; Chung, J-H; Lee, M-O

2007-05-31

Hypoxia-inducible factor-1alpha (HIF-1alpha) plays a central role in oxygen homeostasis. Previously, we reported that the orphan nuclear receptor Nur77 functions in stabilizing HIF-1alpha. Here, we demonstrate that 6-mercaptopurine (6-MP), an activator of the NR4A family members, enhances transcriptional activity of HIF-1. 6-MP enhanced the protein-level of HIF-1alpha as well as vascular endothelial growth factor (VEGF) in a dose- and time-dependent manner. The induction of HIF-1alpha was abolished by the transfection of either a dominant-negative Nur77 mutant or si-Nur77, indicating a critical role of Nur77 in the 6-MP action. The HIF-1alpha protein level remained up to 60 min in the presence of 6-MP when de novo protein synthesis was blocked by cycloheximide, suggesting that 6-MP induces stabilization of the HIF-1alpha protein. The fact that 6-MP decreased the association of HIF-1alpha with von Hippel-Lindau protein and the acetylation of HIF-1alpha, may explain how 6-MP induced stability of HIF-1alpha. Further, 6-MP induced the transactivation function of HIF-1alpha by recruiting co-activator cyclic-AMP-response-element-binding protein. Finally, 6-MP enhanced the expression of HIF-1alpha and VEGF, and the formation of capillary tubes in human umbilical vascular endothelial cells. Together, our results provide a new insight for 6-MP action in the stabilization of HIF-1alpha and imply a potential application of 6-MP in hypoxia-associated human vascular diseases.

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

Energy Technology Data Exchange (ETDEWEB)

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.

Structural Basis of Substrate Recognition in Thiopurine S-Methyltransferase

Energy Technology Data Exchange (ETDEWEB)

Peng, Yi; Feng, Qiping; Wilk, Dennis; Adjei, Araba A.; Salavaggione, Oreste E.; Weinshilboum, Richard M.; Yee, Vivien C. (Case Western); (MCCM)

2008-09-23

Thiopurine S-methyltransferase (TPMT) modulates the cytotoxic effects of thiopurine prodrugs such as 6-mercaptopurine by methylating them in a reaction using S-adenosyl-l-methionine as the donor. Patients with TPMT variant allozymes exhibit diminished levels of protein and/or enzyme activity and are at risk for thiopurine drug-induced toxicity. We have determined two crystal structures of murine TPMT, as a binary complex with the product S-adenosyl-l-homocysteine and as a ternary complex with S-adenosyl-l-homocysteine and the substrate 6-mercaptopurine, to 1.8 and 2.0 {angstrom} resolution, respectively. Comparison of the structures reveals that an active site loop becomes ordered upon 6-mercaptopurine binding. The positions of the two ligands are consistent with the expected S{sub N}2 reaction mechanism. Arg147 and Arg221, the only polar amino acids near 6-mercaptopurine, are highlighted as possible participants in substrate deprotonation. To probe whether these residues are important for catalysis, point mutants were prepared in the human enzyme. Substitution of Arg152 (Arg147 in murine TPMT) with glutamic acid decreases V{sub max} and increases K{sub m} for 6-mercaptopurine but not K{sub m} for S-adenosyl-l-methionine. Substitution at this position with alanine or histidine and similar substitutions of Arg226 (Arg221 in murine TPMT) result in no effect on enzyme activity. The double mutant Arg152Ala/Arg226Ala exhibits a decreased V{sub max} and increased K{sub m} for 6-mercaptopurine. These observations suggest that either Arg152 or Arg226 may participate in some fashion in the TPMT reaction, with one residue compensating when the other is altered, and that Arg152 may interact with substrate more directly than Arg226, consistent with observations in the murine TPMT crystal structure.

DNA-thioguanine nucleotide concentration and relapse-free survival during maintenance therapy of childhood acute lymphoblastic leukaemia (NOPHO ALL2008): a prospective substudy of a phase 3 trial.

Science.gov (United States)

Nielsen, Stine Nygaard; Grell, Kathrine; Nersting, Jacob; Abrahamsson, Jonas; Lund, Bendik; Kanerva, Jukka; Jónsson, Ólafur Gísli; Vaitkeviciene, Goda; Pruunsild, Kaie; Hjalgrim, Lisa Lyngsie; Schmiegelow, Kjeld

2017-04-01

Adjustment of mercaptopurine and methotrexate maintenance therapy of acute lymphoblastic leukaemia by leucocyte count is confounded by natural variations. Cytotoxicity is primarily mediated by DNA-incorporated thioguanine nucleotides (DNA-TGN). The aim of this study was to establish whether DNA-TGN concentrations in blood leucocytes during maintenance therapy are associated with relapse-free survival. In this substudy of the NOPHO ALL2008 phase 3 trial done in 23 hospitals in seven European countries (Denmark, Estonia, Finland, Iceland, Lithuania, Norway, and Sweden), we analysed data from centralised and blinded analyses of 6-mercaptopurine and methotrexate metabolites in blood samples from patients with non-high-risk childhood acute lymphoblastic leukaemia. Eligible patients were aged 1·0-17·9 years; had been diagnosed with non-high-risk precursor B-cell or T-cell leukaemia; had been treated according to the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol; and had reached maintenance therapy in first remission. Maintenance therapy was (mercaptopurine 75 mg/m 2 once per day and methotrexate 20 mg/m 2 once per week, targeted to a leucocyte count of 1·5-3·0 × 10 9 cells per L). We measured DNA-TGN and erythrocyte concentrations of TGN nucleotides, methylated mercaptopurine metabolites, and methotrexate polyglutamates. The primary objective was the association of DNA-TGN concentrations and 6-mercaptopurine and methotrexate metabolites with relapse-free survival. The secondary endpoint was the assessment of DNA-TGN concentration and 6-mercaptopurine and methotrexate metabolites during maintenance therapy phase 2. Between Nov 26, 2008 and June 14, 2016, 1509 patients from the NOPHO ALL2008 study were assessed for eligibility in the DNA-TGN substudy, of which 918 (89%) of 1026 eligible patients had at least one DNA-TGN measurement and were included in the analyses. Median follow-up was 4·6 years (IQR 3·1-6·1). Relapse-free survival was

Influence of the solution pH in the 6-mercaptopurine self-assembled monolayer (6MP-SAM) on a Au(111) single-crystal electrode.

Science.gov (United States)

Madueño, Rafael; García-Raya, Daniel; Viudez, Alfonso J; Sevilla, José M; Pineda, Teresa; Blázquez, Manuel

2007-10-23

Self-assembled monolayers (SAMs) of 6-mercaptopurine (6MP) have been prepared on a Au(111) single-crystal electrode by immersion of the metal surface in a 100 microM 6MP and 0.01 M HClO4 solution. The 6MP-SAM Au(111) single-crystal electrodes were transferred to the cell and allowed to equilibrate with the different aqueous working solutions before the electrochemical experiments. The influence of the solution pH was studied by cyclic voltammetry, double layer capacitance curves, and electrochemical impedance spectroscopy. The electrochemical behavior of the 6MP-SAM in acetic acid at pH 4 presents important differences in comparison to that obtained in 0.1 M KOH solutions. Cyclic voltammograms for the reductive desorption process in acid medium are broad and show some features that can be explained by a phase transition between a chemisorbed and a physisorbed state of the 6MP molecules. The low solubility of these molecules in acid medium could explain this phenomenon and the readsorption of the complete monolayer when the potential is scanned in the positive direction. The variation of the double-layer capacitance values in the potential range of monolayer stability with the pH suggests that the acid-base chemistry of the 6MP molecules is playing a role. This fact has been studied by following the variations of the electron-transfer rate constant of the highly charged redox probes as are Fe(CN)(6)-3/-4 and Ru(NH3)(6)+3/+2 as a function of solution pH. The apparent surface pKa value for the 6MP-SAM (pKa approximately 8) is explained by the total conversion of the different 6MP tautomers that exist in solution to the thiol species in the adsorbed state.

Chemotherapy and Drug Targeting in the Treatment of Leishmaniasis

Science.gov (United States)

1989-05-30

nucleotides with specific enzymes (67). Some commonly used purine analogs 20 6- Mercaptopurine 6-Thioguanine SH SH Ni N N N NH 2 NkN N H H Azathiopine CH3...Chemotherapeutic Drugs. 21 include: 6- Mercaptopurine , which is used for the treatment of acute leukemias (Fig 4). 6-Thioguanine, which is also used in the treatment... degradation of nucleic acids or nucleotides. In contrast, Leihmania. spp. rely primarily on the salvage pathways for their source of nucleotides. They

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.

Bioequivalence of azathioprine products.

Science.gov (United States)

Baker, Daniel E

2003-01-01

All azathioprine oral tablets are considered bioequivalent by the Food and Drug Administration based on traditional testing. However, since these tests were conducted, it has been determined that some patients have a deficiency of the enzyme most responsible for the metabolism of 6-mercaptopurine-thiopurine methyltransferase (TPMT). Azathioprine is rapidly converted to 6-mercaptopurine, its active metabolite. So it is possible that differences in TPMT activity may influence the bioequivalence of azathioprine products among individuals, especially those patients deficient in TPMT enzyme activity. However, this possibility has not been evaluated.

Stability of allopurinol and of five antineoplastics in suspension.

Science.gov (United States)

Dressman, J B; Poust, R I

1983-04-01

The stability of allopurinol, azathioprine, chlorambucil, melphalan, mercaptopurine, and thioguanine each in an extemporaneously prepared suspension was studied. Tablets of each drug were crushed, mixed with a suspending agent, and brought to a final volume of 10, 15, or 20 ml with a 2:1 mixture of simple syrup and wild cherry syrup. Suspensions were prepared in the following concentrations: allopurinol (20 mg/ml), azathioprine (50 mg/ml), chlorambucil (2 mg/ml), melphalan (2 mg/ml), mercaptopurine (50 mg/ml), and thioguanine (40 mg/ml). Using high-performance liquid chromatography or ultraviolet scans, duplicate assays were performed on each suspension periodically during storage for up to 84 days at ambient room temperature or 5 degrees C. The time required for the suspensions to drop below 90% of labeled strength was used as an indicator of drug stability. Allopurinol and azathioprine were stable for at least 56 days at room temperature and at 5 degrees C. Chlorambucil decomposed rapidly at room temperature but was stable for seven days when stored at 5 degrees C. Melphalan suspensions did not meet the stated criteria for stability even at the time of initial assay. Mercaptopurine and thioguanine were stable for 14 and 84 days, respectively, at room temperature; at 5 degrees C, assay values dropped below those obtained at room temperature. In the suspension formulation tested, allopurinol, azathioprine, mercaptopurine, and thioguanine are stable for at least 14 days at room temperature; chlorambucil suspensions should be refrigerated and discarded after seven days. Melphalan decomposes too rapidly to make this suspension formulation feasible for extemporaneous compounding.

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

In vivo comparison of various polymeric and low molecular mass inhibitors of intestinal P-glycoprotein.

Science.gov (United States)

Föger, Florian; Hoyer, Herbert; Kafedjiiski, Krum; Thaurer, Michael; Bernkop-Schnürch, Andreas

2006-12-01

Several polymers have been reported to modulate drug absorption by inhibition of intestinal P-glycoprotein (P-gp). The aim of the present study was to provide a direct in vivo comparison of delivery systems based on Pluronic P85, Myrj 52 and chitosan-4-thiobutylamidine (Ch-TBA) in vivo in rats, using rhodamine-123 (Rho-123) as representative P-gp substrate. Furthermore, the postulated low molecular mass P-gp inhibitors 6-mercaptopurine and reduced glutathione (GSH) were evaluated in vitro and in vivo. In vitro, the permeation enhancing effect of 6-mercaptopurine, GSH, Pluronic P85, Myrj 52, and the combination of Ch-TBA with GSH was evaluated by using freshly excised rat intestinal mucosa mounted in Ussing-type diffusion chambers. In comparison to buffer only, Rho-123 transport in presence of 100 microm 6-mercaptopurine, 0.5% (w/v) GSH, 0.5% (w/v) Pluronic P85, 0.5% (w/v) Myrj 52 and the combination of 0.5% (w/v) Ch-TBA/ 0.5% (w/v) GSH, was 2.1, 1.6, 1.9, 1.8, 3.0-fold improved, respectively. In vivo in rat, enteric-coated tablets based on Pluronic P85, Myrj 52 or Ch-TBA/GSH increased the area under the plasma concentration time curve (AUC(0-12)) of Rho-123 1.6-fold, 2.4-fold, 4.3-fold, respectively, in comparison to control only. Contrariwise, the low molecular mass excipients 6-mercaptopurine and GSH showed no significant effect in vivo at all. This in vivo study showed that polymeric P-gp inhibitors and especially the delivery system based on thiolated chitosan significantly increased the oral bioavailability of P-gp substrate Rho-123.

A phase III randomized prospective trial of external beam radiotherapy, mitomycin C, carmustine, and 6-mercaptopurine for the treatment of adults with anaplastic glioma of the brain

International Nuclear Information System (INIS)

Halperin, Edward C.; Herndon, James; Schold, S. Clifford; Brown, Mark; Vick, Nicholas; Cairncross, J. Gregory; Macdonald, David R.; Gaspar, Laurie; Fischer, Barbara; Dropcho, Edward; Rosenfeld, Steven; Morowitz, Richard; Piepmeier, Joseph; Hait, William; Byrne, Thomas; Salter, Merle; Imperato, Joseph; Khandekar, Janardan; Paleologos, Nina; Burger, Peter; Bentel, Gunilla C.; Friedman, Allan

1996-01-01

Purpose: This study was designed to evaluate strategies to overcome the resistance of anaplastic gliomas of the brain to external beam radiotherapy (ERT) plus carmustine (BCNU). Patients were ≥ 15 years of age, had a histologic diagnosis of malignant glioma, and a Karnofsky performance status (KPS) ≥ 60%. Methods and Materials: In Randomization 1, patients were assigned to receive either ERT alone (61.2 Gy) or ERT plus mitomycin C (Mito, IV 12.5 mg/m 2 ) during the first and fourth week of ERT. After this treatment, patients went on to Randomization 2, where they were assigned to receive either BCNU (i.v. 200 mg/m 2 ) given at 6-week intervals or 6-mercaptopurine (6-MP, 750 mg/m 2 IV daily for 3 days every 6 weeks), with BCNU given on the third day of the 6-MP treatment. Three hundred twenty-seven patients underwent Randomization 1. One hundred sixty-four received ERT alone, and 163 received ERT + Mito [average age 52.7 years; 63% male; 69% glioblastoma multiforme (GBM); 66% had a resection; 56% KPS ≥ 90%]. Step-wise analysis of survival from Randomization 1 or 2 indicates that survival was significantly diminished by: (a) age ≥ 45 years (b) KPS < 90%; (c) GBM/Gliosarcoma histology; (d) stereotactic biopsy as opposed to open biopsy or resection. Median survival from Randomization 1 in both arms (ERT + Mito) was 10.8 months. Median survival from Randomization 2 was 9.3 months for BCNU/6MP vs. 11.4 months for the BCNU group (p = 0.35). Carmustine/6-MP showed a possible survival benefit for histologies other than GBM/GS. Two hundred and thirty-three patients underwent Randomization 2. The proportion of patients in the ERT group who terminated study prior to Randomization 2 was significantly less in the ERT group than in the ERT + Mito group (20 vs. 37%, p < 0.001). Conclusions: (a) The addition of Mito to ERT had no impact on survival; (b) patients treated with ERT + Mito were at greater risk of terminating therapy prior to Randomization 2; (c) there was not a

Immobilization of xanthine oxidase on a polyaniline silicone support.

Science.gov (United States)

Nadruz, W; Marques, E T; Azevedo, W M; Lima-Filho, J L; Carvalho, L B

1996-03-01

A polyaniline silicone support to immobilize xanthine oxidase is proposed as a reactor coil to monitor the action of xanthine oxidase on hypoxanthine, xanthine and 6-mercaptopurine. A purified xanthine oxidase immobilized on this support lost 80% of the initial activity after 12 min of use. Co-immobilization of superoxide dismutase and catalase increased the stability of immobilized xanthine oxidase so that the derivative maintained 79% of its initial activity after 4.6 h of continuous use in which 1.5 mumol purine bases were converted by the immobilized enzyme system. There is no evidence of either polyaniline or protein leaching from the coil during 3 h of continuous use. When solutions (10 ml) of hypoxanthine, xanthine and 6-mercaptopurine were circulated individually through the xanthine oxidase-superoxide dismutase-catalase-polyaniline coil (1 mm internal diameter and 3 m in length, 3 ml internal volume) activities of 8.12, 11.17 and 1.09 nmol min-1 coil-1, respectively, were obtained. The advantages of the reactor configuration and the redox properties of the polymer, particularly with respect to immobilized oxidoreductases, make this methodology attractive for similar enzyme systems. This immobilized enzyme system using polyaniline-silicone as support converted 6-mercaptopurine to 6-thiouric acid with equal efficiency as resins based on polyacrylamide and polyamide 11.

Golimumab Injection

Science.gov (United States)

... with another medication called azathioprine (Imuran) or 6-mercaptopurine (Purinethol). Children and teenagers should not normally receive ... medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. ...

Understanding IBD Medications and Side Effects

Science.gov (United States)

... important not to suddenly stop taking this medication. Immunomodulators: These include azathioprine, 6-mercaptopurine (6-MP), methotrexate, ... ongoing inflammation. Usually given orally (methotrexate is injectable), immunomodulators are typically used in people for whom aminosalicylates ...

Maintenance Therapy in IBD

Science.gov (United States)

... also found to be safe and well tolerated. Immunomodulators 6-MP and Azathioprine 6-mercaptopurine (6-MP, ... to a tumor necrosis factor (TNF) blocker or immunomodulator; or had an inadequate response with, were intolerant ...

6-Mercaptopurine attenuates tumor necrosis factor-α production in microglia through Nur77-mediated transrepression and PI3K/Akt/mTOR signaling-mediated translational regulation.

Science.gov (United States)

Huang, Hsin-Yi; Chang, Hui-Fen; Tsai, Ming-Jen; Chen, Jhih-Si; Wang, Mei-Jen

2016-04-13

The pathogenesis of several neurodegenerative diseases often involves the microglial activation and associated inflammatory processes. Activated microglia release pro-inflammatory factors that may be neurotoxic. 6-Mercaptopurine (6-MP) is a well-established immunosuppressive drug. Common understanding of their immunosuppressive properties is largely limited to peripheral immune cells. However, the effect of 6-MP in the central nervous system, especially in microglia in the context of neuroinflammation is, as yet, unclear. Tumor necrosis factor-α (TNF-α) is a key cytokine of the immune system that initiates and promotes neuroinflammation. The present study aimed to investigate the effect of 6-MP on TNF-α production by microglia to discern the molecular mechanisms of this modulation. Lipopolysaccharide (LPS) was used to induce an inflammatory response in cultured primary microglia or murine BV-2 microglial cells. Released TNF-α was measured by enzyme-linked immunosorbent assay (ELISA). Gene expression was determined by real-time reverse transcription polymerase chain reaction (RT-PCR). Signaling molecules were analyzed by western blotting, and activation of NF-κB was measured by ELISA-based DNA binding analysis and luciferase reporter assay. Chromatin immunoprecipitation (ChIP) analysis was performed to examine NF-κB p65 and coactivator p300 enrichments and histone modifications at the endogenous TNF-α promoter. Treatment of LPS-activated microglia with 6-MP significantly attenuated TNF-α production. In 6-MP pretreated microglia, LPS-induced MAPK signaling, IκB-α degradation, NF-κB p65 nuclear translocation, and in vitro p65 DNA binding activity were not impaired. However, 6-MP suppressed transactivation activity of NF-κB and TNF-α promoter by inhibiting phosphorylation and acetylation of p65 on Ser276 and Lys310, respectively. ChIP analyses revealed that 6-MP dampened LPS-induced histone H3 acetylation of chromatin surrounding the TNF-α promoter

Azathioprine treatment during lactation

DEFF Research Database (Denmark)

Christensen, L.A.; Dahlerup, J.F.; Nielsen, M.J.

2008-01-01

BACKGROUND: Thiopurines are widely used to maintain remission in inflammatory bowel disease. Treatment during pregnancy is generally recommended to improve the chance of a normal birth outcome, but advice concerning breastfeeding is conflicting. Aim To estimate the exposure of breastfed infants...... to 6-mercaptopurine, as a metabolite of azathioprine, from maternal milk. METHODS: Eight lactating women with inflammatory bowel disease receiving maintenance therapy with azathioprine 75-200 mg daily were studied. Milk and plasma samples were obtained 30 and 60 min after drug administration and hourly...... for the following 5 h. RESULTS: The variation in the bioavailability of the drug was reflected in a wide range of peak plasma values of 6-mercaptopurine within the first 3 h. A similar curve, but with an hour's delay and at significantly lower concentrations varying from 2-50 microg/L, was seen in maternal milk...

How strong is the edge effect in the adsorption of anticancer drugs on a graphene cluster?

Science.gov (United States)

Rungnim, Chompoonut; Chanajaree, Rungroj; Rungrotmongkol, Thanyada; Hannongbua, Supot; Kungwan, Nawee; Wolschann, Peter; Karpfen, Alfred; Parasuk, Vudhichai

2016-04-01

The adsorption of nucleobase-analog anticancer drugs (fluorouracil, thioguanine, and mercaptopurine) on a graphene flake (C54H18) was investigated by shifting the site at which adsorption occurs from one end of the sheet to the other end. The counterpoise-corrected M06-2X/cc-pVDZ binding energies revealed that the binding stability decreases in the sequence thioguanine > mercaptopurine > fluorouracil. We found that adsorption near the middle of the sheet is more favorable than adsorption near the edge due to the edge effect. This edge effect is stronger for the adsorption of thioguanine or mercaptopurine than for fluorouracil adsorption. However, the edge effect reduces the binding energy of the drug to the flake by only a small amount, <5 kcal/mol, depending on the adsorption site and the alignment of the drug at this site.

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...

Science, Technology and Arts Research Journal - Vol 3, No 2 (2014)

African Journals Online (AJOL)

http://dx.doi.org/10.4314/star.v3i2.6 ... Preparation, Characterization and In Vitro Drug Release Studies of 6-mercaptopurine Thin Film · EMAIL FREE ... Degradation of Para-Phenylenediamine in Aqueous Solution by Photo-Fenton Oxidation ...

DNA-thioguanine nucleotide concentration and relapse-free survival during maintenance therapy of childhood acute lymphoblastic leukaemia (NOPHO ALL2008)

DEFF Research Database (Denmark)

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

2017-01-01

BACKGROUND: Adjustment of mercaptopurine and methotrexate maintenance therapy of acute lymphoblastic leukaemia by leucocyte count is confounded by natural variations. Cytotoxicity is primarily mediated by DNA-incorporated thioguanine nucleotides (DNA-TGN). The aim of this study was to establish w...

Physicians compliance during maintenance therapy in children with Down syndrome and acute lymphoblastic leukemia

DEFF Research Database (Denmark)

Bohnstedt, C; Levinsen, M; Rosthøj, S

2013-01-01

Children with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) have an inferior prognosis compared with non-DS ALL patients. We reviewed methotrexate (MTX)/mercaptopurine (6MP) maintenance therapy data for children with DS treated according to the Nordic Society of Pediatric Hematology...

Non-IgE-mediated food allergies

African Journals Online (AJOL)

routine treatment for children with EoE:[6,10]. • leukotriene antagonists. • cromolyn sodium. • omalizumab. • anti-interleukin-5 antibodies (mepolizumab, reslizumab ). • azathioprine, 6-mercaptopurine and antitumour necrosis factor. Oesophageal dilation. Oesophageal strictures, which are a recognised complication of EoE,.

DNA incorporation of 6-thioguanine nucleotides during maintenance therapy of childhood acute lymphoblastic leukaemia and non-Hodgkin lymphoma

DEFF Research Database (Denmark)

Hedeland, Rikke L; Hvidt, Kristian; Nersting, Jacob

2010-01-01

To explore the DNA incorporation of 6-thioguanine nucleotide levels (DNA-6TGN) during 6-mercaptopurine (6MP) therapy of childhood acute lymphoblastic leukaemia (ALL) and non-Hodgkin lymphoma (NHL) and its relation to erythrocyte levels of their metabolites: 6-thioguanine-nucleotides (E-6TGN...

Mercaptopurine Ingestion Habits, Red Cell Thioguanine Nucleotide Levels, and Relapse Risk in Children With Acute Lymphoblastic Leukemia: A Report From the Children's Oncology Group Study AALL03N1.

Science.gov (United States)

Landier, Wendy; Hageman, Lindsey; Chen, Yanjun; Kornegay, Nancy; Evans, William E; Bostrom, Bruce C; Casillas, Jacqueline; Dickens, David S; Angiolillo, Anne L; Lew, Glen; Maloney, Kelly W; Mascarenhas, Leo; Ritchey, A Kim; Termuhlen, Amanda M; Carroll, William L; Relling, Mary V; Wong, F Lennie; Bhatia, Smita

2017-05-20

Purpose Children with acute lymphoblastic leukemia (ALL) are generally instructed to take mercaptopurine (6-MP) in the evening and without food or dairy products. This study examines the association between 6-MP ingestion habits and 6-MP adherence, red cell thioguanine nucleotide (TGN) levels, and risk of relapse in children with TMPT wild-type genotype. Methods Participants included 441 children with ALL receiving oral 6-MP for maintenance. Adherence was monitored over 48,086 patient-days using the Medication Event Monitoring System; nonadherence was defined as adherence rate < 95%. 6-MP ingestion habits examined included: takes 6-MP with versus never with food, takes 6-MP with versus never with dairy, and takes 6-MP in the evening versus morning versus varying times. Results Median age at study was 6 years (range, 2 to 20 years); 43.8% were nonadherent. Certain 6-MP ingestion habits were associated with nonadherence (taking 6-MP with dairy [odds ratio (OR), 1.9; 95% CI, 1.3 to 2.9; P = .003] and at varying times [OR, 3.4; 95% CI, 1.8 to 6.3; P = .0001]). After adjusting for adherence and other prognosticators, there was no association between 6-MP ingestion habits and relapse risk (6-MP with food: hazard ratio [HR], 0.7; 95% CI, 0.3 to 1.9; P = .5; with dairy: HR, 0.3; 95% CI, 0.07 to 1.5; P = .2; taken in evening/night: HR, 1.1; 95% CI, 0.2 to 7.8; P = .9; at varying times: HR, 0.3; 95% CI, 0.04 to 2.7; P = .3). Among adherent patients, there was no association between red cell TGN levels and taking 6-MP with food versus without (206.1 ± 107.1 v 220.6 ± 121.6; P = .5), with dairy versus without (220.1 ± 87.8 v 216.3 ± 121.3; P =.7), or in the evening/night versus morning/midday versus varying times (218.8 ± 119.7 v 195.5 ± 82.3 v 174.8 ± 93.4; P = .6). Conclusion Commonly practiced restrictions surrounding 6-MP ingestion might not influence outcome but may hinder adherence. Future recommendations regarding 6-MP intake during maintenance therapy for

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...

Magnetic Study of the Novel Polynuclear Compound [Cu(II)(6-Mercaptopurinolate 2-)] n

Science.gov (United States)

Acevedo-Chávez, Rodolfo; Costas, María. Eugenia; Escudero, Roberto

1997-08-01

Chemical reactions between Cu(II) and 6-mercaptopurine, both in aqueous and in methanolic media, yield the novel amorphous polynuclear compound [Cu(II)(6-mercaptopurinolate)2-]n, which is also obtained from diverse Cu(II)-heterocyclic ligand competitive reactions. The kinetic and thermodynamic stabilities associated with the formation of this compound are inferred as remarkable. The spectroscopic data let us suggest the involvement of the exocyclic S(6) donor site and the N atoms in the imidazolic moiety of the deprotonated heterocyclic ligand in the coordination to Cu(II) atoms, forming a distorted bidimensional metallic network. The magnetic studies show the existence of very weak antiferromagnetic coupling in the solid sample. This system represents the first example of a 1 : 1 metal : 6-mercaptopurinolate2-system with ad-type open shell metallic center. The magnetic study carried out also represents the first example of magnetic characterization for this type of polynuclear Cu(II) systems with the dianionic 6-mercaptopurine ligand.

Rapid Identification of Bacterial Pathogens of Military Interest Using Surface-Enhanced Raman Spectroscopy

Science.gov (United States)

2014-06-11

Failloux, N., Bonnet, 1., Baron, M. H., & Perrier, E. (2003). Quantitative analysis of vitamin A degradation by raman spectroscopy. Applied Spectroscopy...analysis of the Raman-active modes of the anti-tumor agent 6- mercaptopurine . Journal of Raman Spectroscopy, 32(1), 1-8. doi: Doi 10.1002/1097- 4555

Mercaptopurine Ingestion Habits, Red Cell Thioguanine Nucleotide Levels, and Relapse Risk in Children With Acute Lymphoblastic Leukemia: A Report From the Children’s Oncology Group Study AALL03N1

Science.gov (United States)

Landier, Wendy; Hageman, Lindsey; Chen, Yanjun; Kornegay, Nancy; Evans, William E.; Bostrom, Bruce C.; Casillas, Jacqueline; Dickens, David S.; Angiolillo, Anne L.; Lew, Glen; Maloney, Kelly W.; Mascarenhas, Leo; Ritchey, A. Kim; Termuhlen, Amanda M.; Carroll, William L.; Relling, Mary V.; Wong, F. Lennie

2017-01-01

Purpose Children with acute lymphoblastic leukemia (ALL) are generally instructed to take mercaptopurine (6-MP) in the evening and without food or dairy products. This study examines the association between 6-MP ingestion habits and 6-MP adherence, red cell thioguanine nucleotide (TGN) levels, and risk of relapse in children with TMPT wild-type genotype. Methods Participants included 441 children with ALL receiving oral 6-MP for maintenance. Adherence was monitored over 48,086 patient-days using the Medication Event Monitoring System; nonadherence was defined as adherence rate < 95%. 6-MP ingestion habits examined included: takes 6-MP with versus never with food, takes 6-MP with versus never with dairy, and takes 6-MP in the evening versus morning versus varying times. Results Median age at study was 6 years (range, 2 to 20 years); 43.8% were nonadherent. Certain 6-MP ingestion habits were associated with nonadherence (taking 6-MP with dairy [odds ratio (OR), 1.9; 95% CI, 1.3 to 2.9; P = .003] and at varying times [OR, 3.4; 95% CI, 1.8 to 6.3; P = .0001]). After adjusting for adherence and other prognosticators, there was no association between 6-MP ingestion habits and relapse risk (6-MP with food: hazard ratio [HR], 0.7; 95% CI, 0.3 to 1.9; P = .5; with dairy: HR, 0.3; 95% CI, 0.07 to 1.5; P = .2; taken in evening/night: HR, 1.1; 95% CI, 0.2 to 7.8; P = .9; at varying times: HR, 0.3; 95% CI, 0.04 to 2.7; P = .3). Among adherent patients, there was no association between red cell TGN levels and taking 6-MP with food versus without (206.1 ± 107.1 v 220.6 ± 121.6; P = .5), with dairy versus without (220.1 ± 87.8 v 216.3 ± 121.3; P =.7), or in the evening/night versus morning/midday versus varying times (218.8 ± 119.7 v 195.5 ± 82.3 v 174.8 ± 93.4; P = .6). Conclusion Commonly practiced restrictions surrounding 6-MP ingestion might not influence outcome but may hinder adherence. Future recommendations regarding 6-MP intake during maintenance therapy for

Transportation of drug–gold nanocomposites by actinomyosin motor system

International Nuclear Information System (INIS)

Kaur, Harsimran; Chaudhary, Archana; Kaur, Inderpreet; Singh, Kashmir; Bharadwaj, Lalit M.

2011-01-01

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 μm/s for levodopa and 6-mercaptopurine, respectively, as compared to actin filaments with velocity of 4.0–6.0 μm/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.

Transportation of drug-gold nanocomposites by actinomyosin motor system

Science.gov (United States)

Kaur, Harsimran; Chaudhary, Archana; Kaur, Inderpreet; Singh, Kashmir; Bharadwaj, Lalit M.

2011-06-01

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 μm/s for levodopa and 6-mercaptopurine, respectively, as compared to actin filaments with velocity of 4.0-6.0 μm/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.

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.

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

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...

Model Compound Studies of Rigid Rod Aromatic Heterocyclic Polymer Systems, the X-Ray Crystal Structure of 2,6-Diphenylbenzo (1,2-d; 5,4-d’) Diimidazole Tetrahydrate, C2OH14N4. 4H2O, a Model System for the Study of Polymer-Water Interaction in Polybenzimidazoles.

Science.gov (United States)

1983-07-01

begin to degrade . The strong affinity for water is manifested by the ability of PBI’s to dry desiccant! Further- more, the observation that crystals of...25. G. M. Brown (1969), "The Crystal Structure of 6- Mercaptopurine Monohydrate," Acta Crystallogr., 3, 210-214. 26. J. Sletten and L. H. Jensen

Inhibition of inducible nitric oxide synthesis by azathioprine in a macrophage cell line.

Science.gov (United States)

Moeslinger, Thomas; Friedl, Roswitha; Spieckermann, Paul Gerhard

2006-06-20

Azathioprine is used as an anti-inflammatory agent. Although there are numerous data demonstrating cytotoxic and immunosuppressive properties of azathioprine and its metabolite 6-mercaptopurine, the mechanism of the anti-inflammatory action of azathioprine has not yet been fully clarified. During our study, we investigated the effects of azathioprine on the inducible nitric oxide synthase (iNOS) in lipopolysaccharide stimulated murine macrophages (RAW 264.7) by measurement of iNOS protein (immunoblotting), iNOS mRNA (semiquantitative competitive RT-PCR), and NO production (nitrite levels). Azathioprine (0-210 muM) induces a concentration dependent inhibition of inducible nitric oxide synthesis (IC50: 33.5 muM). iNOS protein expression showed a concentration dependent reduction as revealed by immunoblotting when cells were incubated with increasing amounts of azathioprine. Azathioprine decreases iNOS mRNA levels as shown by semiquantitative competitive RT-PCR. In contrast, 6-mercaptopurine showed no inhibition of inducible nitric oxide synthesis. Azathioprine did not reduce iNOS mRNA stability after the addition of actinomycin D. Enzymatic activity assays with increasing concentrations of azathioprine (0-210 muM) showed no statistically significant inhibition of iNOS enzyme activity compared to cell lysates without azathioprine. Nuclear translocation of NF-kappaB p65 subunit and binding of NF-kappaB p50 subunit from nuclear extracts to a biotinylated-consensus sequence was unaffected by azathioprine treatment. iNOS inhibition by azathioprine was associated with a decreased expression of IRF-1 (interferon regulatory factor 1) and IFN-beta (beta-interferon) mRNA. Azathioprine induced iNOS inhibition seems to be associated with an action of the methylnitroimidazolyl substituent. This suggests a route to the rational design of nontoxic anti-inflammatory agents by replacing the 6-mercaptopurine component of azathioprine with other substituents. The inhibition of

Chemotherapy and Biochemistry of Leishmania.

Science.gov (United States)

1986-12-01

in activity of the enzyme. We are now Investigating ways to stabilize this enzyme after purification. 3. * 32 43.5 1,65t, We have begun studies on...Tnhibitory Cone~. Giving 50% Tnhibition *Sangivanmycin 41 uM * Mercaptopurine riboside-5-phosphate 105 uM * S-adenosyl homocystel ne O.83nV4 Diminazine

Application of HPLC to study the kinetics of a branched bi-enzyme system consisting of hypoxanthine-guanine phosphoribosyltransferase and xanthine oxidase--an important biochemical system to evaluate the efficiency of the anticancer drug 6-mercaptopurine in ALL cell line.

Science.gov (United States)

Kalra, Sukirti; Paul, Manash K; Balaram, Hemalatha; Mukhopadhyay, Anup Kumar

2007-05-01

The thiopurine antimetabolite 6-mercaptopurine (6MP) is an important chemotherapeutic drug in the conventional treatment of childhood acute lymphoblastic leukemia (ALL). 6MP is mainly catabolized by both hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and xanthine oxidase (XOD) to form thioinosinic monophosphate (TIMP) (therapeutically active metabolite) and 6-thiouric acid (6TUA) (inactive metabolite), respectively. The activity of both the enzymes varies among ALL patients governing the active and the inactive metabolite profile within the immature lymphocytes. Therefore, an attempt was made to study the kinetic nature of the branched bi-enzyme system acting on 6MP and to quantitate TIMP and 6TUA formed when the two enzymes are present in equal and variable ratios. The quantification of the branched kinetics using spectrophotometric method presents problem due to the closely apposed lambda(max) of the substrates and products. Hence, employing an HPLC method, the quantification of the products was done with the progress of time. The limit of quantification (LOQ) of substrate was found to be 10nM and for products as 50 nM. The limit of detection (LOD) was found to be 1 nM for the substrate and the products. The method exhibited linearity in the range of 0.01-100 microM for 6MP and 0.05-100 microM for both 6TUA and TIMP. The amount of TIMP formed was higher than that of 6TUA in the bi-enzyme system when both the enzymes were present in equivalent enzymatic ratio. It was further found that enzymatic ratios play an important role in determining the amounts of TIMP and 6TUA. This method was further validated using actively growing T-ALL cell line (Jurkat) to study the branched kinetics, wherein it was observed that treatment of 50 microM 6MP led to the generation of 12 microM TIMP and 0.8 microM 6TUA in 6 h at 37 degrees C.

The Synthesis and Study of Azole Carboxamide Nucleosides as Agents Active Against RNA Viruses.

Science.gov (United States)

1986-09-15

44.89 4.80 28.56 Found: 45.01 4.96 28.45 6-Methylthio-9-0--D-ribofuranosylpurine (49). A solution of 9-1-D-ribo- furanosyl-6- mercaptopurine (0.33 g) in...97 reflections. There was no systematic change in these data indicating crystal and electronic stability . The data were merged to 2491 independent

Operational Colour Vision in the Modern Aviation Environment (la Vision des couleurs dans l’environnement aeronautique operationnel d’ aujourd hui)

Science.gov (United States)

2001-03-01

recommended. The Nagel II is no longer in production . Advantages: test has a long and hallowed history that is well respected. Disadvantages: expensive...Illuminator (Catalog No. 1388R) from Richmond Products , 1021 Rogers Circle, Suite 6, Boca Raton FL, 33487-2894. Phones:1-800-448-4538 and 407-994-2112...III Antineoplastics Mercaptopurine II Vincristine II Antirheumatics Ibuprofen II Colours appear faded Indomethacin III Antispasmodics

Molecular Biology and Physiology of Methanogenic Archaebacteria

Science.gov (United States)

1989-06-27

anaerobic food chains, the methanogens contribute to the mineralization of large amounts of organic matter. The end product of their metabolism...of radiolabelled substrate to product [8; Worrell and Nagle, in preparation]. Strain RT103, a formate auxotroph was isolated from the kanamycin...methylmercaptopurine riboside 0. 16 Bacteriocidald 8-aza-2, 6-diaminopurine 0.0011 6-thioguanine 0.0004 8-azaguanine 0.0004 6- mercaptopurine 0 8

Inflammatory Bowel Disease During Pregnancy.

Science.gov (United States)

Rajapakse, Ramona; Korelitz, Burton I.

2001-06-01

The management of both male and female patients with inflammatory bowel disease (IBD) who wish to have a baby is challenging. For women, the most important factor to bear in mind is that the outcome of pregnancy is largely influenced by disease activity at the time of conception. Women with quiescent disease are likely to have an uncomplicated pregnancy with the delivery of a healthy baby, whereas women with active disease are more likely to have complications such as spontaneous abortions, miscarriages, stillbirths, and exacerbation of the disease. This is more true of patients with Crohn's disease than of patients with ulcerative colitis. Although the safety of medications used during pregnancy is an important issue, the impact of the medications used to treat IBD is less important in comparison to disease activity itself. 5-Aminosalicylic acid (5-ASA) products appear to be safe during pregnancy; corticosteroids are probably safe; 6-mercaptopurine and azathioprine should be used with caution; and methotrexate is contraindicated. There are inadequate data on the use of infliximab during pregnancy. In regard to men with IBD, the disease itself does not seem to have any negative impact on fertility. However, there is controversy about the effects of using 6-mercaptopurine and azathioprine prior to and during fertilization. In view of possible adverse pregnancy outcomes, it would be prudent to withhold 6-mercaptopurine and azathioprine therapy in men with IBD for 3 months prior to conception, when feasible. Most IBD medications should be continued before, during, and after pregnancy, with careful attention to the known cautions and exceptions. If IBD in a pregnant patient is in remission, the prognosis for pregnancy is the same as if she did not have IBD. Active disease should therefore be treated aggressively and remission accomplished before pregnancy is attempted. Similarly, a woman who unexpectedly becomes pregnant while her IBD is active should be treated

Biochemistry of Trypanosomatidae of Importance in Africa.

Science.gov (United States)

1982-12-01

product . Compounds which appear as likely candidates include the following: Formycin B Formycin-B-ronophosphate Formycin-A-monophosphate Formycin-A...tetrahydro-2-fur-yl) -purine N6-Dimenthyladenine 2 ,6-bis- Chydroxyamino) -9-B-D-ri-bofuranosy3.- purine 6- Mercaptopurine 6-iodo-9- (tetr-ahydro-2...controlled anti- parasitic vaccines. Membrane antigens differ from one species to another and during the course of infection, making the production of a usqful

Enhanced proteolysis of thiopurine S-methyltransferase (TPMT) encoded by mutant alleles in humans (TPMT∗3A, TPMT∗2): Mechanisms for the genetic polymorphism of TPMT activity

OpenAIRE

Tai, Hung-Liang; Krynetski, Eugene Y.; Schuetz, Erin G.; Yanishevski, Yuri; Evans, William E.

1997-01-01

TPMT is a cytosolic enzyme that catalyzes the S-methylation of aromatic and heterocyclic sulfhydryl compounds, including medications such as mercaptopurine and thioguanine. TPMT activity exhibits autosomal codominant genetic polymorphism, and patients inheriting TPMT deficiency are at high risk of potentially fatal hematopoietic toxicity. The most prevalent mutant alleles associated with TPMT deficiency in humans have been cloned and characterized (TPMT∗2 and TPMT∗3A), but the mechanisms for ...

6-Thioguanine Reactivates Epigenetically Silenced Genes in Acute Lymphoblastic Leukemia Cells by Facilitating Proteasome-mediated Degradation of DNMT1

OpenAIRE

Yuan, Bifeng; Zhang, Jing; Wang, Hongxia; Xiong, Lei; Cai, Qian; Wang, Tina; Jacobsen, Steven; Pradhan, Sriharsa; Wang, Yinsheng

2011-01-01

Thiopurines including 6-thioguanine (SG), 6-mercaptopurine and azathioprine are effective anticancer agents with remarkable success in clinical practice, especially in effective treatment of acute lymphoblastic leukemia (ALL). SG is understood to act as a DNA hypomethylating agent in ALL cells, however, the underlying mechanism leading to global cytosine demethylation remains unclear. Here we report that SG treatment results in reactivation of epigenetically silenced genes in T leukemia cells...

Small-scale screening of anticancer drugs acting specifically on neural stem/progenitor cells derived from human-induced pluripotent stem cells using a time-course cytotoxicity test.

Science.gov (United States)

Fukusumi, Hayato; Handa, Yukako; Shofuda, Tomoko; Kanemura, Yonehiro

2018-01-01

Since the development of human-induced pluripotent stem cells (hiPSCs), various types of hiPSC-derived cells have been established for regenerative medicine and drug development. Neural stem/progenitor cells (NSPCs) derived from hiPSCs (hiPSC-NSPCs) have shown benefits for regenerative therapy of the central nervous system. However, owing to their intrinsic proliferative potential, therapies using transplanted hiPSC-NSPCs carry an inherent risk of undesired growth in vivo . Therefore, it is important to find cytotoxic drugs that can specifically target overproliferative transplanted hiPSC-NSPCs without damaging the intrinsic in vivo stem-cell system. Here, we examined the chemosensitivity of hiPSC-NSPCs and human neural tissue-derived NSPCs (hN-NSPCs) to the general anticancer drugs cisplatin, etoposide, mercaptopurine, and methotrexate. A time-course analysis of neurospheres in a microsphere array identified cisplatin and etoposide as fast-acting drugs, and mercaptopurine and methotrexate as slow-acting drugs. Notably, the slow-acting drugs were eventually cytotoxic to hiPSC-NSPCs but not to hN-NSPCs, a phenomenon not evident in the conventional endpoint assay on day 2 of treatment. Our results indicate that slow-acting drugs can distinguish hiPSC-NSPCs from hN-NSPCs and may provide an effective backup safety measure in stem-cell transplant therapies.

Examination pf Potential Anti-Tumor Activity of N-Thiolated B-Lactam Antibiotics in Nude Mice Bearing Human Breast Tumors

Science.gov (United States)

2005-08-01

their mechanism of action, production of reactive oxygen species (ROS), which leads to toxicity of the cardiomyocytes and subsequent chronic and acute...gemcitabine, and the purine analogs, such as 6- mercaptopurine and 6-thioguanine. These analogs substitute for nucleic acid bases in both DNA and RNA...Bioorg Med Chem Lett 12, 2229-2231 (2002) 14. Holt, R.J. and G.T. Stewart: Production of Amidase and beta-Lactamase by Bacteria. J Gen Microbiol 36

Annual Research Progress Report, Fiscal Year 1988. Volume 2. (Brooke Army Medical Center)

Science.gov (United States)

1988-10-01

Rabies Diagnosis. (0) 339 T-8-86 Production of Positive and Negative Controls for Rabies FA 340 Test. (0) T-9-86 Orthopaedic Microsurgery - A...505 POG 8561 Phase II Study of 6- Mercaptopurine Administered as an Intra- 506 venous Infusion for Malignant Solid Tumors and Acute Leukemia (0) POG...Preliminary results may indicate that the 1-lysine has not affected the concentration of production of SP, but its possible effect on the functional

Mutagenic and Cytotoxic Properties of 6-Thioguanine, S6-Methylthioguanine, and Guanine-S6-sulfonic Acid*S⃞

OpenAIRE

Yuan, Bifeng; Wang, Yinsheng

2008-01-01

Thiopurine drugs, including 6-thioguanine (SG), 6-mercaptopurine, and azathioprine, are widely employed anticancer agents and immunosuppressants. The formation of SG nucleotides from the thiopurine prodrugs and their subsequent incorporation into nucleic acids are important for the drugs to exert their cytotoxic effects. SG in DNA can be methylated by S-adenosyl-l-methionine to give S6-methylthioguanine (S6mG) and oxidized by UVA light to render guanine-S6-sulfonic acid ...

Annual Research Progress Report Fiscal Year 1992. Volume 2. Department of Clinical Investigation (Brooke Army Medical Center)

Science.gov (United States)

1992-01-01

Vesico-Colonic Anastomosis. (T) A-4-90 Botulinum Toxin Detection by Mouse Bioassay. (0) 294 A-5-90 Production of Mouse Positive and Negative Control...Protocol for Acute 518 Lymphocytic Leukemia. (0) POG 9005 ALinC 15: Dose Intensification of Methotrexate and 519 6- Mercaptopurine for ALL in Childhood...cultures, food products , serum and fecal specimens. Technical Approach: Pairs of mice are selected and anesthetized with 2 ml of halothane in an

Thiopurines and inhibition of Rac1 in vascular disease

OpenAIRE

Marinković, G.

2015-01-01

The mechanism of immunosuppressive drug azathioprine is not clear, while azathioprine has been used for 60 years in clinical practice in patients undergoing transplantation surgery or to combat autoimmune disease. Part of the function of azathioprine became evident in specific immune cells, namely T cells, demonstrating that small GTPase Rac1 was inhibited by azathioprine and thereby reduced their inflammatory response. We show that 6-mercaptopurine and thiopurines 6-thio-GDP and 6-thio-GTP, ...

Resistance to chemotherapeutic antimetabolites: a function of salvage pathway involvement and cellular response to DNA damage.

OpenAIRE

Kinsella, A. R.; Smith, D.; Pickard, M.

1997-01-01

The inherent or acquired (induced) resistance of certain tumours to cytotoxic drug therapy is a major clinical problem. There are many categories of cytotoxic agent: the antimetabolites, e.g. methotrexate (MTX), N-phosphonacetyl-L-aspartate (PALA), 5-fluorouracil (5-FU), 6-mercaptopurine (6-TG), hydroxyurea (HU) and 1-beta-D-arabinofuranosylcytosine (AraC); the alkylating agents, e.g. the nitrogen mustards and nitrosoureas; the antibiotics, e.g. doxorubicin and mitomycin C; the plant alkaloid...

Adenosine deaminase organic effect in normal and abnormal cerebrospinal fluid

International Nuclear Information System (INIS)

Hamad, A.M.; Samarai, M.A.

2007-01-01

To study the effect of the organic substances on adenosine deaminase (ADA) activity in normal and abnormal cerebrospinal fluid (CSF). Various concentrations of 2-mercaptopurine, Ame-tycine, Adenosine analogues (Guanine, Thymine) and ATP were tested to see their effect on ADA activity in normal and abnormal CSF. ADA activity in normal and abnormal CSF was remarkably decreased with the increasing of concentrations of substances tested. These effects may have important therapeutic implications. (author)

Department of Clinical Investigation Annual Research Progress Report, Fiscal Year 1993. Volume 2

Science.gov (United States)

1993-10-01

A-5-90 Production of Mouse Positive and Negative Control Slides for 382 Use in Rabies FRA Test. (0) A-7-90 Clinical Investigation on the...Possible 402 Diagnostic and Therapeutic Manuever as Tested in a Mouse Model Utilizing PET Scanning. (0) A-93-04 Production of Monoclonal Antibodies to...xlv Project Page Number POG 9005 ALinC 15: Dose Intensification of Methotrexate and 583 6- Mercaptopurine for ALL in Childhood. (0) P00 9006 ALinC 15

Annual Research Progress Report. Fiscal Year 1989. Volume 2

Science.gov (United States)

1989-10-01

Microsurgery - A Training Protocol. (T) 359 T-7-86 Mouse Inoculation Test (MI) - Rabies Diagnosis. (0) 360 xxvii Project Page Number T-8-86 Production of...Page Number POG 8552 A Case-Control Study of Childhood Rhabdomyosarcoma. (0) 511 PO 8561 Phase II Study of 6- Mercaptopurine Administered as an Intra...T-8-86 Status: Ongoing Title: Production of Positive and Negative Controls for Rabies FA Test Start Date 4 Apr 86 Est Comp Date: Principal

Department of Clinical Investigation: Annual Research Progress Report for Fiscal Year 1992. Volume 2

Science.gov (United States)

1993-01-01

A-5-90 Production of Mouse Positive and Negative Control Slides for 295 Use in Rabies FRA Test. (0) A-7-90 Clinical Investigation on the...Dose Intensification of Methotrexate and 519 6- Mercaptopurine for ALL in Childhood. (0) POG 9006 ALinC 15: Up-Front 6-MP/MTX vs. Up-Front Alternating 520...for the mouse bioassay as a means for detecting Clostridium botulinum toxin in cultures, food products , serum and fecal specimens. Technical Approach

6-Thioguanine alters the structure and stability of duplex DNA and inhibits quadruplex DNA formation.

OpenAIRE

Marathias, V M; Sawicki, M J; Bolton, P H

1999-01-01

The ability to chemically synthesize biomolecules has opened up the opportunity to observe changes in structure and activity that occur upon single atom substitution. In favorable cases this can provide information about the roles of individual atoms. The substitution of 6-thioguanine (6SG) for guanine is a potentially very useful single atom substitution as 6SG has optical, photocrosslinking, metal ion binding and other properties of potential utility. In addition, 6-mercaptopurine is a clin...

[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.

Small-scale screening of anticancer drugs acting specifically on neural stem/progenitor cells derived from human-induced pluripotent stem cells using a time-course cytotoxicity test

Directory of Open Access Journals (Sweden)

Hayato Fukusumi

2018-01-01

Full Text Available Since the development of human-induced pluripotent stem cells (hiPSCs, various types of hiPSC-derived cells have been established for regenerative medicine and drug development. Neural stem/progenitor cells (NSPCs derived from hiPSCs (hiPSC-NSPCs have shown benefits for regenerative therapy of the central nervous system. However, owing to their intrinsic proliferative potential, therapies using transplanted hiPSC-NSPCs carry an inherent risk of undesired growth in vivo. Therefore, it is important to find cytotoxic drugs that can specifically target overproliferative transplanted hiPSC-NSPCs without damaging the intrinsic in vivo stem-cell system. Here, we examined the chemosensitivity of hiPSC-NSPCs and human neural tissue—derived NSPCs (hN-NSPCs to the general anticancer drugs cisplatin, etoposide, mercaptopurine, and methotrexate. A time-course analysis of neurospheres in a microsphere array identified cisplatin and etoposide as fast-acting drugs, and mercaptopurine and methotrexate as slow-acting drugs. Notably, the slow-acting drugs were eventually cytotoxic to hiPSC-NSPCs but not to hN-NSPCs, a phenomenon not evident in the conventional endpoint assay on day 2 of treatment. Our results indicate that slow-acting drugs can distinguish hiPSC-NSPCs from hN-NSPCs and may provide an effective backup safety measure in stem-cell transplant therapies.

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.

Chemical Preparation Laboratory IND Candidate Compounds.

Science.gov (United States)

1986-01-21

and final products unreported in the chemical literature were fully characterized by elemental and spectral analyses. 3 V% TABLE OF CONTENTS Page I...resulting crystalline material was filtered and washed with water to yield 2.0 g. An additional 0.2 g of the product was recovered from the above filtrate... mercaptopurine (Tri-C- acetvlthioinosine) (3): To a well stirred mixture of 2 (93.0 g, 0.236 mol) and pyridine (3570 mL), phosphorus pentasulfide (220.0 g, 0.49

Piecewise Geometric Estimation of a Survival Function.

Science.gov (United States)

1985-04-01

Langberg (1982). One of the by- products of the estimation process is an estimate of the failure rate function: here, another issue is raised. It is evident...envisaged as the infinite product probability space that may be constructed in the usual way from the sequence of probability spaces corresponding to the...received 6 MP (a mercaptopurine used in the treatment of leukemia). The ordered remis- sion times in weeks are: 6, 6, 6, 6+, 7, 9+, 10, 10+, 11+, 13, 16

The Synthesis and Study of New Ribavirin Derivatives and Related Nucleoside Azole Carboxamides as Agents Active against RNA Viruses.

Science.gov (United States)

1981-09-01

of the nitrate salt or degradation of the starting heterocycle. An alternate procedure for obtaining aromatic nitro compounds is the oxidation of the...SAcO OAc AcO OAc RO OR S102 99103, R-Ac 1--04, RC H -OH N HcO 0 cOY RO ᝹ HO O Ac RO OR 102 0_6 103, R - Ac 108, R = H 6- mercaptopurine riboside...occurring C-nucleoside antibiotic and unlike N-nucleosides, formycin B will not suffer enzymatic cleavage * 29 and degradation by phosphorolysis

Crohn's disease complicated by Epstein-Barr virus-driven haemophagocytic lymphohistiocytosis successfully treated with rituximab.

Science.gov (United States)

Thompson, Grace; Pepperell, Dominic; Lawrence, Ian; McGettigan, Benjamin David

2017-02-22

We report a case of Epstein-Barr virus (EBV)-driven haemophagocytic lymphohistiocytosis (HLH) in a man with Crohn's disease treated with 6-mercaptopurine and adalimumab therapy who was successfully treated with rituximab therapy alone. This is the first published case in an adult patient with EBV-driven HLH in the setting of thiopurine use and inflammatory bowel disease to be successfully treated with rituximab therapy alone. Here, we will discuss putative immunological mechanisms which may contribute to this potentially life-threatening complication. 2017 BMJ Publishing Group Ltd.

The effects of inherited NUDT15 polymorphisms on thiopurine active metabolites in Japanese children with acute lymphoblastic leukemia

DEFF Research Database (Denmark)

Moriyama, Takaya; Nishii, Rina; Lin, Ting-Nien

2017-01-01

Thiopurines [e.g. mercaptopurine (MP)] are widely used as chemotherapeutic agents in the treatment of pediatric acute lymphoblastic leukemia with dose-limiting hematopoietic toxicity. Recently, germline variants in NUDT15 have been identified as a major genetic cause for MP-related bone marrow...... children with acute lymphoblastic leukemia, we simultaneously measured both thioguanine nucleotides (TGN) in red blood cells and DNA-incorporated thioguanine (DNA-TG) in white blood cells. TGN levels were significantly lower in patients with NUDT15 deficiency, likely because of toxicity-related MP dose...

Epstein-Barr-virus-associeret lymfom hos en patient med colitis ulcerosa i behandling med azathioprin

DEFF Research Database (Denmark)

Kofoed, Kristian; Kiszka-Kanowitz, Marianne; Albrectsen, Jens Mørch

2008-01-01

A 28 year-old man with ulcerative colitis treated for 10 years with azathioprine (AZA) returned from Central Asia with fever, swollen lymph glands, hepatosplenomegaly, and pancytopenia. He was tested positive for acute Epstein-Barr virus (EBV) infection. Before the final diagnosis of EBV......-associated large B-cell lymphoma was confirmed, he died from multiple organ failure. AZA and 6-mercaptopurine are associated with the development of EBV-positive lymphomas in organ-transplanted patients. This type of lymphoma is a rare complication in inflammatory bowel disease....

Partition coefficients of some purine derivatives and its application to pharmacokinetics.

Science.gov (United States)

Chrzanowska, M; Sobiak, J; Kuehn, M; Dorawa, E; Hermann, T

2009-12-01

Metazathioprine (MAZA), a methylated derivative of azathioprine (AZA), demonstrated the greatest values of apparent and specific partition coefficients in n-octanol/phosphate buffer at pH 5.7 and pH 7.4 among purine derivatives such as 6-mercaptopurine (6-MP), 6-thioguanine (6-TG) and AZA. Introduction of a methyl group into the imidazole ring of AZA increases lipophilic properties of MAZA compared to AZA. Mass balance of purine derivatives in n-octanol and in phosphate buffer indicated their chemical stability in those media.

Thiopurine methyltransferase genotype–phenotype discordance and thiopurine active metabolite formation in childhood acute lymphoblastic leukaemia

Science.gov (United States)

Lennard, Lynne; Cartwright, Cher Suzanne; Wade, Rachel; Richards, Susan M; Vora, Ajay

2013-01-01

Aims In children with acute lymphoblastic leukaemia (ALL) bone marrow activity can influence red blood cell (RBC) kinetics, the surrogate tissue for thiopurine methyltransferase (TPMT) measurements. The aim of this study was to investigate TPMT phenotype–genotype concordance in ALL, and the influence of TPMT on thiopurine metabolite formation. Methods We measured TPMT (activity, as units ml−1 packed RBCs and genotype) at diagnosis (n = 1150) and TPMT and thioguanine nucleotide (TGN) and methylmercaptopurine nucleotide (MeMPN) metabolites (pmol/8 × 108 RBCs) during chemotherapy (n = 1131) in children randomized to thioguanine or mercaptopurine on the United Kingdom trial ALL97. Results Median TPMT activity at diagnosis (8.5 units) was significantly lower than during chemotherapy (13.8 units, median difference 5.1 units, 95% confidence interval (CI) 4.8, 5.4, P mercaptopurine, median TGNs were higher in TPMT heterozygous genotype (754 pmol) than wild-type (360 pmol) patients (median difference 406 pmol, 95% CI 332, 478, P products of the TPMT reaction, were higher in wild-type (10 650 pmol) than heterozygous patients (3868 pmol) (P < 0.0001). In TPMT intermediate activity patients with a wild-type genotype, TGN (median 366 pmol) and MeMPN (median 8590 pmol) concentrations were similar to those in wild-type, high activity patients. Conclusions In childhood ALL, TPMT activity should not be used to predict heterozygosity particularly in blood samples obtained at disease diagnosis. Genotype is a better predictor of TGN accumulation during chemotherapy. PMID:23252716

Cutaneous lymphoproliferative disorder complicating infectious mononucleosis in an immunosuppressed patient.

Science.gov (United States)

Owen, Cindy England; Callen, Jeffrey P; Bahrami, Soon

2011-01-01

Infectious mononucleosis is the syndrome produced by primary infection with Epstein-Barr virus during adolescence or early adulthood. In immunosuppressed individuals, depressed T-cell function allows the Epstein-Barr virus-driven B-cell proliferation to continue unabated, potentially leading to a lymphoproliferative disorder. A 15-year-old girl with a history of ulcerative colitis treated with 6-mercaptopurine and mesalamine presented with the acute onset of a rapidly enlarging, ulcerative nodule on her left lower eyelid 4 weeks following recovery from infectious mononucleosis. The biopsy revealed an Epstein-Barr virus-positive lymphoproliferative disorder. Systemic disease was absent. Following discontinuation of 6-mercaptopurine, the patient was treated with two courses of intravenous cyclophosphamide. The lesion resolved completely and she remains disease free at 14 months following diagnosis. We report a solitary cutaneous lesion of an immunosuppression-related lymphoproliferative disorder (IR-LPD) occurring as a complication of infectious mononucleosis, and review the pathogenesis and reported cases of Epstein-Barr virus-related immunosuppression-related lymphoproliferative disorder arising in the setting of inflammatory bowel disease. It is important for dermatologists and dermatopathologists to be aware of the occurrence of IR-LPD in patients being treated for inflammatory conditions, including inflammatory bowel disease. Given the role of primary infection with Epstein-Barr virus in the development of IR-LPD, consideration may be given to assessing Epstein-Barr virus status prior to initiating immunosuppressive therapy in young patients. © 2010 Wiley Periodicals, Inc.

Mercaptopurine/Methotrexate Maintenance Therapy of Childhood Acute Lymphoblastic Leukemia

DEFF Research Database (Denmark)

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

2014-01-01

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...

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 dose...... levels of 6-thioguanine nucleotides or MTX (including its polyglutamates) to be significant relapse predictors. The parameters significantly associated with risk of relapse (N = 83) were male sex (hazard ratio [HR] 2.0 [1.3-3.1], P = 0.003), WBC at diagnosis (HR = 1.04 per 10 × 10(9) /l rise [1...

The degree of myelosuppression during maintenance therapy of adolescents with B-lineage intermediate risk acute lymphoblastic leukemia predicts risk of relapse

DEFF Research Database (Denmark)

Schmiegelow, K; Donovan, Martin Heyman; Sherson, Maiken Gustafsson

2010-01-01

Drug doses, blood levels of drug metabolites and myelotoxicity during 6-mercaptopurine/methotrexate (MTX) maintenance therapy were registered for 59 adolescents (10 years) and 176 non-adolescents (leukemia (ALL) and a white blood cell count (WBC......) diagnosis. Event-free survival was lower for adolescents than non-adolescents (pEFS12y:0.71 vs 0.83, P=0.04). For adolescents staying in remission, the mean WBC during maintenance therapy (mWBC) was related to age (rS=0.36, P=0.02), which became nonsignificant for those who relapsed (r...

[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.

[Autoimmune hepatitis].

Science.gov (United States)

Färkkilä, Martti

2013-01-01

Autoimmune hepatitis is chronic liver disease with two subtypes, type 1 with anti nuclear or smooth muscle antibodies and type 2 with LKM1 or LC1 antibodies, and both with hypergammaglobulinemia and typical histology. Prevalence of AIH is between 10 to 17 per 100000 in Europe. Up to 20-40 % of cases present with acute hepatitis. Budesonide can be used as a first line induction therapy in non-cirrhotic patients, and tiopurines, mercaptopurine or mycophenolic acid as maintenance therapies. Patients not responding to conventional therapy can be treated with ciclosporin, tacrolimus or rituximab or finally with liver transplantation.

Thiopurine methyltransferase genotype-phenotype discordance and thiopurine active metabolite formation in childhood acute lymphoblastic leukaemia.

Science.gov (United States)

Lennard, Lynne; Cartwright, Cher Suzanne; Wade, Rachel; Richards, Susan M; Vora, Ajay

2013-07-01

In children with acute lymphoblastic leukaemia (ALL) bone marrow activity can influence red blood cell (RBC) kinetics, the surrogate tissue for thiopurine methyltransferase (TPMT) measurements. The aim of this study was to investigate TPMT phenotype-genotype concordance in ALL, and the influence of TPMT on thiopurine metabolite formation. We measured TPMT (activity, as units ml(-1) packed RBCs and genotype) at diagnosis (n = 1150) and TPMT and thioguanine nucleotide (TGN) and methylmercaptopurine nucleotide (MeMPN) metabolites (pmol/8 × 10(8) RBCs) during chemotherapy (n = 1131) in children randomized to thioguanine or mercaptopurine on the United Kingdom trial ALL97. Median TPMT activity at diagnosis (8.5 units) was significantly lower than during chemotherapy (13.8 units, median difference 5.1 units, 95% confidence interval (CI) 4.8, 5.4, P mercaptopurine, median TGNs were higher in TPMT heterozygous genotype (754 pmol) than wild-type (360 pmol) patients (median difference 406 pmol, 95% CI 332, 478, P products of the TPMT reaction, were higher in wild-type (10 650 pmol) than heterozygous patients (3868 pmol) (P < 0.0001). In TPMT intermediate activity patients with a wild-type genotype, TGN (median 366 pmol) and MeMPN (median 8590 pmol) concentrations were similar to those in wild-type, high activity patients. In childhood ALL, TPMT activity should not be used to predict heterozygosity particularly in blood samples obtained at disease diagnosis. Genotype is a better predictor of TGN accumulation during chemotherapy. © 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

Acute lymphocytic leukaemia in children in the Netherlands

International Nuclear Information System (INIS)

Does-van den Berg, A. van der.

1980-01-01

Some features, present at diagnosis in children with acute lymphocytic leukaemia, investigated during the period 1973-1975, and the results of treatment according to protocol AL II of the Dutch Childhood Leukaemia Study Group (SNWLK), are described. This report concerns the results of induction treatment, elective treatment of the central nervous system, and also of the prospective comparative study on the influence of the addition of cyclophosphamide to maintenance treatment with 6-mercaptopurine and methotrextate. In the context of the investigation of long-term side effects of disease and treatment, the immunocompetence of children with acute lymphocytic leukaemia in continuous remission after cessation of therapy was studied. (Auth.)

Monitoring of thiopurine metabolites in patients with inflammatory bowel disease-what is actually measured?

Science.gov (United States)

Vikingsson, Svante; Carlsson, Björn; Almer, Sven H C; Peterson, Curt

2009-06-01

Azathioprine and 6-mercaptopurine are often used in the treatment of patients with inflammatory bowel disease (IBD). They are prodrugs and undergo a complex metabolism to active and inactive metabolites. Thiopurine treatment is monitored in many laboratories by measuring metabolite concentrations in erythrocytes (red blood cells). The metabolites of interest are not measured directly but as hydrolysis products, which can be produced from several metabolites. The aim of this study was to examine which metabolites are actually measured during routine monitoring. Samples from 18 patients treated with a thiopurine were analyzed by a typical routine high-performance liquid chromatography method for therapeutic drug monitoring and by a newly developed specific method measuring thioguanosine monophosphate (TGMP), thioguanosine diphosphate (TGDP), and thioguanosine triphosphate (TGTP), as well as methylthioinosine monophosphate (meTIMP), and the results were compared. 6-Thioguanine nucleotide (TGN) values detected by the routine method were 69% (range 40%-90%) of the sum of TGMP, TGDP, and TGTP measured by the specific method. TGTP and TGDP contributed 85% (range 78%-90%) and 14% (range 10%-21%) of the TGN total, respectively. Thioguanosine was not found in any patient sample. The concentration of meTIMP obtained by the routine method was 548% of the value obtained by the specific method (range 340%-718%). The difference in TGN measurements between the routine and specific methods can be explained by low hydrolysis efficiency in the routine method, although the most likely explanation for the difference in meTIMP values is that not yet identified metabolites are codetermined in the routine high-performance liquid chromatography method. Concentrations reported as TGN during therapeutic drug monitoring of thiopurine metabolites consist of TGDP and TGTP with a minor contribution of the TGMP. Concentrations reported as meTIMP or methyl mercaptopurine consist in part of me

[Classical medications in the treatment of inflammatory bowel diseases].

Science.gov (United States)

Duvnjak, Marko; Bilić, Ante; Barsić, Neven; Tomasić, Vedran; Stojsavljević, Sanja

2013-04-01

The treatment of inflammatory bowel diseases is complex and requires individual approach to every single patient. Traditionally, the approach is based on introduction of so called "classical" medication into the treatment regimen, from ones less potent and with fewer side effects to the ones more toxic but also therapeutically more effective. Aminosalicylates were the first choice of treatment for a long time. However, the role of aminosalicylates is becoming more and more diminished, although they are still the drug of choice in the treatment of mild to moderate ulcerative colitis. Corticosteroids are the therapy of choice in treatment of active IBD for achieving remission in moderate to severe disease. Azathioprine and 6- mercaptopurine belong to a group of thiopurines with an immunomodulatory effect which, in Crohn's disease as well as in ulcerative colitis, primarily have a role in a steroid dependant or steroid refractory type of disease and in maintenance of remission. Lately, early introduction of these medications is proposed to enhance the number of patients that remain in remission. Methotrexate is used for the therapy of active and relapsing Crohn's disease and represents an alternative in patients who do not tolerate or do not respond to azathioprine or 6-mercaptopurine therapy. Cyclosporine is used in treating steroid refractory ulcerative colitis and in some patients can postpone the need for colectomy. Antibiotics do not have a proven effect on the course of inflammatory bowel diseases and their primary role is to treat septic complications. Classic medications today represent a standard in the management of inflammatory bowel diseases, and the combination of the previously mentioned drugs often has a more potent effect on the course of the disease than any medication on its own and their combination is still an object of investigations and clinical studies.

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

Dose—response relationships for agents inhibiting the immune response

Science.gov (United States)

Berenbaum, M. C.; Brown, I. N.

1964-01-01

Mice were injected with T.A.B. vaccine and, 2 days later, with various doses of different compounds. The relation between dose of compound, mortality and antibody production was studied, and therapeutic indices were calculated for a number of compounds. The most effective agent in suppressing antibody production at relatively non-toxic doses was cyclophosphamide, with next amethopterin (the effect of which was, however, inexplicably erratic), 6-thioguanine and 6-mercaptopurine, in that order. Vincaleukoblastine, triethylene melamine, triethylenethiophosphoramide, mannomustine and 5-fluorouracil were less effective. Compounds of a miscellaneous group (boric acid, caffeine, sodium nitrite, bacitracin, neomycin and polymyxin `B') were studied in the same way: they had no effect on antibody production, even in lethal doses. PMID:14113077

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.

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.

Birth outcome in women with ulcerative colitis and Crohn's disease, and pharmacoepidemiological aspects of anti-inflammatory drug therapy.

Science.gov (United States)

Nørgård, Bente Mertz

2011-12-01

during pregnancy our data suggest. No significantly increased overall relative risk of congenital abnormalities and no significantly increased risks of selected congenital abnormalities. After exposure to 5-aminosalicylic acid during pregnancy our data suggest. No significantly increased relative risk of low birth weight, intrauterine growth retardation or congenital abnormalities (evaluated overall). A significantly increased relative risk of preterm birth and stillbirth in ulcerative colitis women, compared to women with no prescription of reimbursed medicine in pregnancy - and also after comparing with women with chronic inflammatory bowel disease not taking 5-aminosalicylic acid during pregnancy. It is not clear whether these associations are causal or influenced by confounding by disease activity in particular. After maternal exposure to azathioprine/6-mercaptopurine during pregnancy our data suggest. An increased relative risk of preterm birth, congenital abnormalities, and perinatal mortality - also after using controls with similar underlying diseases. It is difficult to rule out an influence of uncontrolled confounding. These were the first published data from a controlled observational study on exposed women with chronic inflammatory bowel disease. After preconceptional paternal use of azathioprine/6-mercaptopurine our data suggest An increased risk of congenital abnormalities, although not significantly increased. The birth outcomes in women with Crohn's disease are examined in nationwide sub-cohorts classified according to type of anti-inflammatory drug exposure during pregnancy, and based on data from the Danish National Hospital Discharge Registry, the nationwide Danish Prescription Database and the Danish Medical Birth Registry. Furthermore, birth outcomes are examined in Crohn's disease women with disease activity during pregnancy, based on data from review of hospital records, the Danish National Hospital Discharge Registry and the Danish Medical Birth

Thiopurines in inflammatory bowel disease revisited

Science.gov (United States)

Bär, Florian; Sina, Christian; Fellermann, Klaus

2013-01-01

Although a great variety of new drugs have been introduced for the therapy of inflammatory bowel diseases so far, a definite cure of the disease is still out of scope. An anti-inflammatory approach to induce remission followed by maintenance therapy with immunosupressants is still the mainstay of therapy. Thiopurines comprising azathioprine and its active metabolite mercaptopurine as well as tioguanine, are widely used in the therapy of chronic active inflammatory bowel disease (IBD). Their steroid sparing potential and efficacy in remission maintenance are out of doubt. Unfortunately, untoward adverse events are frequently observed and may preclude further administration or be life threatening. This review will focus on new aspects of thiopurine therapy in IBD, its efficacy and safety. PMID:23555158

Genetic tests for predicting the toxicity and efficacy of anticancer chemotherapy.

Science.gov (United States)

Mladosievicova, B; Carter, A; Kristova, V

2007-01-01

The standard anticancer therapy based "on one size fits all" modality has been determined to be ineffective or to be the cause of adverse drug reactions in many oncologic patients. Most pharmacogenetic and pharmacogenomic studies so far have been focused on toxicity of anticancer drugs such as 6-mercaptopurine, thioguanine, irinotecan, methotrexate, 5-fluorouracil (5-FU). Variation in genes are known to influence not only toxicity, but also efficacy of chemotherapeutics such as platinum analogues, 5-FU and irinotecan. The majority of current pharmacogenetic studies focus on single enzyme deficiencies as predictors of drug effects; however effects of most anticancer drugs are determined by the interplay of several gene products. These effects are polygenic in nature. This review briefly describes genetic variations that may impact efficacy and toxicity of drugs used in cancer chemotherapy.

Epstein-Barr-virus-associeret lymfom hos en patient med colitis ulcerosa i behandling med azathioprin

DEFF Research Database (Denmark)

Kofoed, Kristian; Kiszka-Kanowitz, Marianne; Albrectsen, Jens Mørch

2008-01-01

A 28 year-old man with ulcerative colitis treated for 10 years with azathioprine (AZA) returned from Central Asia with fever, swollen lymph glands, hepatosplenomegaly, and pancytopenia. He was tested positive for acute Epstein-Barr virus (EBV) infection. Before the final diagnosis of EBV-associat......A 28 year-old man with ulcerative colitis treated for 10 years with azathioprine (AZA) returned from Central Asia with fever, swollen lymph glands, hepatosplenomegaly, and pancytopenia. He was tested positive for acute Epstein-Barr virus (EBV) infection. Before the final diagnosis of EBV......-associated large B-cell lymphoma was confirmed, he died from multiple organ failure. AZA and 6-mercaptopurine are associated with the development of EBV-positive lymphomas in organ-transplanted patients. This type of lymphoma is a rare complication in inflammatory bowel disease....

Expert opinion: Experience with 6-mercaptopurine in the treatment of inflammatory bowel disease

OpenAIRE

Korelitz, Burton I

2013-01-01

Arbitrarily, modern day treatment of inflammatory bowel disease begins with the introduction of immunosuppressives for ulcerative colitis. Clinical improvement with sulfasalazine had been meaningful but modest. Treatment with adrenocorticotropic hormone and corticosteroids led to clinical responses never before realized but it took much too long to recognize that they were not capable of maintaining remission, that adverse reactions were subtle but potentially devastating and that some other ...

Azathioprine and mercaptopurine in the management of patients with chronic, active microscopic colitis

DEFF Research Database (Denmark)

Münch, A; Fernandez-Banares, F; Munck, L K

2013-01-01

BACKGROUND: Microscopic colitis (MC) is a common chronic diarrhoeal disease, and remission can be induced with budesonide. However, diarrhoea relapses frequently when budesonide is tapered and a few patients become budesonide intolerant. AIM: To examine retrospectively the effect of azathioprine ...... leading to cessation of treatment. However, further studies are needed to explore the efficacy, acceptance, tolerance and safety of MP in patients with chronic, active MC refractory to budesonide....... patients (46%) obtained clinical remission. Thus, the overall response rate to thiopurines was 19/46 (41%). The main side effects were nausea/vomiting and abnormally elevated liver enzymes. CONCLUSIONS: In this retrospective case series, the majority of chronic, active MC patients were intolerant to AZA...

Spontaneous mutation rate in Chinese hamster cell clones differing in UV-sensitivity

International Nuclear Information System (INIS)

Manuilova, E.S.; Bagrova, A.M.; Moskovskij Gosudarstvennyj Univ.

1983-01-01

The spontaneous rate of appearance of mutations to 6-mercaptopurine (6 MP) resistence in the cells of CHR2 and CHs2 clones dofferent in sensitivity to lethal and matagenous effect of UV-rays, is investigated. Increased UV-sensitivity of CHs2 clone is caused by the violation of postreplicative DNA reparation. It is established that the purity of spontaneously occuring mutations in both clones turns out to be similar, i.e. (1.5-1.8)x10 -5 for the cell pergeneration. It is shown that the effect of postreplicative DNA reparation in the cells of chinese hamster is not connected with the increase of spontaneous mutation ability. The problem on the possible role of reparation in the mechanism of appearance of spontaneous and induced mutations in the cells of Chinese hamster with increased UV-sensitivity is discussed

Absence of hypoxanthine:guanine phosphoribosyltransferase activity in murine Dunn osteosarcoma

International Nuclear Information System (INIS)

Abelson, H.T.; Gorka, C.

1983-01-01

The transplantable murine Dunn osteosarcoma has no detectable hypoxanthine:guanine phosphoribosyltransferase (EC 2.4.2.8) activity. This was established from the tumors directly and from tissue culture cell lines derived from the tumor using a variety of assays: e.g., no [3H]hypoxanthine uptake into tumor or tissue culture cells, no conversion of [3H]hypoxanthine to [3H]IMP by cell extracts from tumors or tissue culture cells, no growth of tissue culture cells in hypoxanthine:aminopterin:thymidine medium, and normal growth of these cells in 10 microM 6-mercaptopurine. Ten human osteosarcomas have been assayed, and two have no apparent hypoxanthine:guanine phosphoribosyltransferase enzyme activity. After high-dose methotrexate treatment in vivo, murine tumors could be selectively killed and normal tissues could be spared by using a rescue regimen of hypoxanthine-thymidine-allopurinol

Immune Thrombocytopenia in a Child with T Cell Lymphoblastic Lymphoma

Directory of Open Access Journals (Sweden)

Kayo Tokeji

2016-01-01

Full Text Available We describe the case of a 13-year-old boy who presented with persistent thrombocytopenia during maintenance chemotherapy with mercaptopurine and methotrexate for T cell lymphoblastic lymphoma. He was diagnosed with immune thrombocytopenia (ITP after thorough investigations for the relapse of lymphoma and was successfully treated with immunoglobulin and steroids. ITP is known to be associated with chronic lymphocytic leukemia, Hodgkin lymphoma, and various types of non-Hodgkin lymphoma but rarely with T cell non-Hodgkin lymphoma or in children. Diagnosis of ITP with lymphoma is challenging due to the many factors affecting platelet counts, and ITP often complicates the diagnosis or treatment course of lymphoma. The underlying mechanism of ITP with NHL is still unclear. Drug-induced immunomodulation with a reduction of regulatory T cells might have contributed to the development of ITP in our case.

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.

Pharmacogenetics predictive of response and toxicity in acute lymphoblastic leukemia therapy.

Science.gov (United States)

Mei, Lin; Ontiveros, Evelena P; Griffiths, Elizabeth A; Thompson, James E; Wang, Eunice S; Wetzler, Meir

2015-07-01

Acute lymphoblastic leukemia (ALL) is a relatively rare disease in adults accounting for no more than 20% of all cases of acute leukemia. By contrast with the pediatric population, in whom significant improvements in long term survival and even cure have been achieved over the last 30years, adult ALL remains a significant challenge. Overall survival in this group remains a relatively poor 20-40%. Modern research has focused on improved pharmacokinetics, novel pharmacogenetics and personalized principles to optimize the efficacy of the treatment while reducing toxicity. Here we review the pharmacogenetics of medications used in the management of patients with ALL, including l-asparaginase, glucocorticoids, 6-mercaptopurine, methotrexate, vincristine and tyrosine kinase inhibitors. Incorporating recent pharmacogenetic data, mainly from pediatric ALL, will provide novel perspective of predicting response and toxicity in both pediatric and adult ALL therapies. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

OpenAIRE

Dorniani, Dena; Zobir Hussein,Mohd; Kura,Aminu Umar; Fakurazi,Sharida; Halim Shaari,Abdul; Ahmad,Zalinah

2013-01-01

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 beca...

Bone marrow necrosis in a patient with acute promyelocytic leukemia during re-induction therapy with arsenic trioxide.

Science.gov (United States)

Ishitsuka, Kenji; Shirahashi, Akihiko; Iwao, Yasuhiro; Shishime, Mikiko; Takamatsu, Yasushi; Takatsuka, Yoshifusa; Utsunomiya, Atae; Suzumiya, Junji; Hara, Syuji; Tamura, Kazuo

2004-04-01

Arsenic trioxide (As2O3) therapy at a daily dose of 0.15 mg/kg was given to a 60-yr-old Japanese male with refractory acute promyelocytic leukemia. White blood cell (WBC) of 6.6 x 10(3)/microl increased to 134 x 10(3)/microl following the administration of As2O3. Daily hydroxyurea (HU), and 6-mercaptopurine (6-MP) were added on days 7 and 19, respectively. Both HU and 6-MP were discontinued on day 28, when WBC declined to 54.0 x 10(3)/microl. He developed unexplained fever and profound cytopenia requiring multiple blood products transfusions. Bone marrow examination on day 42 revealed massive necrosis. Pharmacokinetics confirmed a mean maximum plasma arsenic concentration (Cpmax) and a half-life time (t1/2) of 6.9 microm and 3.2 h, respectively, in the therapeutic range. This is the first case of bone marrow necrosis after standard-dose As2O3 therapy.

Reinduction therapy for adult acute leukemia with adriamycin, vincristine, and prednisone: a Southwest Oncology Group study.

Science.gov (United States)

Elias, L; Shaw, M T; Raab, S O

1979-08-01

In an attempt to improve remissions and survivals in previously treated patients with adult acute leukemia, we gave Adriamycin, vincristine, and prednisone for induction therapy, followed by 6-mercaptopurine and methotrexate for maintenance therapy to patients attaining complete remission (CR). The study group consisted of 18 patients with acute myeloblastic leukemia (AML), ten with acute lymphoblastic leukemia, and one with acute undifferentiated leukemia. Only one patient had previously received Adriamycin. Overall, there were ten CRs and two partial remissions. The five CRs and one partial remission in patients with AML occurred among those with one prior induction attempt; none of the eight AML patients with more than one prior induction attempt responded. The actuarial median duration of CR was 15 weeks and was similar for AML and acute lymphoblastic leukemia patients. Responders had a longer median survival (30 weeks) than nonresponders (9 weeks). Thus, although a reasonable number of responses in previously treated patients were obtained with this program, improvements in maintenance therapy are clearly needed.

Guidelines for treatment with infliximab for Crohn's disease.

Science.gov (United States)

Hommes, D W; Oldenburg, B; van Bodegraven, A A; van Hogezand, R A; de Jong, D J; Romberg-Camps, M J L; van der Woude, J; Dijkstra, G

2006-01-01

Infliximab is an accepted induction and maintenance treatment for patients with Crohn's disease. The effectiveness of infliximab has been demonstrated for both active luminal disease and for enterocutaneous fistulisation. In addition, infliximab can be administered for extraintestinal symptoms of Crohn's disease, such as pyoderma gangrenosum, uveitis and arthropathy. Maintenance treatment with infliximab is effective and is regarded as safe as long as the necessary safety measures are heeded. Infusion reactions occur in 3 to 17% of the patients and are associated with the formation of antibodies to infliximab. A reduction in infusion reactions is possible by the concurrent administration of steroids and the use of immunosuppressants (azathioprine, 6-mercaptopurine, methotrexate). Furthermore, immunosuppressants increase the duration of the response to infliximab. For these reasons, the concomitant use of immunosuppressants with infliximab is recommended. Infections and most specifically tuberculosis need to be ruled out before infliximab is administered. Up to now, there are no indications for a connection between an increased risk for malignancies and treatment with infliximab.

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.

Hemophagocytic lymphohistiocytosis caused by primary Epstein-Barr virus in patient with Crohn's disease.

Science.gov (United States)

Virdis, Francesco; Tacci, Sara; Messina, Federico; Varcada, Massimo

2013-11-27

We present a case of a 19-year-old man with a 6-year history of Crohn's disease (CD), previously treated with 6-mercaptopurine, who was admitted to our department for Epstein-Barr virus (EBV) infection and subsequently developed a hemophagocytic lymphohistiocytosis (HLH). HLH is a rare disease which causes phagocytosis of all bone marrow derived cells. It can be a primary form as a autosomic recessive disease, or a secondary form associated with a variety of infections; EBV is the most common, the one with poorer prognosis. The incidence of lymphoproliferative disorders was increased in patients with inflammatory bowel disease (IBD) treated with thiopurines. Specific EBV-related clinical and virological management should be considered when treating a patient with IBD with immunosuppressive therapy. Moreover EBV infection in immunosuppressed patient can occur with more aggressive forms such as encephalitis and diffuse large B cell lymphoma. Our case confirms what is described in the literature; patients with IBD, particularly patients with CD receiving thiopurine therapy, who present 5 d of fever and cervical lymphadenopathy or previous evidence of lymphopenia should be screened for HLH.

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).

Thiopurines, a previously unrecognised cause for fatigue in patients with inflammatory bowel disease.

Science.gov (United States)

Lee, Thomas W T; Iser, John H; Sparrow, Miles P; Newnham, Evan D; Headon, Belinda J; Gibson, Peter R

2009-09-01

Active inflammatory bowel disease, anaemia, iron deficiency and depression, alone or in combination, are known contributing factors of fatigue in inflammatory bowel disease. However, in some patients, fatigue cannot be attributed to known causes. Thiopurines are not a recognized cause. To describe the clinical scenario of a series of patients where thiopurines were the likely cause of fatigue. The clinical scenario of 5 patients was examined with specific reference to the temporal association of thiopurine therapy with fatigue, the effect of its withdrawal and rechallenge, and drug specificity. The onset of severe fatigue was related to the introduction of azathioprine or 6-mercaptopurine, rapid relief was experienced on its withdrawal in all patients, and fatigue rapidly occurred on rechallenge. The speed of onset was rapid in two patients and in the context of gradual withdrawal of moderate steroid dose, but recurred rapidly on rechallenge when not on steroids. Marked fatigue is a previously unrecognized adverse effect of thiopurines. It does not appear to be drug-specific. Its onset might be masked by concurrent steroid therapy.

6-Thioguanine alters the structure and stability of duplex DNA and inhibits quadruplex DNA formation.

Science.gov (United States)

Marathias, V M; Sawicki, M J; Bolton, P H

1999-07-15

The ability to chemically synthesize biomolecules has opened up the opportunity to observe changes in structure and activity that occur upon single atom substitution. In favorable cases this can provide information about the roles of individual atoms. The substitution of 6-thioguanine (6SG) for guanine is a potentially very useful single atom substitution as 6SG has optical, photocrosslinking, metal ion binding and other properties of potential utility. In addition, 6-mercaptopurine is a clinically important pro-drug that is activated by conversion into 6SG by cells. The results presented here indicate that the presence of 6SG blocks the formation of quadruplex DNA. The presence of 6SG alters the structure and lowers the thermal stability of duplex DNA, but duplex DNA can be formed in the presence of 6SG. These results indicate that some of the cytotoxic activity of 6SG may be due to disruption of the quadruplex structures formed by telomere and other DNAs. This additional mode of action is consistent with the delayed onset of cytotoxicity.

Establishment and characterization of arsenic trioxide resistant KB/ATO cells.

Science.gov (United States)

Zhang, Yun-Kai; Dai, Chunling; Yuan, Chun-Gang; Wu, Hsiang-Chun; Xiao, Zhijie; Lei, Zi-Ning; Yang, Dong-Hua; Le, X Chris; Fu, Liwu; Chen, Zhe-Sheng

2017-09-01

Arsenic trioxide (ATO) is used as a chemotherapeutic agent for the treatment of acute promyelocytic leukemia. However, increasing drug resistance is reducing its efficacy. Therefore, a better understanding of ATO resistance mechanism is required. In this study, we established an ATO-resistant human epidermoid carcinoma cell line, KB/ATO, from its parental KB-3-1 cells. In addition to ATO, KB/ATO cells also exhibited cross-resistance to other anticancer drugs such as cisplatin, antimony potassium tartrate, and 6-mercaptopurine. The arsenic accumulation in KB/ATO cells was significantly lower than that in KB-3-1 cells. Further analysis indicated that neither application of P-glycoprotein inhibitor, breast cancer resistant protein (BCRP) inhibitor, or multidrug resistance protein 1 (MRP1) inhibitor could eliminate ATO resistance. We found that the expression level of ABCB6 was increased in KB/ATO cells. In conclusion, ABCB6 could be an important factor for ATO resistance in KB/ATO cells. The ABCB6 level may serve as a predictive biomarker for the effectiveness of ATO therapy.

Randomised clinical trial: efficacy, safety and dosage of adjunctive allopurinol in azathioprine/mercaptopurine nonresponders (AAA Study).

Science.gov (United States)

Friedman, A B; Brown, S J; Bampton, P; Barclay, M L; Chung, A; Macrae, F A; McKenzie, J; Reynolds, J; Gibson, P R; Hanauer, S B; Sparrow, M P

2018-04-01

Thiopurine hypermethylation towards 6-methylmercaptopurine (6MMP) instead of 6-thioguanine nucleotides (6TGN) is associated with inefficacy in patients with IBD. Allopurinol reverses such hypermethylation. To prospectively determine efficacy of allopurinol-thiopurine combination and to compare 2 doses of allopurinol. In a multicentre, double-blind trial, patients with clinically active or steroid-dependent IBD and thiopurine shunting were randomised to 50 or 100 mg/d allopurinol and 25% of their screening thiopurine dose, which was subsequently optimised, aiming for 6TGN of 260-500 pmol/8x10 8 RBCs. The primary endpoint was steroid-free clinical remission at 24 weeks. Of 73 patients, 39 (53% [95% CI 42-65]) achieved steroid-free remission, (54% with 50 mg/d and 53% with 100 mg/d). 81% were able to discontinue steroids. Therapeutic 6TGN levels were achieved in both groups. Final thiopurine doses were lower with 100 mg/d allopurinol (P stability and lower thiopurine dose without additional toxicity. © 2018 John Wiley & Sons Ltd.

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.

Unanticipated Mycobacterium tuberculosis complex culture inhibition by immune modulators, immune suppressants, a growth enhancer, and vitamins A and D: clinical implications.

Science.gov (United States)

Greenstein, Robert J; Su, Liya; Shahidi, Azra; Brown, William D; Clifford, Anya; Brown, Sheldon T

2014-09-01

The development of novel antibiotics to treat multidrug-resistant (MDR) tuberculosis is time-consuming and expensive. Multiple immune modulators, immune suppressants, anti-inflammatories, and growth enhancers, and vitamins A and D, inhibit Mycobacterium avium subspecies paratuberculosis (MAP) in culture. We studied the culture inhibition of Mycobacterium tuberculosis complex by these agents. Biosafety level two M. tuberculosis complex (ATCC 19015 and ATCC 25177) was studied in radiometric Bactec or MGIT culture. Agents evaluated included clofazimine, methotrexate, 6-mercaptopurine, cyclosporine A, rapamycin, tacrolimus, monensin, and vitamins A and D. All the agents mentioned above caused dose-dependent inhibition of the M. tuberculosis complex. There was no inhibition by the anti-inflammatory 5-aminosalicylic acid, which causes bacteriostatic inhibition of MAP. We conclude that, at a minimum, studies with virulent M. tuberculosis are indicated with the agents mentioned above, as well as with the thioamide 5-propothiouricil, which has previously been shown to inhibit the M. tuberculosis complex in culture. Our data additionally emphasize the importance of vitamins A and D in treating mycobacterial diseases. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

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.

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. Copyright © 2016 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.

Novel DNA lesions generated by the interaction between therapeutic thiopurines and UVA light.

Science.gov (United States)

Zhang, Xiaohong; Jeffs, Graham; Ren, Xiaolin; O'Donovan, Peter; Montaner, Beatriz; Perrett, Conal M; Karran, Peter; Xu, Yao-Zhong

2007-03-01

The therapeutic effect of the thiopurines, 6-thioguanine (6-TG), 6-mercaptopurine, and its prodrug azathioprine, depends on the incorporation of 6-TG into cellular DNA. Unlike normal DNA bases, 6-TG absorbs UVA radiation, and UVA-mediated photochemical damage of DNA 6-TG has potentially harmful side effects. When free 6-TG is UVA irradiated in solution in the presence of molecular oxygen, reactive oxygen species are generated and 6-TG is oxidized to guanine-6-sulfonate (G(SO3)) and guanine-6-thioguanine in reactions involving singlet oxygen. This conversion is prevented by antioxidants, including the dietary vitamin ascorbate. DNA G(SO3) is also the major photoproduct of 6-TG in DNA and it can be selectively introduced into DNA or oligonucleotides in vitro by mild chemical oxidation. Thermal stability measurements indicate that G(SO3) does not form stable base pairs with any of the normal DNA bases in duplex oligonucleotides and is a powerful block for elongation by Klenow DNA polymerase in primer extension experiments. In cultured human cells, DNA damage produced by 6-TG and UVA treatment is associated with replication inhibition and provokes a p53-dependent DNA damage response.

Radiotherapy, chemotherapy, and growth-hormone deficiency

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Schiliro, G; Russo, A; Sciotto, A; Distefano, G; Vigo, R [Catania Univ. (Italy). 1. and 2. Paediatric Clinics

1976-11-06

Measurements have been made of the growth hormone (GH) responses of nine children with acute lymphoblastic leukaemia to the insulin and arginine tolerance tests. All the patients had received induction treatment with prednisone, vincristine and doxorubicin ('Adriamycin') for 4 weeks followed by 2400 rad of orthovoltage cranial irradiation plus five intrathecal injections of methotrexate. During the study all the children were in complete remission, which had been maintained with 6-mercaptopurine and methotrexate for 4 to 26 months. No pulses of steroids were used in remission. Five patients in early remission did not respond to either stimulation test, three having longer remissions showed a late and low response to the insulin test and the one patient with the longest remission (26 months) had a normal GH response. Heights and bone ages were normal. These results, which suggest the possibility of a gradual recovery after the end of CNS treatment including orthovoltage cranial irradiation, are contrasted with those for megavoltage treatment reported by Shalet et al. (Shalet, S.M., Beardwell, C.G., Morris-Jones, P.H., Pearson, D., Archs. Dis. Childh., 1976, vol. 51, 489).

Kinetic study of the interaction of glutathione with four antitumor disulfides: possible mechanism for cellular glutathione depletion.

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Kirkpatrick, D L

1989-01-01

The reactions between the cellular tripeptide, glutathione (GSH) and four disulfide derivatives of 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) (compounds 1-4) were studied kinetically. The decyl and phenyl derivatives of 6-MP and 6-TG were reacted with GSH in phosphate buffer (pH 7.4 or 6.0) at 25.0 degrees C and were monitored spectrophotometrically by observing the release of 6-MP and 6-TG. Second order kinetics were observed, with rate constants of 142, 564, 4174 and 429 M-1 s-1 being measured for compounds 1-4, respectively. When the reactions were carried out in the presence of GSH-S-transferase the rates were enhanced 1.3-5.4 times those observed in the absence of enzyme. Products of the reactions were isolated by chromatography and tentatively identified by TLC or fast atom bombardment mass spectrometry. It was observed that GSH reacted with each disulfide in a 1:1 manner, forming a mixed disulfide between GSH and decanethiol or thiophenol while releasing 6-MP or 6-TG. It was concluded that the reported depletion of GSH from EMT6 cells after exposure to these disulfides could be due to their reaction with GSH, and the formation of the mixed disulfides.

Lack of cross-reactivity between 5-aminosalicylic acid-based drugs: a case report and review of the literature.

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Kung, Shiang-Ju; Choudhary, Cuckoo; McGeady, Stephen J; Cohn, John R

2006-09-01

5-Aminosalicylic acid (5-ASA)-containing drugs are the mainstay of therapy in inflammatory bowel disease, but adverse reactions to these medications are relatively common. Because there may be a lack of cross-reactivity among the various 5-ASA formulations, treatment with alternative preparations is sometimes possible even after an apparent allergic reaction to a 5-ASA product. To describe a patient with a possible allergy to 2 different 5-ASA drugs who tolerated a third. A 27-year-old man with Crohn disease developed a rash while taking mesalamine (Pentasa and Asacol). Treatment with 5-ASA products was discontinued, and 6-mercaptopurine and prednisone were prescribed. He then experienced multiorgan failure secondary to herpes simplex infection, which required discontinuation of the immunosuppressive therapy. After recovery from the acute infection, he underwent successful graded challenge with balsalazide. The patient continued treatment with balsalazide for 9 months, with good control of his inflammatory bowel disease and no adverse effects. Adverse reactions to 1 or more 5-ASA medications do not necessarily preclude the use of others in the same class. A treatment algorithm for patients with adverse reactions to 5-ASA is outlined based on the case report and review of the literature.

Photo-oxidation of 6-thioguanine by UVA: the formation of addition products with low molecular weight thiol compounds.

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Ren, Xiaolin; Xu, Yao-Zhong; Karran, Peter

2010-01-01

The thiopurine, 6-thioguanine (6-TG) is present in the DNA of patients treated with the immunosuppressant and anticancer drugs azathioprine or mercaptopurine. The skin of these patients is selectively sensitive to UVA radiation-which comprises >90% of the UV light in incident sunlight-and they suffer high rates of skin cancer. UVA irradiation of DNA 6-TG produces DNA lesions that may contribute to the development of cancer. Antioxidants can protect 6-TG against UVA but 6-TG oxidation products may undergo further reactions. We characterize some of these reactions and show that addition products are formed between UVA-irradiated 6-TG and N-acetylcysteine and other low molecular weight thiol compounds including β-mercaptoethanol, cysteine and the cysteine-containing tripeptide glutathione (GSH). GSH is also adducted to 6-TG-containing oligodeoxynucleotides in an oxygen- and UVA-dependent nucleophilic displacement reaction that involves an intermediate oxidized 6-TG, guanine sulfonate (G(SO3) ). These photochemical reactions of 6-TG, particularly the formation of a covalent oligodeoxynucleotide-GSH complex, suggest that crosslinking of proteins or low molecular weight thiol compounds to DNA may be a previously unrecognized hazard in sunlight-exposed cells of thiopurine-treated patients. © 2010 The Authors. Journal Compilation. The American Society of Photobiology.

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

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Zhou, Hui-yun; Chen, Xi-guang

2008-12-01

In this study, chitosan/cellulose acetate microspheres (CCAM) were prepared by W/O/W emulsification and solvent evaporation as a drug delivery system. The microspheres were spherical, free-flowing and non-aggregated. The CCAM had good flow and suspension ability. The loading efficiency of different model drugs increased with the increasing hydrophobicity of the drug. The loading 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 different 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.

[Acute lymphoblastic leukemia: a genomic perspective].

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Jiménez-Morales, Silvia; Hidalgo-Miranda, Alfredo; Ramírez-Bello, Julián

In parallel to the human genome sequencing project, several technological platforms have been developed that let us gain insight into the genome structure of human entities, as well as evaluate their usefulness in the clinical approach of the patient. Thus, in acute lymphoblastic leukemia (ALL), the most common pediatric malignancy, genomic tools promise to be useful to detect patients at high risk of relapse, either at diagnosis or during treatment (minimal residual disease), and they also increase the possibility to identify cases at risk of adverse reactions to chemotherapy. Therefore, the physician could offer patient-tailored therapeutic schemes. A clear example of the useful genomic tools is the identification of single nucleotide polymorphisms (SNPs) in the thiopurine methyl transferase (TPMT) gene, where the presence of two null alleles (homozygous or compound heterozygous) indicates the need to reduce the dose of mercaptopurine by up to 90% to avoid toxic effects which could lead to the death of the patient. In this review, we provide an overview of the genomic perspective of ALL, describing some strategies that contribute to the identification of biomarkers with potential clinical application. Copyright © 2017 Hospital Infantil de México Federico Gómez. Publicado por Masson Doyma México S.A. All rights reserved.

Impact of genetic polymorphisms on chemotherapy toxicity in childhood acute lymphoblastic leukemia

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Guillermo eGervasini

2012-11-01

Full Text Available The efficacy of chemotherapy in pediatric acute lymphoblastic leukemia (ALL patients has significantly increased in the last twenty years; as a result, the focus of research is slowly shifting from trying to increase survival rates to reduce chemotherapy-related toxicity.At the present time, the cornerstone of therapy for ALL is still formed by a reduced number of drugs with a highly toxic profile. In recent years, a number of genetic polymorphisms have been identified that can play a significant role in modifying the pharmacokinetics and pharmacodynamics of these drugs. The best example is that of the TPMT gene, whose genotyping is being incorporated to clinical practice in order to individualize doses of mercaptopurine. However, there are additional genes that are relevant for the metabolism, activity and/or transport of other chemotherapy drugs that are widely use in ALL, such as methotrexate, cyclophosphamide, vincristine, L-asparaginase, etoposide, cytarabine or cytotoxic antibiotics. These genes can also be affected by genetic alterations that could therefore have clinical consequences.In this review we will discuss recent data on this field, with special focus on those polymorphisms that could be used in clinical practice to tailor chemotherapy for ALL in order to reduce the occurrence of serious adverse effects.

Gold Nanoclusters@Ru(bpy)₃²⁺-Layered Double Hydroxide Ultrathin Film as a Cathodic Electrochemiluminescence Resonance Energy Transfer Probe.

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Yu, Yingchang; Lu, Chao; Zhang, Meining

2015-08-04

Herein, it is the first report that a cathodic electrochemiluminescence (ECL) resonance energy transfer (ERET) system is fabricated by layer-by-layer (LBL) electrostatic assembly of CoAl layered double hydroxide (LDH) nanosheets with a mixture of blue BSA-gold nanoclusters (AuNCs) and Ru(bpy)3(2+) (denoted as AuNCs@Ru) on an Au electrode. The possible ECL mechanism indicates that the appearance of CoAl-LDH nanosheets generates a long-range stacking order of the AuNCs@Ru on an Au electrode, facilitating the occurrence of the ERET between BSA-AuNC donors and Ru(bpy)3(2+) acceptors on the as-prepared AuNCs@Ru-LDH ultrathin films (UTFs). Furthermore, it is observed that the cathodic ECL intensity can be quenched efficiently in the presence of 6-mercaptopurine (6-MP) in a linear range of 2.5-100 nM with a detection limit of 1.0 nM. On the basis of these interesting phenomena, a facile cathodic ECL sensor has successfully distinguished 6-MP from other thiol-containing compounds (e.g., cysteine and glutathione) in human serum and urine samples. The proposed sensing scheme opens a way for employing the layered UTFs as a platform for the cathodic ECL of Ru(bpy)3(2+).

A mathematical model relating response durations to amount of subclinical resistant disease.

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Gregory, W M; Richards, M A; Slevin, M L; Souhami, R L

1991-02-15

A mathematical model is presented which seeks to determine, from examination of the response durations of a group of patients with malignant disease, the mean and distribution of the resistant tumor volume. The mean tumor-doubling time and distribution of doubling times are also estimated. The model assumes that in a group of patients there is a log-normal distribution both of resistant disease and of tumor-doubling times and implies that the shapes of certain parts of an actuarial response-duration curve are related to these two factors. The model has been applied to data from two reported acute leukemia trials: (a) a recent acute myelogenous leukemia trial was examined. Close fits were obtained for both the first and second remission-duration curves. The model results suggested that patients with long first remissions had less resistant disease and had tumors with slower growth rates following second line treatment; (b) an historical study of maintenance therapy for acute lymphoblastic leukemia was used to estimate the mean cell-kill (approximately 10(4) cells) achieved with single agent, 6-mercaptopurine. Application of the model may have clinical relevance, for example, in identifying groups of patients likely to benefit from further intensification of treatment.

The study of teratogenic effect of Cyclosporine in vitro

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Ostad SN

2001-07-01

Full Text Available The use of immunosuppressive medication such as Azathioprine, methoterxate and mercaptopurine in treatment of rheumatic disease in women at childbearing age has some risks of teratogeniesis. Cyclosporine is one of the newer medicines, which has been introduced for this disease but little is known about its teratogenicity. This study was designed to investigate the possible teratogenicity of this drug by using cultured rat limb bud cells, which were obtained from rat embryos 13 days after conception. Cells were incubated in trypsin-EDTA solution for 30 min at 37°C and then filtered through 50 µm nylon filters. The resultant cell suspension was cultivated in 1 ml Dulbecco modified Eagle medium (DMEM containing 10% fetal bovine serum and 445 µg/L L-glutamine at 37°C with 5% CO2. After 8 days of culture the differentiated foci extract were measured by staining with 1% alcian blue. To assess the teratogenic effects of cyclosporine, it was placed in the culture well together with the cells. Results showed that the decrease in the expression of the extracellular matrix at dose of 0.01 molar of cyclosporine is due to limb bud cell toxicity rather than inhibition of cell differentiation.

Capillary Electrophoresis Hyphenated with Mass Spectrometry for Determination of Inflammatory Bowel Disease Drugs in Clinical Urine Samples

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Katarína Maráková

2017-11-01

Full Text Available Azathioprine is the main thiopurine drug used in the treatment of immune-based inflammations of gastrointestinal tract. For the purpose of therapy control and optimization, effective and reliable analytical methods for a rapid drug monitoring in biological fluids are essential. Here, we developed a separation method based on the capillary electrophoresis (CE hyphenated with tandem mass spectrometry (MS/MS for the simultaneous determination of azathioprine and its selected metabolites (6-thioguanine, 6-mercaptopurine, and 6-methylmercaptopurine as well as other co-medicated drugs (mesalazine, prednisone, and allopurinol. The optimized CE-MS/MS conditions provided a very efficient and stable system for the separation and sensitive detection of these drugs in human urine matrices. The developed method was successfully applied for the assay of the targeted drugs and their selected metabolites in urine samples collected from patients suffering from inflammatory bowel disease (IBD and receiving azathioprine therapy. The developed CE-MS/MS method, due to its reliability, short analysis time, production of complex clinical profiles, and favorable performance parameters, evaluated according to FDA guidelines for bioanalytical method validation, is proposed for routine clinical laboratories to optimize thiopurine therapy, estimate enzymatic activity, and control patient compliance with medication and co-medication.

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

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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.

[Androgens and prolonged complete remissions in acute non lymphoblastic leukemias. Results of a systematic treatment with stanozolol associated with chemotherapy (author's transl)].

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Sotto, J J; Hollard, D; Schaerer, R; Bensa, J C; Seigneurin, D

1975-01-01

An androgen (stanozolol: 0,15 mg/kg/d) was systematically associated to the treatment of acute non lymphoblastic leukemias, since the beginning of induction therapy (vincristin, daunorubicin, prednisone) and throughout the maintenance period (6-mercaptopurine and methotrexate). Thirty-six patients less than 60 years old (median age: 44 years) presenting with acute non-lymphoblastic leukemia were entered to the study. Sixteen achieved complete remission (C.R.), i.e. 44% of the whole and 53% of treated patients. Out of 16 patients with complete remission, 4 relapsed during the observation period which lasted 4-1/2 years. The stability of the hematologic equilibrium in patients in C.R. is the main finding of the present study. The actuarial curve of the duration of the first complete remission reaches a "plateau"; after the 8th month only one relapse was observed in 9 patients. The rate of C.R. at 2 years is 76 +/- 23%. As compared to the results from other schedules of treatment, this rate appears significantly better, specially in the case of immunotherapy (p less than 0,001). A prospective randomized study is now suggested as to confirm this result; its therapeutic and theoretical basis and perspectives are discussed.

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

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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. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Intensification of mercaptopurine/methotrexate maintenance chemotherapy may increase the risk of relapse for some children with acute lymphoblastic leukemia

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Schmiegelow, Kjeld; Björk, Olle; Glomstein, Anders

2003-01-01

by erythrocyte (E) levels of TGN and MTX (including polyglutamates) could improve outcome in childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: A total of 538 children with ALL were randomly assigned to have their oral MP/MTX maintenance therapy adjusted by white cell counts (WBC), E-TGN, and E......-MTX (pharmacology group), or by WBC only (control group). RESULTS: After a median follow-up of 7.8 years, 79 patients had relapsed. Cox regression analysis showed an increased risk of relapse for boys (P =.00003), high WBC at diagnosis (P =.03), pharmacology arm (6.6 times increased relapse hazard for girls), high...

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

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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.

A sensitive turn on fluorescent probe for detection of biothiols using MnO2@carbon dots nanocomposites

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Garg, Dimple; Mehta, Akansha; Mishra, Amit; Basu, Soumen

2018-03-01

Presently, the combination of carbon quantum dots (CQDs) and metal oxide nanostructures in one frame are being considered for the sensing of purine compounds. In this work, a combined system of CQDs and MnO2 nanostructures was used for the detection of anticancer drugs, 6-Thioguanine (6-TG) and 6-Mercaptopurine (6-MP). The CQDs were synthesized through microwave synthesizer and the MnO2 nanostructures (nanoflowers and nanosheets) were synthesized using facile hydrothermal technique. The CQDs exhibited excellent fluorescence emission at 420 nm when excited at 320 nm wavelength. By combining CQDs and MnO2 nanostructures, quenching of fluorescence was observed which was attributed to fluorescence resonance energy transfer (FRET) mechanism, where CQDs act as electron donor and MnO2 act as acceptor. This fluorescence quenching behaviour disappeared on the addition of 6-TG and 6-MP due to the formation of Mn-S bond. The detection limit for 6-TG (0.015 μM) and 6-MP (0.014 μM) was achieved with the linear range of concentration (0-50 μM) using both MnO2 nanoflowers and nanosheets. Moreover, the as-prepared fluorescence-sensing technique was successfully employed for the detection of bio-thiol group in enapril drug. Thus a facile, cost-effective and benign chemistry approach for biomolecule detection was designed.

Hyaluronic acid oligosaccharide modified redox-responsive mesoporous silica nanoparticles for targeted drug delivery.

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Zhao, Qinfu; Geng, Hongjian; Wang, Ying; Gao, Yikun; Huang, Jiahao; Wang, Yan; Zhang, Jinghai; Wang, Siling

2014-11-26

A redox-responsive delivery system based on colloidal mesoporous silica (CMS) has been developed, in which 6-mercaptopurine (6-MP) was conjugated to vehicles by cleavable disulfide bonds. The oligosaccharide of hyaluronic acid (oHA) was modified on the surface of CMS by disulfide bonds as a targeting ligand and was able to increase the stability and biocompatibility of CMS under physiological conditions. In vitro release studies indicated that the cumulative release of 6-MP was less than 3% in the absence of glutathione (GSH), and reached nearly 80% within 2 h in the presence of 3 mM GSH. Confocal microscopy and fluorescence-activated cell sorter (FACS) methods were used to evaluate the cellular uptake performance of fluorescein isothiocyanate (FITC) labeled CMS, with and without oHA modification. The CMS-SS-oHA exhibited a higher cellular uptake performance via CD44 receptor-mediated endocytosis in HCT-116 (CD44 receptor-positive) cells than in NIH-3T3 (CD44 receptor-negative) cells. 6-MP loaded CMS-SS-oHA exhibited greater cytotoxicity against HCT-116 cells than NIH-3T3 cells due to the enhanced cell uptake behavior of CMS-SS-oHA. This study provides a novel strategy to covalently link bioactive drug and targeting ligand to the interiors and exteriors of mesoporous silica to construct a stimulus-responsive targeted drug delivery system.

Paternal use of azathioprine/6-mercaptopurine or methotrexate within 3 months before conception and long-term health outcomes in the offspring

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Friedman, S; Larsen, M D; Magnussen, B

2017-01-01

hyperactivity disorder (ADHD). RESULTS: Outcomes: of children: AZA/6-MP exposure: one with leukemia (0.14%), one with ASD/schizophrenia (0.14%) and three with ADHD (0.41%); MTX exposure: three with ADHD (1.4%). Unexposed: 1710 with malignancies (0.16%), 2107 with ASD/schizophrenia (0.20%), 2799 with ADHD (0...

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

not use AZA/6-MP 3 months prior to conception constituted the unexposed cohort (N=1 012 624). The outcomes were congenital abnormalities (CAs), preterm birth and small for gestational age (SGA). We adjusted for multiple covariates and performed a restricted analysis of men with IBD. RESULTS: There were...

Hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites

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Toksvang, Linea Natalie; De Pietri, Silvia; Nielsen, Stine N.

2017-01-01

BACKGROUND: Hepatic sinusoidal obstruction syndrome (SOS) during treatment of childhood acute lymphoblastic leukemia (ALL) has mainly been associated with 6-thioguanine. The occurrence of several SOS cases after the introduction of extended pegylated asparaginase (PEG-asparaginase) therapy...... in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol led us to hypothesize that PEG-asparaginase, combined with other drugs, may trigger SOS during 6-thioguanine-free maintenance therapy. PROCEDURE: In children with ALL treated in Denmark according to the NOPHO ALL2008 protocol...... children receiving PEG-asparaginase biweekly, 29 developed SOS (≥2 criteria: hyperbilirubinemia, hepatomegaly, ascites, weight gain ≥2.5%, unexplained thrombocytopenia

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

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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.

Determination of thiopurine S-methyltransferase activity by hydrophilic interaction liquid chromatography hyphenated with mass spectrometry.

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Pecher, Daniel; Dokupilová, Svetlana; Zelinková, Zuzana; Peppelenbosch, Maikel; Mikušová, Veronika; Mikuš, Peter

2017-08-05

Thiopurine S-methyltransferase (TPMT) plays an important role in the metabolism of thiopurines used in the therapy of inflammatory bowel diseases (IBD). In this work a new progressive method for the determination of TPMT activity in red blood cells lysates was developed. Analysis was carried out by means of hydrophilic interaction liquid chromatography (HILIC) hyphenated with mass spectrometry (MS). In comparison with reversed-phase high-performance liquid chromatography (RP-HPLC), that has been typically applied in determination of TPMT activity, the HILIC significantly improved the analytical signal provided by MS, shortened analysis time, and improved chromatographic resolution. The HILIC-HPLC-MS method was optimized and validated, providing favorable parameters of detection and quantitation limits (5.5 and 16.5pmol/mL, respectively), linearity (coefficient of determination 0.9999 in the range of 0.01-1.0nmol/mL), recovery and precision (93.25-100.37% with RSD 1.06-1.32% in the whole concentration range of QC samples). Moreover, in contrast to the conventional RP-HPLC-UV approach, the complex phenotype TPMT profiles can be reliably and without interferences monitored using the HILIC-HPLC-MS method. Such advanced monitoring can provide valuable detail information on the thiopurines (e.g. evaluating ratio of methylated and non-methylated 6-mercaptopurine) and, by that, TPMT action in biological systems before and during the therapy of IBD. Copyright © 2017 Elsevier B.V. All rights reserved.

The Promise of Pharmacogenomics in Reducing Toxicity During Acute Lymphoblastic Leukemia Maintenance Treatment

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Shoshana Rudin

2017-04-01

Full Text Available Pediatric acute lymphoblastic leukemia (ALL affects a substantial number of children every year and requires a long and rigorous course of chemotherapy treatments in three stages, with the longest phase, the maintenance phase, lasting 2–3 years. While the primary drugs used in the maintenance phase, 6-mercaptopurine (6-MP and methotrexate (MTX, are necessary for decreasing risk of relapse, they also have potentially serious toxicities, including myelosuppression, which may be life-threatening, and gastrointestinal toxicity. For both drugs, pharmacogenomic factors have been identified that could explain a large amount of the variance in toxicity between patients, and may serve as effective predictors of toxicity during the maintenance phase of ALL treatment. 6-MP toxicity is associated with polymorphisms in the genes encoding thiopurine methyltransferase (TPMT, nudix hydrolase 15 (NUDT15, and potentially inosine triphosphatase (ITPA, which vary between ethnic groups. Moreover, MTX toxicity is associated with polymorphisms in genes encoding solute carrier organic anion transporter family member 1B1 (SLCO1B1 and dihydrofolate reductase (DHFR. Additional polymorphisms potentially associated with toxicities for MTX have also been identified, including those in the genes encoding solute carrier family 19 member 1 (SLC19A1 and thymidylate synthetase (TYMS, but their contributions have not yet been well quantified. It is clear that pharmacogenomics should be incorporated as a dosage-calibrating tool in pediatric ALL treatment in order to predict and minimize the occurrence of serious toxicities for these patients.

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

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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.

Proliferation and Differentiation of Autologic and Allogenic Stem Cells in Supralethally X-Irradiated Dogs

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Chertkov, I. L. [Department of Radiobiology, Central Institute of Haematology and Blood Transfusion, Moscow, USSR (Russian Federation)

1967-07-15

Full text: Allogenic bone marrow after transplantation into dogs irradiated with 1000 R X-rays differentiates in the normal way only for 3-4 days, afterwards transforming into lymphoid cells. This transformation is due to the antigen stimulus of the host on the grafted stem cells. The lymphoid cells, obtained from the host's blood on the 7-8th day after grafting, showed specific, immune activity under the Immune Lymphocyte Transfer test. Within a short duration of the immune response immunoblasts and immunocytes Undergo degenerative changes: destroyed mitochondria, formation of autophagic vacuoles and, finally, lysis of the cells. These changes are suggested to be the result of overloading of immune cells with antigen. Preliminary sensitization of the donor with prospective host's haemopoietic tissue does not hasten the immune transformation of haemopoiesis. Injections of bacterial pyrogen, cortisone or 6-mercaptopurine into recipients, as well as incubation of bone marrow at 37 Degree-Sign C for 2 hours, do not prevent the immune transformation. Preliminary thymectomy of the prospective recipients prevents in some of the cases immune transformation of the bone-marrow graft. The delay of allogenic bone-marrow transplantation for 5-6 days prevents in some dogs (X-irradiated with 1000 R, but not with 1200 R) the immune transformation. Transplantation of autologic bone marrow or shielding of the legs during irradiation is accompanied with good restoration of normal haemopoiesis without lymphoid transformation. (author)

Binding of several anti-tumor drugs to bovine serum albumin: Fluorescence study

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Bi Shuyun [College of Chemistry, Changchun Normal University, Changchun 130032 (China)], E-mail: sy_bi@sina.com; Sun Yantao [College of Chemistry, Jilin University, Changchun 130023 (China); College of Chemistry, Jilin Normal University, Siping 136000 (China); Qiao Chunyu; Zhang Hanqi [College of Chemistry, Jilin University, Changchun 130023 (China); Liu Chunming [College of Chemistry, Changchun Normal University, Changchun 130032 (China)

2009-05-15

The interactions of mitomycin C (MMC), fluorouracil (FU), mercaptopurine (MP) and doxorubicin hydrochloride (DXR) with bovine serum albumin (BSA) were studied by spectroscopic method. Quenching of fluorescence of serum albumin by these drugs was found to be a static quenching process. The binding constants (K{sub A}) were 9.66x10{sup 3}, 2.08x10{sup 3}, 8.20x10{sup 2} and 7.50x10{sup 3} L mol{sup -1} for MMC-, FU-, MP- and DXR-BSA, respectively, at pH 7.4 Britton-Robinson buffer at 28 deg. C. The thermodynamic functions such as enthalpy change ({delta}H), entropy change ({delta}S) and Gibbs free-energy change ({delta}G) for the reactions were also calculated according to the thermodynamic equations. The main forces in the interactions of these drugs with BSA were evaluated. It was found that the interactions of MMC and FU with BSA were exothermic processes and those of MP and DXR with BSA were endothermic. In addition, the binding sites on BSA for the four drugs were probed by the changes of binding properties of these drugs with BSA in the presence of two important site markers such as ibuprofen and indomethacin. Based on the Foester theory of non-radiation energy transfer, the binding distances between the drugs and tryptophane were calculated and they were 3.00, 1.14, 2.85, and 2.79 nm for MMC, FU, MP and DXR, respectively.

Pan-pathway based interaction profiling of FDA-approved nucleoside and nucleobase analogs with enzymes of the human nucleotide metabolism.

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Egeblad, Louise; Welin, Martin; Flodin, Susanne; Gräslund, Susanne; Wang, Liya; Balzarini, Jan; Eriksson, Staffan; Nordlund, Pär

2012-01-01

To identify interactions a nucleoside analog library (NAL) consisting of 45 FDA-approved nucleoside analogs was screened against 23 enzymes of the human nucleotide metabolism using a thermal shift assay. The method was validated with deoxycytidine kinase; eight interactions known from the literature were detected and five additional interactions were revealed after the addition of ATP, the second substrate. The NAL screening gave relatively few significant hits, supporting a low rate of "off target effects." However, unexpected ligands were identified for two catabolic enzymes guanine deaminase (GDA) and uridine phosphorylase 1 (UPP1). An acyclic guanosine prodrug analog, valaciclovir, was shown to stabilize GDA to the same degree as the natural substrate, guanine, with a ΔT(agg) around 7°C. Aciclovir, penciclovir, ganciclovir, thioguanine and mercaptopurine were also identified as ligands for GDA. The crystal structure of GDA with valaciclovir bound in the active site was determined, revealing the binding of the long unbranched chain of valaciclovir in the active site of the enzyme. Several ligands were identified for UPP1: vidarabine, an antiviral nucleoside analog, as well as trifluridine, idoxuridine, floxuridine, zidovudine, telbivudine, fluorouracil and thioguanine caused concentration-dependent stabilization of UPP1. A kinetic study of UPP1 with vidarabine revealed that vidarabine was a mixed-type competitive inhibitor with the natural substrate uridine. The unexpected ligands identified for UPP1 and GDA imply further metabolic consequences for these nucleoside analogs, which could also serve as a starting point for future drug design.

Novel variants in NUDT15 and thiopurine intolerance in children with acute lymphoblastic leukemia from diverse ancestry.

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Moriyama, Takaya; Yang, Yung-Li; Nishii, Rina; Ariffin, Hany; Liu, Chengcheng; Lin, Ting-Nien; Yang, Wenjian; Lin, Dong-Tsamn; Yu, Chih-Hsiang; Kham, Shirley; Pui, Ching-Hon; Evans, William E; Jeha, Sima; Relling, Mary V; Yeoh, Allen Eng-Juh; Yang, Jun J

2017-09-07

Prolonged exposure to thiopurines (eg, mercaptopurine [MP]) is essential for curative therapy in acute lymphoblastic leukemia (ALL), but is also associated with frequent dose-limiting hematopoietic toxicities, which is partly explained by inherited genetic polymorphisms in drug metabolizing enzymes (eg, TPMT ). Recently, our group and others identified germ line genetic variants in NUDT15 as another major cause of thiopurine-related myelosuppression, particularly in Asian and Hispanic people. In this article, we describe 3 novel NUDT15 coding variants (p.R34T, p.K35E, and p.G17_V18del) in 5 children with ALL enrolled in frontline protocols in Singapore, Taiwan, and at St. Jude Children's Research Hospital. Patients carrying these variants experienced significant toxicity and reduced tolerance to MP across treatment protocols. Functionally, all 3 variants led to partial to complete loss of NUDT15 nucleotide diphosphatase activity and negatively influenced protein stability. In particular, the p.G17_V18del variant protein showed extremely low thermostability and was completely void of catalytic activity, thus likely to confer a high risk of thiopurine intolerance. This in-frame deletion was only seen in African and European patients, and is the first NUDT15 risk variant identified in non-Asian, non-Hispanic populations. In conclusion, we discovered 3 novel loss-of-function variants in NUDT15 associated with MP toxicity, enabling more comprehensive pharmacogenetics-based thiopurine dose adjustments across diverse populations. © 2017 by The American Society of Hematology.

Hemoglobin bioconjugates with surface-protected gold nanoparticles in aqueous media: The stability depends on solution pH and protein properties.

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Del Caño, Rafael; Mateus, Lucia; Sánchez-Obrero, Guadalupe; Sevilla, José Manuel; Madueño, Rafael; Blázquez, Manuel; Pineda, Teresa

2017-11-01

The identification of the factors that dictate the formation and physicochemical properties of protein-nanomaterial bioconjugates are important to understand their behavior in biological systems. The present work deals with the formation and characterization of bioconjugates made of the protein hemoglobin (Hb) and gold nanoparticles (AuNP) capped with three different molecular layers (citrate anions (c), 6-mercaptopurine (MP) and ω-mercaptoundecanoic acid (MUA)). The main focus is on the behavior of the bioconjugates in aqueous buffered solutions in a wide pH range. The stability of the bioconjugates have been studied by UV-visible spectroscopy by following the changes in the localized surface resonance plasmon band (LSRP), Dynamic light scattering (DLS) and zeta-potential pH titrations. It has been found that they are stable in neutral and alkaline solutions and, at pH lower than the protein isoelectric point, aggregation takes place. Although the surface chemical properties of the AuNPs confer different properties in respect to colloidal stability, once the bioconjugates are formed their properties are dictated by the Hb protein corona. The protein secondary structure, as analyzed by Attenuated total reflectance infrared (ATR-IR) spectroscopy, seems to be maintained under the conditions of colloidal stability but some small changes in protein conformation take place when the bioconjugates aggregate. These findings highlight the importance to keep the protein structure upon interaction with nanomaterials to drive the stability of the bioconjugates. Copyright © 2017 Elsevier Inc. All rights reserved.

Clinical impact of concomitant immunomodulators on biologic therapy: Pharmacokinetics, immunogenicity, efficacy and safety.

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Xu, Zhenhua; Davis, Hugh M; Zhou, Honghui

2015-03-01

Immune-mediated inflammatory diseases encompass a variety of different clinical syndromes, manifesting as either common diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and psoriasis, or rare diseases such as cryopyrin-associated periodic syndromes. The therapy for these diseases often involves the use of a wide range of drugs including nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, immunomodulators, and biologic therapies. Due to the abundance of relevant clinical data, this article provides a general overview on the clinical impact of the concomitant use of immunomodulators and biologic therapies, with a focus on anti-tumor necrosis factor-α agents (anti-TNFα), for the treatment of RA and Crohn's disease (CD). Compared to biologic monotherapy, concomitant use of immunomodulators (methotrexate, azathioprine, and 6-mercaptopurine) often increases the systemic exposure of the anti-TNFα agent and decreases the formation of antibodies to the anti-TNFα agent, consequently enhancing clinical efficacy. Nevertheless, long-term combination therapy with immunomodulators and anti-TNFα agents may be associated with increased risks of serious infections and malignancies. Therefore, the determination whether combination therapy is suitable for a patient should always be based on an individualized benefit-risk evaluation. More research should be undertaken to identify and validate prognostic markers for predicting patients who would benefit the most and those who are at greater risk from combination therapy with immunomodulators and anti-TNFα agents. © 2015, The American College of Clinical Pharmacology.

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

of maintenance therapy. The TMP/SMX2–7 group received lower oral 6MP doses than TMP/SMXnever patients (50.6 vs. 63.9 mg/m2/d; P ANC) (median 1.7 vs. 2.0 × 109/L; P ANC levels (P = 0.04) and male gender (P = 0.......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...

Crohn's disease.

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von Roon, Alexander C; Reese, George E; Orchard, Timothy R; Tekkis, Paris P

2007-11-07

Crohn's disease is a long-term chronic condition of the gastrointestinal tract. It is characterised by transmural, granulomatous inflammation that occurs in a discontinuous pattern, with a tendency to form fistulae. The cause is unknown but may depend on interactions between genetic predisposition, environmental triggers, and mucosal immunity. We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of medical treatments in adults to induce remission in Crohn's disease? What are the effects of lifestyle interventions in adults with Crohn's disease to maintain remission? What are the effects of surgical interventions in adults with small-bowel Crohn's disease to induce remission? What are the effects of surgical interventions in adults with colonic Crohn's disease to induce remission? What are the effects of medical interventions to maintain remission in adults with Crohn's disease; and to maintain remission following surgery? We searched: Medline, Embase, The Cochrane Library and other important databases up to March 2006 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We found 60 systematic reviews, RCTs, or observational studies that met our inclusion criteria. In this systematic review we present information relating to the effectiveness and safety of the following interventions: aminosalicylates, antibiotics, azathioprine/mercaptopurine, ciclosporin, corticosteroids (oral), enteral nutrition, fish oil, infliximab, methotrexate, probiotics, resection, segmental colectomy, smoking cessation, and strictureplasty.

Murine and human leukemias.

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Burchenal, J H

1975-01-01

Essentially all the drugs which are active against human leukemias and lymphomas are active against one type or another of the rodent leukemias and lymphomas. Leukemia L1210 has been generally the most successful screening tool for clinically active compounds. Leukemia P388, however, seems to be better in detecting active antibiotics and natural products and P1534 is particularly sensitive to the Vinca alkaloids, while L5178Y, EARAD, and 6C3HED are useful in detecting the activities of various asparaginase containing fractions. Cell cultures of these leukemias can demonstrate mechanism of drug action and quantitate resistance. Spontaneous AKR leukemia is a model of the advanced human disease. In these leukemias vincristine and prednisone produce a 4 log cell kill. Cytoxan and arabinosyl cytosine (Ara-C) are also effective. On the other hand drugs such as mercaptopurine (6MP) and methotrexate which are highly active in the maintenance phase of acute lymphocytic leukemia (ALL) and in L1210 have little or no activity against the AKR spontaneous system. Mouse leukemias can also detect schedule dependence, synergistic combinations, cross resistance, oral activity, and the ability of drugs to pass the blood brain barrier. A case in point is the Ara-C analog 2,2'-anhydro-arabinofuranosyl-5-fluorocytosine (AAFC) which is not schedule dependent, is active orally, is potentiated by thioguanine, and is effective against intracerebrally inoculated mouse leukemia. AAFC and its analogs might thus be a considerable improvement over Ara-C which is at the present time the most important component of the combination treatment of acute myelogenous leukemia (AML).

Patients' Adherence in the Maintenance Therapy of Children and Adolescents with Acute Lymphoblastic Leukemia.

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Kremeike, K; Juergens, C; Alz, H; Reinhardt, D

2015-11-01

Acute lymphoblastic leukemia (ALL) is the most common form of paediatric cancer. Maintenance therapy as last treatment phase includes oral chemotherapy with methotrexate (MTX) and mercaptopurine (6-MP), self- or parent-administered at home, given for about 1 ½ years, and qualified as decisive for an optimum therapy outcome. The aim of our study was to analyze factors influencing the adherence of patients with ALL undergoing maintenance therapy and their families. A multi-method study was undertaken between 11/2011 and 10/2014 with patients surveyed by the Hannover Medical School outpatient clinic, including a questionnaire survey and qualitative interviews with parents as well as blood samples of the patients. 33 questionnaires, 27 interviews and blood samples of 26 patients could be analyzed. Only one third of the blood samples showed concentrations of the 6-MP active metabolite within the therapeutic reference range. Parents named the clinical doctor as their main advisor on medication intake. 36% (12/33) of the participants stated that medication intake has not always occurred the way medication was prescribed. Drug formulation and drug intake information could be identified as determinants of adherence. Parents' problems to obtain information are partly caused by different study results concerning the correct timing of the drug intake and drug interactions with milk products. Parents' information on drug therapy should be more consistent and the pharmaceutical formulations have to be adapted to patients' needs to improve adherence and thereby the chance of long-term remission. © Georg Thieme Verlag KG Stuttgart · New York.

The influence of detoxification agents on the intensity of side effects caused by medium-high doses of methotrexate in children with acute lymphoblastic leukemia: Case series

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Šumar Jovana S.

2014-01-01

Full Text Available Objective The treatment of childhood acute lymphoblastic leukemia (ALL in Serbia is conducted according to protocol ALL IC BMF-2009. The therapy includes the application of cytostatic drugs methotrexate and 6-mercaptopurine, and drug detoxifying Calcium Folinate. At the moment, 80% of affected children could be cured with current treatment, but resistance to the therapy and its toxic effects remain serious clinical problems. The aim of the study was to investigate the influence of detoxification agents (Calcium Folinate, silymarin and ursodeoxycholic acid on the side effects of methotrexate, applied in this protocol. Methods A modified acute toxicity form (GPOH was used for side effects monitoring. The research included children with either standard or intermediate risk ALL in the consolidation therapy phase, who were hospitalised at the Institute for Child and Youth Health Care of Vojvodina in Novi Sad during the period from July 2010 to February 2011. Results The most frequent side effect after 40 applications of methotrexate in ten children was bone marrow depression. Methotrexate caused: leukopenia in 10 patients, thrombocytopenia in 5 patients; after the use of folic acid, platelet count grew in 8 patients, leukocyte in 2 patients. Less frequent side effects: an increase serum transaminase activity, the state of fever, bronchopneumonia, diarrhoea with mild cramps and hypercalcaemia. Conclusion The application of Calcium Folinate, silymarin and ursodeoxycholic acid prevented the occurrence of severe adverse effects caused by medium-high doses of methotrexate. Observed adverse effects were of mild to moderate intensity, reversible and did not significantly disturb the quality of life in treated patients.

Comparison of Direct Sequencing, Real-Time PCR-High Resolution Melt (PCR-HRM) and PCR-Restriction Fragment Length Polymorphism (PCR-RFLP) Analysis for Genotyping of Common Thiopurine Intolerant Variant Alleles NUDT15 c.415C>T and TPMT c.719A>G (TPMT*3C).

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Fong, Wai-Ying; Ho, Chi-Chun; Poon, Wing-Tat

2017-05-12

Thiopurine intolerance and treatment-related toxicity, such as fatal myelosuppression, is related to non-function genetic variants encoding thiopurine S-methyltransferase (TPMT) and Nudix hydrolase 15 (NUDT15). Genetic testing of the common variants NUDT15:NM_018283.2:c.415C>T (Arg139Cys, dbSNP rs116855232 T allele) and TPMT: NM_000367.4:c.719A>G (TPMT*3C, dbSNP rs1142345 G allele) in East Asians including Chinese can potentially prevent treatment-related complications. Two complementary genotyping approaches, real-time PCR-high resolution melt (PCR-HRM) and PCR-restriction fragment length morphism (PCR-RFLP) analysis were evaluated using conventional PCR and Sanger sequencing genotyping as the gold standard. Sixty patient samples were tested, revealing seven patients (11.7%) heterozygous for NUDT15 c.415C>T, one patient homozygous for the variant and one patient heterozygous for the TPMT*3C non-function allele. No patient was found to harbor both variants. In total, nine out of 60 (15%) patients tested had genotypic evidence of thiopurine intolerance, which may require dosage adjustment or alternative medication should they be started on azathioprine, mercaptopurine or thioguanine. The two newly developed assays were more efficient and showed complete concordance (60/60, 100%) compared to the Sanger sequencing results. Accurate and cost-effective genotyping assays by real-time PCR-HRM and PCR-RFLP for NUDT15 c.415C>T and TPMT*3C were successfully developed. Further studies may establish their roles in genotype-informed clinical decision-making in the prevention of morbidity and mortality due to thiopurine intolerance.

Equivalence of intrathecal chemotherapy and radiotherapy as central nervous system prophylaxis in children with acute lymphatic leukemia: a pediatric oncology group study

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Sullivan, M.P. (M.D. Anderson Hospital and Tumor Inst., Houston, TX); Chen, T.; Dyment, P.G.; Hvizdala, E.; Steuber, C.P.

1982-10-01

The efficacy of intrathecal (i.t.) chemoprophylaxis was compared with cranial radiotherapy plus i.t. methotrexate (MTX) in a Southwest Oncology Group (SWOG) study accessing 408 patients from September 10, 1974, to October 29, 1976. Randomization was stratified by prognostic groups (PGs) based on age and white blood cell count at diagnosis. All received induction therapy with vincristine and prednisone (Pred); maintenance therapy consisted of daily 6-mercaptopurine and weekly MTX. Consolidation for arm 1 employed cyclophosphamide and L-asparaginase followed by biwekly 5-day courses of parenteral MTX. The first dose of each course of MTX was given i.t. in triple chemoprophylaxis (MTX, hydrocortisone, and cytosine arabinoside). During maintenance, i.t. chemoprophylaxis was bimonthly and 28-day Pred ''pulses'' were given every 3 mo. Arm 2 i.t. chemoprophylaxis was initiated on achievement of remission, and arm 3 i.t. on treatment day 1; both continued 1 yr. Arm 4 induction included two doses of L-asparaginase. On achievement of remission, CNS prophylaxis (radiotherapy, 2400 rad plus i.t. MTX) was given. For all, therapy was discontinued after 3 yr of continuous complete remission. Survival and the incidence of extramedullary relapse were similar for the treatment employing either i.t. chemoprophylaxis or radiotherapy plus i.t. MTX upon achievement of remission. The study indicates that i.t. chemoprophylaxis may be substituted for cranial radiotherapy when utilizing effective systemic regimens. Additionally, chemoprophylaxis may be reduced from 3 to 1 yr in patients with good prognostic factors. (JMT)

Managing refractory Crohn's disease: challenges and solutions

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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

Acute lymphoblastic leukemia: Are Egyptian children adherent to maintenance therapy?

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Elhamy Rifky Abdel Khalek

2015-01-01

Full Text Available Background, Aims, Settings and Design: Poor adherence to oral maintenance chemotherapy can cause relapse of acute lymphoblastic leukemia (ALL. A multicenter study for the evaluation of adherence to oral 6-mercaptopurine (6-MP maintenance chemotherapy for childhood ALL in Egypt to identify contributing factors and possible steps to promote adherence. Materials and Methods: The study included 129 children with ALL in complete remission receiving 6-MP single daily oral dose in the evening. Evaluation was done through specific questionnaires for the patients as well as serum 6-MP measurements. Results: Nonadherence was detected in around 56% by questionnaires and around 50% by serum 6-MP level measurement. There was a highly significant correlation between nonadherence as found by the questionnaire and 6-MP level (P - 0.001. Nonadherence was significantly associated with low socioeconomic standard, noneducation and low educational level and large family size by both methods. High cost to come for follow-up visits was significant by questionnaire but not by 6-MP measurement. Adolescent age, the higher number of siblings, lack of written instructions, long time spent per visit, were all associated with higher rates of nonadherence, although none reached statistical significance. Conclusions: Nonadherence is a real problem in pediatric patients. Specific questionnaires can be an excellent reliable method for the routine follow-up of these children, and drug level assay can be requested only for confirmation. This protocol is especially effective in developing countries where financial resources may be limited. Every effort should be made to uncover its true incidence, contributing factors, and best methods of intervention.

Decreased enzymatic activity of 5,10-methylene tetrahydrofolate reductase affects the development of several diseases

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Maša Vidmar

2016-07-01

Full Text Available The importance of folates in human physiology is well known, as are various pathologies associated with low folate status. Folate deficiency can occur due to low dietary intake, genetic predisposition or treatment with medicines affecting the folate status. The aim of this paper is to explore the importance of determining genetic polymorphisms which influence the levels of biologically active folate. MTHFR is involved in the transformation of 5,10-methylene-THF to 5-methyl-THF. Polymorphisms of the MTHRF gene are associated with decreased enzymatic activity.Only 9.3 % of the population in Slovenia displays full activity of the MTHFR enzyme; these subjects are non-mutated homozygotes (wild-type alleles. In contrast, the average enzymatic activity in subjects with mutated alleles is between 50 and 60 %. MTHFR polymorphism is associated with an increased risk of hyperhomocysteinemia and cardiovascular diseases, neurological disorders and various types of cancer. There is also an increased risk for congenital malformations. Folic acid food fortification was introduced in some countries in order to assure an adequate folate status in the population. However, this approach does not address the decreased activity of MTHFR.Polymorphism in the key enzymes of the folate cycle is common. Determination of the genetic predisposition is therefore plausible in the most vulnerable groups of the population, such as pregnant women and patients receiving medicines influencing the folate cycle in various ways, e.g. 5-fluorouracil, methotrexate and 6-mercaptopurine. Genotyping would allow the identification of patients at high risk for suboptimal folate status.

[Separation of purines, pyrimidines, pterins and flavonoids on magnolol-bonded silica gel stationary phase by high performance liquid chromatography].

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Chen, Hong; Li, Laishen; Zhang, Yang; Zhou, Rendan

2012-10-01

A new magnolol-bonded silica gel stationary phase (MSP) was used to separate the basic drugs including four purines, eight pyrimidines, four pterins and five flavonoids as polar representative samples by high performance liquid chromatography (HPLC). To clarify the separation mechanism, a commercial ODS column was also tested under the same chromatographic conditions. The high selectivities and fast baseline separations of the above drugs were achieved by using simple mobile phases on MSP. Although there is no end-caped treatment, the peak shapes of basic drugs containing nitrogen such as purines, pyrimidines and pterins were rather symmetrical on MSP, which indicated the the magnolol as ligand with multi-sites could shield the side effect of residual silanol groups on the surface of silica gel. Although somewhat different in the separation resolution, it was found that the elution orders of some drugs were generally similar on both MSP and ODS. The hydrophobic interaction should play a significant role in the separations of the above basic drugs, which was attributed to their reversed-phase property in the nature. However, MSP could provide the additional sites for many polar solutes, which was a rational explanation for the high selectivity of MSP. For example, in the separation of purines, pyrimidines and pterins on MSP, hydrogen-bonding and dipole-dipole interactions played leading roles besides hydrophobic interaction. Some solute molecules (such as mercaptopurine, vitexicarpin) and MSP can form the strong pi-pi stacking in the separation process. All enhanced the retention and improved the separation selectivity of MSP, which facilitated the separation of the basic drugs.

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

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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.

The effect of thiopurine drugs on DNA methylation in relation to TPMT expression.

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Hogarth, L A; Redfern, C P F; Teodoridis, J M; Hall, A G; Anderson, H; Case, M C; Coulthard, S A

2008-10-15

The thiopurine drugs 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) are well-established agents for the treatment of leukaemia but their main modes of action are controversial. Thiopurine methyltransferase (TPMT) metabolises thiopurine drugs and influences their cytotoxic activity. TPMT, like DNA methyltransferases (DNMTs), transfers methyl groups from S-adenosylmethionine (SAM) and generates S-adenosylhomocysteine (SAH). Since SAM levels are dependent on de novo purine synthesis (DNPS) and the metabolic products of 6-TG and 6-MP differ in their ability to inhibit DNPS, we postulated that 6-TG compared to 6-MP would have differential effects on changes in SAM and SAH levels and global DNA methylation, depending on TPMT status. To test this hypothesis, we used a human embryonic kidney cell line with inducible TPMT. Although changes in SAM and SAH levels occurred with each drug, decrease in global DNA methylation more closely reflected a decrease in DNMT activity. Inhibition was influenced by TPMT for 6-TG, but not 6-MP. The decrease in global methylation and DNMT activity with 6-MP, or with 6-TG when TPMT expression was low, were comparable to 5-aza-2'-deoxycytidine. However, this was not reflected in changes in methylation at the level of an individual marker gene (MAGE1A). The results suggest that a non-TPMT metabolised metabolite of 6-MP and 6-TG and the TPMT-metabolised 6-MP metabolite 6-methylthioguanosine 5'-monophosphate, contribute to a decrease in DNMT levels and global DNA methylation. As demethylating agents have shown promise in leukaemia treatment, inhibition of DNA methylation by the thiopurine drugs may contribute to their cytotoxic affects.

Thiopurine treatment in patients with Crohn's disease leads to a selective reduction of an effector cytotoxic gene expression signature revealed by whole-genome expression profiling.

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Bouma, G; Baggen, J M; van Bodegraven, A A; Mulder, C J J; Kraal, G; Zwiers, A; Horrevoets, A J; van der Pouw Kraan, C T M

2013-07-01

Crohn's disease (CD) is characterized by chronic inflammation of the gastrointestinal tract, as a result of aberrant activation of the innate immune system through TLR stimulation by bacterial products. The conventional immunosuppressive thiopurine derivatives (azathioprine and mercaptopurine) are used to treat CD. The effects of thiopurines on circulating immune cells and TLR responsiveness are unknown. To obtain a global view of affected gene expression of the immune system in CD patients and the treatment effect of thiopurine derivatives, we performed genome-wide transcriptome analysis on whole blood samples from 20 CD patients in remission, of which 10 patients received thiopurine treatment, compared to 16 healthy controls, before and after TLR4 stimulation with LPS. Several immune abnormalities were observed, including increased baseline interferon activity, while baseline expression of ribosomal genes was reduced. After LPS stimulation, CD patients showed reduced cytokine and chemokine expression. None of these effects were related to treatment. Strikingly, only one highly correlated set of 69 genes was affected by treatment, not influenced by LPS stimulation and consisted of genes reminiscent of effector cytotoxic NK cells. The most reduced cytotoxicity-related gene in CD was the cell surface marker CD160. Concordantly, we could demonstrate an in vivo reduction of circulating CD160(+)CD3(-)CD8(-) cells in CD patients after treatment with thiopurine derivatives in an independent cohort. In conclusion, using genome-wide profiling, we identified a disturbed immune activation status in peripheral blood cells from CD patients and a clear treatment effect of thiopurine derivatives selectively affecting effector cytotoxic CD160-positive cells. Copyright © 2013 Elsevier Ltd. All rights reserved.

Mutagenic and cytotoxic properties of 6-thioguanine, S6-methylthioguanine, and guanine-S6-sulfonic acid.

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Yuan, Bifeng; Wang, Yinsheng

2008-08-29

Thiopurine drugs, including 6-thioguanine ((S)G), 6-mercaptopurine, and azathioprine, are widely employed anticancer agents and immunosuppressants. The formation of (S)G nucleotides from the thiopurine prodrugs and their subsequent incorporation into nucleic acids are important for the drugs to exert their cytotoxic effects. (S)G in DNA can be methylated by S-adenosyl-l-methionine to give S(6)-methylthioguanine (S(6)mG) and oxidized by UVA light to render guanine-S(6)-sulfonic acid ((SO3H)G). Here, we constructed single-stranded M13 shuttle vectors carrying a (S)G, S(6)mG, or (SO3H)G at a unique site and allowed the vectors to propagate in wild-type and bypass polymerase-deficient Escherichia coli cells. Analysis of the replication products by using the competitive replication and adduct bypass and a slightly modified restriction enzyme digestion and post-labeling assays revealed that, although none of the three thionucleosides considerably blocked DNA replication in all transfected E. coli cells, both S(6)mG and (SO3H)G were highly mutagenic, which resulted in G-->A mutation at frequencies of 94 and 77%, respectively, in wild-type E. coli cells. Deficiency in bypass polymerases does not result in alteration of mutation frequencies of these two lesions. In contrast to what was found from previous steady-state kinetic analysis, our data demonstrated that 6-thioguanine is mutagenic, with G-->A transition occurring at a frequency of approximately 10%. The mutagenic properties of 6-thioguanine and its derivatives revealed in the present study offered important knowledge about the biological implications of these thionucleosides.

Tratamiento de la leucemia promielocítica con ácido transretinoico y quimioterapia intensiva: Evolución clínica y molecular Treatment of promyelocytic leukemia using transretinoic acid and intensive chemotherapy: Clinical and molecular progress

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Porfirio Hernández Ramírez

2002-08-01

Full Text Available Cuarenta y nueve pacientes con diagnóstico de leucemia promielocítica se trataron con ácido retinoico (45-50 mg/m2/día durante la inducción, después se hizo consolidación con rubidomicina y arabinósido de citosina, seguida de un matenimiento con 6 mercaptopurina y metotrexate durante 2,5 años. Se realizó un estudio evolutivo clínico hematológico y molecular. Cuarenta y tres pacientes lograron remisión completa (88 %; 9 (47 % de 19 enfermos, y 18 (90 % de 20, se encontraban en remisión molecular después de la inducción y la consolidación, respectivamente. La sobrevida global a los 5 años fue de 65 % ± 8 % y la sobrevida libre de evento fue 63 % ± 7 %. La sobrevida libre de enfermedad fue de 71 % ± 7 % en igual períodoForty nine patients diagnosed with promyelocytic leukemia were treated with retinoic acid (45-50 mg/m2/day during induction; afterwards, a consolidation therapy was applied with daunorubicin and arabinosylcitosine, followed by a maintenance therapy with 6 mercaptopurine and methotrexate for 2 years and a half. An evolving clinical, hematological and molecular study was performed. Forty three patients achieved complete remission (88%; 9 (47% of 19 patients and 18(90% of 20 patients had reached molecular remission after induction and consolidation respectively. Global survival rate at 5 years was 65%±8% and event-free survival rate was 63%±7%. Disease-free survival rate was 71%± 7% in the same period

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

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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.

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

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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. PMID:26226448

Zinc blocks SOS-induced antibiotic resistance via inhibition of RecA in Escherichia coli.

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Bunnell, Bryan E; Escobar, Jillian F; Bair, Kirsten L; Sutton, Mark D; Crane, John K

2017-01-01

Zinc inhibits the virulence of diarrheagenic E. coli by inducing the envelope stress response and inhibiting the SOS response. The SOS response is triggered by damage to bacterial DNA. In Shiga-toxigenic E. coli, the SOS response strongly induces the production of Shiga toxins (Stx) and of the bacteriophages that encode the Stx genes. In E. coli, induction of the SOS response is accompanied by a higher mutation rate, called the mutator response, caused by a shift to error-prone DNA polymerases when DNA damage is too severe to be repaired by canonical DNA polymerases. Since zinc inhibited the other aspects of the SOS response, we hypothesized that zinc would also inhibit the mutator response, also known as hypermutation. We explored various different experimental paradigms to induce hypermutation triggered by the SOS response, and found that hypermutation was induced not just by classical inducers such as mitomycin C and the quinolone antibiotics, but also by antiviral drugs such as zidovudine and anti-cancer drugs such as 5-fluorouracil, 6-mercaptopurine, and azacytidine. Zinc salts inhibited the SOS response and the hypermutator phenomenon in E. coli as well as in Klebsiella pneumoniae, and was more effective in inhibiting the SOS response than other metals. We then attempted to determine the mechanism by which zinc, applied externally in the medium, inhibits hypermutation. Our results show that zinc interferes with the actions of RecA, and protects LexA from RecA-mediated cleavage, an early step in initiation of the SOS response. The SOS response may play a role in the development of antibiotic resistance and the effect of zinc suggests ways to prevent it.

Zinc blocks SOS-induced antibiotic resistance via inhibition of RecA in Escherichia coli.

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Bryan E Bunnell

Full Text Available Zinc inhibits the virulence of diarrheagenic E. coli by inducing the envelope stress response and inhibiting the SOS response. The SOS response is triggered by damage to bacterial DNA. In Shiga-toxigenic E. coli, the SOS response strongly induces the production of Shiga toxins (Stx and of the bacteriophages that encode the Stx genes. In E. coli, induction of the SOS response is accompanied by a higher mutation rate, called the mutator response, caused by a shift to error-prone DNA polymerases when DNA damage is too severe to be repaired by canonical DNA polymerases. Since zinc inhibited the other aspects of the SOS response, we hypothesized that zinc would also inhibit the mutator response, also known as hypermutation. We explored various different experimental paradigms to induce hypermutation triggered by the SOS response, and found that hypermutation was induced not just by classical inducers such as mitomycin C and the quinolone antibiotics, but also by antiviral drugs such as zidovudine and anti-cancer drugs such as 5-fluorouracil, 6-mercaptopurine, and azacytidine. Zinc salts inhibited the SOS response and the hypermutator phenomenon in E. coli as well as in Klebsiella pneumoniae, and was more effective in inhibiting the SOS response than other metals. We then attempted to determine the mechanism by which zinc, applied externally in the medium, inhibits hypermutation. Our results show that zinc interferes with the actions of RecA, and protects LexA from RecA-mediated cleavage, an early step in initiation of the SOS response. The SOS response may play a role in the development of antibiotic resistance and the effect of zinc suggests ways to prevent it.

Increased PRPP synthetase activity in cultured rat hepatoma cells containing mutations in the hypoxanthine-guanine phosphoribosyltransferase gene.

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Graf, L H; McRoberts, J A; Harrison, T M; Martin, D W

1976-07-01

Nine independently derived clones of mutagenized rat hepatoma cells selected for resistance to 6-mercaptopurine (6-MP) or 6-thioguanine (6-ThioG) have been isolated. Each has severely reduced catalytic activity of hypoxanthine-guanine phosphoribosyltransferase (HPRT) and seven of them possess significantly increased activities of phosphoribosylpyrophosphate (PRPP) synthetase. The degrees of elevations of PRPP synthetase activities do not correlate with the degrees of deficiencies of HPRT activities. The cells from one of these clones, 1020/12, posses 40% of the normal HPRT catalytic activity and overproduce purines. We have extensively examined the cells from this clone. Immunotration studies of 1020/12 cells indicate that there is a mutation in the structural gene for HPRT. Although they possess increased specific catalytic activities of the enzyme. PRPP synthetase, the catalytic parameters, heat stability, and isoelectric pH of PRPP synthetase from 1020/12 cells are indistinguishable from those of the enzyme from wild-type cells. The cause of purine overproduction by 1020/12 cells appears to be the elevated PRPP synthetase activity, rather than a PRPP "sparing" effect stemming from reduced HPRT activity. Support for this idea is provided by the observation that the complete loss of HPRT activity in a clone derived from 1020/12 cells does not further enhance the levels of PRPP synthetase or purine overproduction. We propose that the elevated levels of PRPP synthetase activity in these HPRT deficient cells result from a mutational event in the structural gene for HPRT, and that this causes the disruption of a previously undescribed regulatory function of this gene on the expression of the PRPP synthetase gene.

Regulation of Nur77 protein turnover through acetylation and deacetylation induced by p300 and HDAC1.

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Kang, Shin-Ae; Na, Hyelin; Kang, Hyun-Jin; Kim, Sung-Hye; Lee, Min-Ho; Lee, Mi-Ock

2010-09-15

Although the roles of Nur77, an orphan member of the nuclear hormone receptor superfamily, in the control of cellular proliferation, apoptosis, inflammation, and glucose metabolism, are well recognized, the molecular mechanism regulating the activity and expression of Nur77 is not fully understood. Acetylation of transcription factors has emerged recently as a major post-translational modification that regulates protein stability and transcriptional activity. Here, we examined whether Nur77 is acetylated, and we characterized potential associated factors. First, Nur77 was found to be an acetylated protein when examined by immunoprecipitation and western blotting using acetyl protein-specific antibodies. Second, expression of p300, which possesses histone acetyltransferase activity, enhanced the acetylation and protein stability of Nur77. Treatment with a histone deacetylase (HDAC) inhibitor, trichostatin A, also increased Nur77 acetylation. Among the several types of HDACs, HDAC1 was found as the major enzyme affecting protein level of Nur77. HDAC1 decreased the acetylation level, protein level, and transcriptional activity of Nur77. Interestingly, overexpression of Nur77 induced expression of both p300 and HDAC1. Finally, the expression of Nur77 increased along with that of p300, but decreased with induction of HDAC1 after treatment with epithelial growth factor, nerve growth factor, or 6-mercaptopurine, suggesting that the self-control of the acetylation status contributes to the transient induction of Nur77 protein. Taken together, these results demonstrate that acetylation of Nur77 is modulated by p300 and HDAC1, and suggest that acetylation is an important post-translational modification for the rapid turnover of Nur77 protein. Copyright 2010 Elsevier Inc. All rights reserved.

Effects of pH, temperature, and chemical structure on the stability of S-(purin-6-yl)-L-cysteine: evidence for a novel molecular rearrangement mechanism to yield N-(purin-6-yl)-L-cysteine.

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Elfarra, A A; Hwang, I Y

1996-01-01

The stability of S-(purin-6-yl)-L-cysteine (SPC), a kidney-selective prodrug of 6-mercaptopurine and a putative metabolite of 6-chloropurine, was investigated under various pH and temperature conditions. At room temperature, the half-life (t 1/2) of SPC at either highly acidic (pH 3.6) or basic conditions (pH 9.6) was longer than at neutral or slightly acidic or basic conditions (pH 5.7-8.75). The primary degradation product, N-(purin-6-yl)-L-cysteine (NPC), was isolated using Sephadex LH-20 chromatography and characterized by 1H NMR and FAB/MS after derivatization with 2-iodoacetic acid. These results reveal novel stability requirements and implicate the cysteinyl amino group and the purinyl N-1 nitrogen in the mechanism of SPC rearrangement to NPC. Further evidence for this hypothesis was provided by the findings that the stability of SPC in phosphate buffer (pH 7.4) at 37 degrees C was similar to that of S-(guanin-6-yl)-L-cysteine, whereas S-(purin-6-yl)-N-acetyl-L-cysteine and S-(purin-6-yl)glutathione which have their cysteine amino groups blocked were much more stable than SPC. S-(Purin-6-yl)-L-homocysteine (SPHC) was also more stable than SPC, possibly because the formation of a 6-membered ring transition state as would be expected with SPHC is kinetically less favored than the formation of a 5-membered ring transition state as would be expected with SPC. These results may explain previous in vivo metabolism results of SPC and its analogs and may contribute to a better understanding of stability of structurally related cysteine S-conjugates.

Tolerability profile of thiopurines in inflammatory bowel disease: a prospective experience.

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Macaluso, Fabio Salvatore; Renna, Sara; Maida, Marcello; Dimarco, Mariangela; Sapienza, Chiara; Affronti, Marco; Orlando, Emanuele; Rizzuto, Giulia; Orlando, Rosalba; Ventimiglia, Marco; Cottone, Mario; Orlando, Ambrogio

2017-09-01

The occurrence of thiopurine-related adverse events (AEs) may complicate the management of patients with inflammatory bowel disease (IBD). We aimed to evaluate the tolerability of thiopurines in a current IBD setting. All consecutive patients who started a treatment with azathioprine (AZA) from January 2010 to March 2016 were entered in a prospectively maintained database, and the AEs which led to the permanent discontinuation of the drug were reported. Two hundred and fifty three patients were included. Median total follow-up was 32 months (range: 0.2-75 months). At the end of the study, AZA was discontinued in 160 patients (63.2%). The main reason leading to drug withdrawal was the occurrence of AEs (109/160 patients [68.1%]; cumulative incidence among the entire cohort: 43.1%). Overall, the most frequent AEs leading to treatment withdrawal were nausea (31/253 patients, 12.3%) and subjective symptoms, i.e., poorly defined side effects such as fatigue, headache and muscle pain (20/253 patients, 7.9%). Among the 109 AZA-intolerant patients, a switch to 6-mercaptopurine (6-MP) was performed in 44 cases (40.4%). At the end of follow-up, 6-MP was discontinued in 35/44 patients (79.5%), mostly due to AEs (29/35 patients, 82.8%). Azathioprine-induced hepatic and pancreatic toxicity was associated with male gender (p = .01 and p = .03, respectively), and occurrence of nausea with Crohn's disease (p = .04). Our real-life prospective cohort showed the higher cumulative incidence of thiopurine withdrawal due to AEs reported to date. Switching from AZA to 6-MP was often ineffective.

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

Gene set analysis of purine and pyrimidine antimetabolites cancer therapies.

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Fridley, Brooke L; Batzler, Anthony; Li, Liang; Li, Fang; Matimba, Alice; Jenkins, Gregory D; Ji, Yuan; Wang, Liewei; Weinshilboum, Richard M

2011-11-01

Responses to therapies, either with regard to toxicities or efficacy, are expected to involve complex relationships of gene products within the same molecular pathway or functional gene set. Therefore, pathways or gene sets, as opposed to single genes, may better reflect the true underlying biology and may be more appropriate units for analysis of pharmacogenomic studies. Application of such methods to pharmacogenomic studies may enable the detection of more subtle effects of multiple genes in the same pathway that may be missed by assessing each gene individually. A gene set analysis of 3821 gene sets is presented assessing the association between basal messenger RNA expression and drug cytotoxicity using ethnically defined human lymphoblastoid cell lines for two classes of drugs: pyrimidines [gemcitabine (dFdC) and arabinoside] and purines [6-thioguanine and 6-mercaptopurine]. The gene set nucleoside-diphosphatase activity was found to be significantly associated with both dFdC and arabinoside, whereas gene set γ-aminobutyric acid catabolic process was associated with dFdC and 6-thioguanine. These gene sets were significantly associated with the phenotype even after adjusting for multiple testing. In addition, five associated gene sets were found in common between the pyrimidines and two gene sets for the purines (3',5'-cyclic-AMP phosphodiesterase activity and γ-aminobutyric acid catabolic process) with a P value of less than 0.0001. Functional validation was attempted with four genes each in gene sets for thiopurine and pyrimidine antimetabolites. All four genes selected from the pyrimidine gene sets (PSME3, CANT1, ENTPD6, ADRM1) were validated, but only one (PDE4D) was validated for the thiopurine gene sets. In summary, results from the gene set analysis of pyrimidine and purine therapies, used often in the treatment of various cancers, provide novel insight into the relationship between genomic variation and drug response.

Human glutathione transferases catalyzing the bioactivation of anticancer thiopurine prodrugs.

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Eklund, Birgitta I; Gunnarsdottir, Sjofn; Elfarra, Adnan A; Mannervik, Bengt

2007-06-01

cis-6-(2-Acetylvinylthio)purine (cAVTP) and trans-6-(2-acetylvinylthio)guanine (tAVTG) are thiopurine prodrugs provisionally inactivated by an alpha,beta-unsaturated substituent on the sulfur of the parental thiopurines 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG). The active thiopurines are liberated intracellularly by glutathione (GSH) in reactions catalyzed by glutathione transferases (GSTs) (EC 2.5.1.18). Catalytic activities of 13 human GSTs representing seven distinct classes of soluble GSTs have been determined. The bioactivation of cAVTP and tAVTG occurs via a transient addition of GSH to the activated double bond of the S-substituent of the prodrug, followed by elimination of the thiopurine. The first of these consecutive reactions is rate-limiting for thiopurine release, but GST-activation of this first addition is shifting the rate limitation to the subsequent elimination. Highly active GSTs reveal the transient intermediate, which is detectable by UV spectroscopy and HPLC analysis. LC/MS analysis of the reaction products demonstrates that the primary GSH conjugate, 4-glutathionylbuten-2-one, can react with a second GSH molecule to form the 4-(bis-glutathionyl)butan-2-one. GST M1-1 and GST A4-4 were the most efficient enzymes with tAVTG, and GST M1-1 and GST M2-2 had highest activity with cAVTP. The highly efficient GST M1-1 is polymorphic and is absent in approximately half of the human population. GST P1-1, which is overexpressed in many cancer cells, had no detectable activity with cAVTP and only minor activity with tAVTG. Other GST-activated prodrugs have targeted GST P1-1-expressing cancer cells. Tumors expressing high levels of GST M1-1 or GST A4-4 can be predicted to be particularly vulnerable to chemotherapy with cAVTP or tAVTG.

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

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Toshiyuki Sato

2017-07-01

Full Text Available Background/Aims: 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.Methods: One hundred sixty thiopurine-treated patients with IBD were enrolled. Genotyping was performed using TaqMan SNP Genotyping Assays or Sanger sequencing.Results: 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.Conclusions: 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.

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

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Schmiegelow, Kjeld; Nersting, Jacob; Nielsen, Stine Nygaard; Heyman, Mats; Wesenberg, Finn; Kristinsson, Jon; Vettenranta, Kim; Schrøeder, Henrik; Weinshilboum, Richard; Jensen, Katrine Lykke; Grell, Kathrine; Rosthoej, Susanne

2016-12-01

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 dose adjustment guidelines. To identify relapse predictors, we collected 28,255 data sets on drug doses and blood counts (median: 47/patient) and analyzed erythrocyte (Ery) levels of cytotoxic 6MP/MTX metabolites in 9,182 blood samples (median: 14 samples/patient) from 532 children on MTX/6MP maintenance therapy targeted to a white blood cell count (WBC) of 1.5-3.5 × 10 9 /l. After a median follow-up of 13.8 years for patients in remission, stepwise Cox regression analysis did not find age, average doses of 6MP and MTX, hemoglobin, absolute lymphocyte counts, thrombocyte counts, or Ery levels of 6-thioguanine nucleotides or MTX (including its polyglutamates) to be significant relapse predictors. The parameters significantly associated with risk of relapse (N = 83) were male sex (hazard ratio [HR] 2.0 [1.3-3.1], P = 0.003), WBC at diagnosis (HR = 1.04 per 10 × 10 9 /l rise [1.00-1.09], P = 0.048), the absolute neutrophil count (ANC; HR = 1.7 per 10 9 /l rise [1.3-2.4], P = 0.0007), and Ery thiopurine methyltransferase activity (HR = 2.7 per IU/ml rise [1.1-6.7], P = 0.03). WBC was significantly related to ANC (Spearman correlation coefficient, r s  = 0.77; P best hematological target for dose adjustments of maintenance therapy. © 2016 Wiley Periodicals, Inc.

Optimal chemotherapy for leukemia: a model-based strategy for individualized treatment.

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Devaraj Jayachandran

Full Text Available Acute Lymphoblastic Leukemia, commonly known as ALL, is a predominant form of cancer during childhood. With the advent of modern healthcare support, the 5-year survival rate has been impressive in the recent past. However, long-term ALL survivors embattle several treatment-related medical and socio-economic complications due to excessive and inordinate chemotherapy doses received during treatment. In this work, we present a model-based approach to personalize 6-Mercaptopurine (6-MP treatment for childhood ALL with a provision for incorporating the pharmacogenomic variations among patients. Semi-mechanistic mathematical models were developed and validated for i 6-MP metabolism, ii red blood cell mean corpuscular volume (MCV dynamics, a surrogate marker for treatment efficacy, and iii leukopenia, a major side-effect. With the constraint of getting limited data from clinics, a global sensitivity analysis based model reduction technique was employed to reduce the parameter space arising from semi-mechanistic models. The reduced, sensitive parameters were used to individualize the average patient model to a specific patient so as to minimize the model uncertainty. Models fit the data well and mimic diverse behavior observed among patients with minimum parameters. The model was validated with real patient data obtained from literature and Riley Hospital for Children in Indianapolis. Patient models were used to optimize the dose for an individual patient through nonlinear model predictive control. The implementation of our approach in clinical practice is realizable with routinely measured complete blood counts (CBC and a few additional metabolite measurements. The proposed approach promises to achieve model-based individualized treatment to a specific patient, as opposed to a standard-dose-for-all, and to prescribe an optimal dose for a desired outcome with minimum side-effects.

Patient Safety in Medication Nomenclature: Orthographic and Semantic Properties of International Nonproprietary Names.

Directory of Open Access Journals (Sweden)

Rachel Bryan

Full Text Available Confusion between look-alike and sound-alike (LASA medication names (such as mercaptamine and mercaptopurine accounts for up to one in four medication errors, threatening patient safety. Error reduction strategies include computerized physician order entry interventions, and 'Tall Man' lettering. The purpose of this study is to explore the medication name designation process, to elucidate properties that may prime the risk of confusion.We analysed the formal and semantic properties of 7,987 International Non-proprietary Names (INNs, in relation to naming guidelines of the World Health Organization (WHO INN programme, and have identified potential for errors. We explored: their linguistic properties, the underlying taxonomy of stems to indicate pharmacological interrelationships, and similarities between INNs. We used Microsoft Excel for analysis, including calculation of Levenshtein edit distance (LED. Compliance with WHO naming guidelines was inconsistent. Since the 1970s there has been a trend towards compliance in formal properties, such as word length, but longer names published in the 1950s and 1960s are still in use. The stems used to show pharmacological interrelationships are not spelled consistently and the guidelines do not impose an unequivocal order on them, making the meanings of INNs difficult to understand. Pairs of INNs sharing a stem (appropriately or not often have high levels of similarity (<5 LED, and thus have greater potential for confusion.We have revealed a tension between WHO guidelines stipulating use of stems to denote meaning, and the aim of reducing similarities in nomenclature. To mitigate this tension and reduce the risk of confusion, the stem system should be made clear and well ordered, so as to avoid compounding the risk of confusion at the clinical level. The interplay between the different WHO INN naming principles should be further examined, to better understand their implications for the problem of LASA

Surface-enhanced Raman spectroscopy based on conical holed enhancing substrates

International Nuclear Information System (INIS)

Chen, Yao; Chen, Zeng-Ping; Zuo, Qi; Shi, Cai-Xia; Yu, Ru-Qin

2015-01-01

In this contribution, surface-enhanced Raman spectroscopy (SERS) based on conical holed glass substrates deposited with silver colloids was reported for the first time. It combines the advantages of both dry SERS assays based on plane films deposited with silver colloids and wet SERS assays utilizing cuvettes or capillary tubes. Compared with plane glass substrates deposited with silver colloids, the conical holed glass substrates deposited with silver colloids exhibited five-to ten-folds of increase in the rate of signal enhancement, due to the internal multiple reflections of both the excitation laser beam and the Raman scattering photons within conical holes. The application of conical holed glass substrates could also yield significantly stronger and more reproducible SERS signals than SERS assays utilizing capillary tubes to sample the mixture of silver colloids and the solution of the analyte of interest. The conical holed glass substrates in combination with the multiplicative effects model for surface-enhanced Raman spectroscopy (MEM SERS ) achieved quite sensitive and precise quantification of 6-mercaptopurine in complex plasma samples with an average relative prediction error of about 4% and a limit of detection of about 0.02 μM using a portable i-Raman 785H spectrometer. It is reasonable to expect that SERS technique based on conical holed enhancing substrates in combination with MEM SERS model can be developed and extended to other application areas such as drug detection, environmental monitoring, and clinic analysis, etc. - Highlights: • A novel conical holed SERS enhancing substrate was designed and manufactured. • The optimal conical holed glass substrates can produce stronger SERS signal. • The novel substrates can overcome the shortcomings of both dry and wet methods. • The novel substrates coupled with MEM SERS can realize quantitative SERS assays

Orphan nuclear receptor Nur77 is a novel negative regulator of endothelin-1 expression in vascular endothelial cells.

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Qin, Qing; Chen, Ming; Yi, Bing; You, Xiaohua; Yang, Ping; Sun, Jianxin

2014-12-01

Endothelin-1 (ET-1) produced by vascular endothelial cells plays essential roles in the regulation of vascular tone and development of cardiovascular diseases. The objective of this study is to identify novel regulators implicated in the regulation of ET-1 expression in vascular endothelial cells (ECs). By using quantitative real-time PCR (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA), we show that either ectopic expression of orphan nuclear receptor Nur77 or pharmacological activation of Nur77 by 6-mercaptopurine (6-MP) substantially inhibits ET-1 expression in human umbilical vein endothelial cells (HUVECs), under both basal and thrombin-stimulated conditions. Furthermore, thrombin-stimulated ET expression is significantly augmented in both Nur77 knockdown ECs and aort from Nur77 knockout mice, suggesting that Nur77 is a negative regulator of ET-1 expression. Inhibition of ET-1 expression by Nur77 occurs at gene transcriptional levels, since Nur77 potently inhibits ET-1 promoter activity, without affecting ET-1 mRNA stability. As shown in electrophoretic mobility shift assay (EMSA), Nur77 overexpression markedly inhibits both basal and thrombin-stimulated transcriptional activity of AP-1. Mechanistically, we demonstrate that Nur77 specially interacts with c-Jun and inhibits AP-1 dependent c-Jun promoter activity, which leads to a decreased expression of c-Jun, a critical component involved in both AP-1 transcriptional activity and ET-1 expression in ECs. These findings demonstrate that Nur77 is a novel negative regulator of ET-1 expression in vascular ECs through an inhibitory interaction with the c-Jun/AP-1 pathway. Activation of Nur77 may represent a useful therapeutic strategy for preventing certain cardiovascular diseases, such as atherosclerosis and pulmonary artery hypertension. Copyright © 2014 Elsevier Ltd. All rights reserved.

Inflammatory bowel diseases (IBD) - critical discussion of etiology, pathogenesis, diagnostics, and therapy

International Nuclear Information System (INIS)

Ochsenkuehn, T.; Sackmann, M.; Goeke, B.

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 rather be adapted to the

CoMFA and CoMSIA 3D-QSAR studies on S(6)-(4-nitrobenzyl)mercaptopurine riboside (NBMPR) analogs as inhibitors of human equilibrative nucleoside transporter 1 (hENT1).

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Gupte, Amol; Buolamwini, John K

2009-01-15

3D-QSAR (CoMFA and CoMSIA) studies were performed on human equlibrative nucleoside transporter (hENT1) inhibitors displaying K(i) values ranging from 10,000 to 0.7nM. Both CoMFA and CoMSIA analysis gave reliable models with q2 values >0.50 and r2 values >0.92. The models have been validated for their stability and robustness using group validation and bootstrapping techniques and for their predictive abilities using an external test set of nine compounds. The high predictive r2 values of the test set (0.72 for CoMFA model and 0.74 for CoMSIA model) reveals that the models can prove to be a useful tool for activity prediction of newly designed nucleoside transporter inhibitors. The CoMFA and CoMSIA contour maps identify features important for exhibiting good binding affinities at the transporter, and can thus serve as a useful guide for the design of potential equilibrative nucleoside transporter inhibitors.

Inhibition of thiopurine S-methyltransferase activity by impurities in commercially available substrates: a factor for differing results of TPMT measurements.

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Kröplin, T; Fischer, C; Iven, H

1999-06-01

Thiopurine S-methyltransferase (TPMT) activity, when measured in red blood cells (RBC) with a recently published TPMT activity assay using 6-thioguanine (6-TG) as substrate, could not be reproduced in another laboratory. We investigated factors which could influence the results of the TPMT activity measurement. We tested twelve 6-TG and four 6-mercaptopurine (6-MP) compounds from different suppliers as substrates and determined the enzyme kinetic parameters Km and Vmax. Furthermore, we studied the influence of different 6-TG compounds on the affinity of the methyl donor S-adenosyl-L-methionine (SAM) to the TPMT enzyme. All 6-TG products were of equal purity (declared >98% by the supplier): this was ascertained by HPLC. However, the rate of methylation obtained following incubation with 6-TG from different suppliers ranged from 10% to 100% when incubated with the same RBC lysate. The lowest apparent Km value for a 6-TG was 22.3 micromol x l(-1), while the product with the highest methylation rate showed a Km of 156 micromol x l(-1). From these results we assume that there is a contaminant in some 6-TG products, which acts as a strong inhibitor of TPMT activity. Compounds possibly used for the synthesis of 6-TG (guanine, pyridine, 6-chloroguanine) did not affect the methylation rate. Thioxanthine, which is known to be a strong inhibitor of TPMT when added to the assay system to give a 2% contamination, reduced TPMT activity from 100% to 72%. Using 6-MP from different suppliers as substrate resulted in Km values ranging from 110 to 162 micromol x l(-1) and Vmox values ranging from 54 to 68 nmol 6-MMP x g(-1)Hb x h(-1). The Km value for the methyl donor SAM was similar to and independent from the thiopurine substrates tested (range 4.9-11 micromol-l(-1) SAM). In contrast to other investigators, we found non-enzymatic S-methylation, which was negligible under our assay conditions (3% with 128 micromol x l(-1) SAM), but could become relevant in experiments using higher

Improved outcome for children with acute lymphoblastic leukemia after risk-adjusted intensive therapy: a single institution experience

International Nuclear Information System (INIS)

Al-Nasser, A.; El-Solh, H.; Al-Mahr, M.

2008-01-01

Because of need for more comprehensive information on the least toxic and most effective forms of therapy for children with acute lymphoblastic leukemia (ALL), we reviewed our experience in the treatment of children with ALL at King Faisal Specialist Hospital and Research Centre (KFSHRC) and King Fahd National Center for Children's Cancer and Research (KFNCCCR) over a period of 18 years with a focus on patient characteristics and outcome. During the period of 1981 to 1988, records of children with ALL were retrospectively reviewed with respect to clinical presentation, laboratory findings, risk factors, stratification, therapy and outcome. The protocols used in treatment included 4 local protocols (KFSH 81, 84, 87 and 90) and subsequently. Children's Cancer Group (CCG) protocols and these were grouped as Era (1981-1992) and Era 2 (1993-1998). Of 509 children with ALL treated during this period, 316 were treated using local protocols and 193 using CCG protocols. Drugs used in Era 1 included a 4-drug induction using etoposid (VP-16) instead of L-asparaginase. Consolidation was based on high dose methotexate (MTX) 1g/m2 and maintenance was based on oral mercaptopurine (6-MP) and MTX with periodic pulses using intravenous teniposide (VM-26), Ara-C, L-asparaginase, adriamycin, prednisone, VP-16 cyclophosphamide .International protocols were introduced in Era 2, which was also marked by intensification of early treatment, a wider selection of cytoreductive agents, and the alternating use of non-cross-resistant pairs of drugs using the post-remission period. The end of induction remission rate improved from 90% in Era 1 to 95% in Era 2, which was of borderline statistical significance (P=0.49). The 5-year event-free survival (EFS) improved from 30.6% in Era 1 to 64.2% in Era 2 (P<.001). Improvement in outcome was achieved without any significant increase in morbidity or mortality, due to improvement in both systemic therapy and supportive care. The most important

Propionyl-L-carnitine hydrochloride for treatment of mild to moderate colonic inflammatory bowel diseases.

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Merra, Giuseppe; Gasbarrini, Giovanni; Laterza, Lucrezia; Pizzoferrato, Marco; Poscia, Andrea; Scaldaferri, Franco; Arena, Vincenzo; Fiore, Francesca; Cittadini, Achille; Sgambato, Alessandro; Franceschi, Francesco; Gasbarrini, Antonio

2012-09-28

To assess clinical and endoscopic response to propionyl-L-carnitine hydrochloride (PLC) in colonic inflammatory bowel disease. Patients suffering from mild to moderate ulcerative colitis (UC) or Crohn's disease (CD) colitis, with disease activity index (DAI) between 3 and 10 and under stable therapy with oral aminosalicylates, mercaptopurine or azathioprine, for at least 8 wk prior to baseline assessments, were considered suitable for enrollment. Fourteen patients were enrolled to assume PLC 2 g/d (two active tablets twice daily) orally. Clinical-endoscopic and histological activity were assessed by DAI and histological index (HI), respectively, following a colonoscopy performed immediately before and after 4 wk treatment. Clinical response was defined as a lowering of at least 3 points in DAI and clinical remission as a DAI score ≤ 2. Histological response was defined as an improvement of HI of at least 1 point. We used median values for the analysis. Differences pre- and post-treatment were analyzed by Wilcoxon signed rank test. All patients enrolled completed the study. One patient, despite medical advice, took deflazacort 5 d before follow-up colonoscopy examination. No side effects were reported by patients during the trial. After treatment, 71% (SE 12%) of patients achieved clinical response, while 64% (SE 13%) obtained remission. Separating UC from CD patients, we observed a clinical response in 60% (SE 16%) and 100%, respectively. Furthermore 60% (SE 16%) of UC patients and 75% (SE 25%) of CD patients were in clinical remission after therapy. The median DAI was 7 [interquartile range (IQR): 4-8] before treatment and decreased to 2 (IQR: 1-3) (P stability; none showed HI worsening. Median HI decreased from 1 (IQR: 1-2), to 0.5 (IQR: 0-1) at the endoscopic control in the whole population (P < 0.01), while it changed from 1 (IQR: 1-2) to 0.5 (IQR: 0-1) in UC patients (P < 0.01) and from 1.5 (IQR: 1-2) to 0.5 (IQR: 0-1) in CD patients (P = not significant

Non-detectable levels of 6-thioguanine nucleotides and 6-methylmercaptopurine in a patient treated with azathioprine: a case report

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Wong, D R; den Dulk, M O; Derijks, L J J; Gemmeke, E H K M; Hooymans, P M

2007-01-01

Introduction: Azathioprine (AZA) is a thiopurine prodrug clinically used for immunosuppression in the treatment of auto-immune inflammatory diseases and in regimens of organ transplantations. The pharmacological action of AZA is based on the formation of 6-mercaptopurine (6-MP), which is metabolised into a variety of active thiopurine-nucleotide metabolites. We report the case of a 55 year old woman (bodyweight 30 kg) with chronic pancreatitis, weight loss, and progressive elevation of liver transaminases and serum amylase. Case description: The woman was treated with prednisolone (30 mg 1 dd; tapered 5 mg each week) and AZA (75 mg 1 dd; 5 weeks later 150 mg 1 dd). Despite good patient-compliance verified during hospital-stay, none of the active metabolites of AZA, 6-thioguanine-nucleotides (6TGN) and 6-methylmercaptopurine ribonucleotides (6MMPR), were detected in erythrocytes. After two months of treatment clinical improvement was achieved, but no normalisation of laboratory parameters. Subsequently, AZA was switched to 6-MP 75 mg 1 dd, and allopurinol 100 mg 1 dd was added. After one week the 6TGN level was 616 pmol/ 8 × 108 red blood cells (RBC), the 6MMPR level was 1319 pmol/ 8 × 108 RBC. Two weeks later the 6TGN level was 1163 pmol/ 8 × 108 RBC and the 6MMPR level 10015 pmol/ 8 × 108 RBC. These 6TGN and 6MMPR levels were higher than the upper limits of the therapeutic ranges (500 pmol/ 8 × 108 RBC and 5700 pmol/ 8 × 108 RBC, respectively). Therefore, treatment with 6-MP was discontinued. A week later the 6TGN and 6MMPR levels decreased to 686 pmol/ 8 × 108 RBC and 4027 pmol/ 8 × 108 RBC, respectively. Genotyping of the enzym thiopurine S-methyl transferase (TPMT) revealed a wild-type TPMT (*1/*1) genotype. Discussion: To our knowledge this is the first report of a patient who was not able to form detectable active thiopurine metabolites on the treatment with AZA. AZA is normally rapidly and almost completely converted to 6-MP and methylnitroimidazole

Use of arsenic trioxide in remission induction and consolidation therapy for acute promyelocytic leukaemia in the Australasian Leukaemia and Lymphoma Group (ALLG) APML4 study: a non-randomised phase 2 trial.

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Iland, Harry J; Collins, Marnie; Bradstock, Ken; Supple, Shane G; Catalano, Alberto; Hertzberg, Mark; Browett, Peter; Grigg, Andrew; Firkin, Frank; Campbell, Lynda J; Hugman, Amanda; Reynolds, John; Di Iulio, Juliana; Tiley, Campbell; Taylor, Kerry; Filshie, Robin; Seldon, Michael; Taper, John; Szer, Jeff; Moore, John; Bashford, John; Seymour, John F

2015-09-01

Initial treatment of acute promyelocytic leukaemia traditionally involves tretinoin (all-trans retinoic acid) combined with anthracycline-based risk-adapted chemotherapy, with arsenic trioxide being the treatment of choice at relapse. To try to reduce the relapse rate, we combined arsenic trioxide with tretinoin and idarubicin in induction therapy, and used arsenic trioxide with tretinoin as consolidation therapy. Patients with previously untreated genetically confirmed acute promyelocytic leukaemia were eligible for this study. Eligibilty also required Eastern Cooperative Oncology Group performance status 0-3, age older than 1 year, normal left ventricular ejection fraction, Q-Tc interval less than 500 ms, absence of serious comorbidity, and written informed consent. Patients with genetic variants of acute promyelocytic leukaemia (fusion of genes other than PML with RARA) were ineligible. Induction comprised 45 mg/m(2) oral tretinoin in four divided doses daily on days 1-36, 6-12 mg/m(2) intravenous idarubicin on days 2, 4, 6, and 8, adjusted for age, and 0·15 mg/kg intravenous arsenic trioxide once daily on days 9-36. Supportive therapy included blood products for protocol-specified haemostatic targets, and 1 mg/kg prednisone daily as prophylaxis against differentiation syndrome. Two consolidation cycles with tretinoin and arsenic trioxide were followed by maintenance therapy with oral tretinoin, 6-mercaptopurine, and methotrexate for 2 years. The primary endpoints of the study were freedom from relapse and early death (within 36 days of treatment start) and we assessed improvement compared with the 2 year interim results. To assess durability of remission we compared the primary endpoints and disease-free and overall survival at 5 years in APML4 with the 2 year interim APML4 data and the APML3 treatment protocol that excluded arsenic trioxide. This study is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12605000070639. 124

A comprehensive review and update on Crohn's disease.

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Gajendran, Mahesh; Loganathan, Priyadarshini; Catinella, Anthony P; Hashash, Jana G

2018-02-01

) enterography is the most preferred first-line radiologic study used in the assessment of small bowel CD. The diagnostic accuracy of magnetic resonance enterography/enteroclysis is similar to that of CT scans and also prevents exposure to ionizing radiation. Endoscopic scores are considered to be the gold standard tool to measure the activity of CD and they are used more commonly in the clinical trials to measure the efficacy of various drugs on inducing and maintaining mucosal healing. The most common scoring systems used to measure clinical disease activity include Crohn's Disease Activity Index (CDAI), HBI- Harvey-Bradshaw index (HBI), short inflammatory bowel disease questionnaire (SIBDQ) and Lehmann score. Management of Crohn's disease has been seen as an evolving challenge owing to its widely heterogeneous manifestations, overlapping characteristics with other inflammatory disorders, often elusive extraintestinal manifestations and uncertain etiology. Therapeutic interventions are tailored to address symptomatic response and subsequent tolerance of the intervention. Chronology of treatment should favor treatment dose acute disease or "induction therapy", followed by maintenance of adequate response or remission, i.e. "maintenance therapy". The medications which are highly effective in inducing remission include steroids and Tumor Necrosis Factor (TNF) inhibitors. Medications used to maintain remission include 5-aminosalicyclic acid products, immunomodulators (Azathioprine, 6-mercaptopurine, methotrexate) and TNF inhibitors (infliximab, adalimumab, certolizumab and golimumab). Surgical interventions like bowel resection, stricturoplasty or drainage of abscess is required in up to two thirds of CD patients during their lifetime. The most common indications for surgical resection are medically refractory disease, perforation, persisting or recurrent obstruction, abscess not amenable to percutaneous drainage, intractable hemorrhage, dysplasia or cancer. Endoscopic recurrence