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1.
World J Gastroenterol ; 27(38): 6348-6356, 2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34720526

RESUMO

Thiopurines are immunomodulators used in the treatment of acute lymphoblastic leukemia and inflammatory bowel diseases. Adverse reactions to these agents are one of the main causes of treatment discontinuation or interruption. Myelosuppression is the most frequent adverse effect; however, approximately 5%-20% of patients develop gastrointestinal toxicity. The identification of biomarkers able to prevent and/or monitor these adverse reactions would be useful for clinicians for the proactive management of long-term thiopurine therapy. In this editorial, we discuss evidence supporting the use of PACSIN2, RAC1, and ITPA genes, in addition to TPMT and NUDT15, as possible biomarkers for thiopurine-related gastrointestinal toxicity.


Assuntos
Mercaptopurina , Pirofosfatases , Azatioprina/efeitos adversos , Biomarcadores , Humanos , Fatores Imunológicos , Mercaptopurina/efeitos adversos , Metiltransferases/genética
2.
Int J Nanomedicine ; 16: 6937-6955, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34703223

RESUMO

Background: 6-Mercaptopurine (6-MP) is a potential anti-cancer agent which its therapeutic and limitation applicability due to its high toxicity. Objective: Herein, 6-MP was loaded into tri-layered sandwich nanofibrous scaffold (the top layer composed of poly methyl methacrylate/polycaprolactone (PMMA/PCL), the middle layer was PCL/PMMA/6-MP, and the bottom layer was PCL/PMMA to improve its bioactivity, adjusting the release-sustainability and reduce its toxicity. Methods: Electrospun tri-layered nanofibers composed of PCL/PMMA were utilized as nano-mats for controlling sustained drug release. Four groups of sandwich scaffold configurations were investigated with alteration of (PMMA: PCL) composition. Results: The sandwich scaffold composed of 2%PCL/4%PMMA/1%6-MP showed the best miscibility, good homogeneity and produced the smoothest nanofibers and low crystallinity. All fabricated 6-MP-loaded-PCL/PMMA scaffolds exhibited antimicrobial properties on the bacterial and fungal organisms, where the cytotoxicity evaluation proved the safety of scaffolds on normal cells, even at high concentration. Scaffolds provided a sustained-drug release profile that was strongly dependent on (PCL: PMMA). As (PCL: PMMA) decreased, the sustained 6-MP release from PCL/PMMA scaffolds increased. Results established that ~18% and 20% of 6-MP were released after 23h from (4%PCL/4%PMMA/1%6-MP) and (2%PCL/4%PMMA/1%6-MP), respectively, where this release was maintained for more than 20 days. The anti-cancer activity of all fabricated scaffolds was also investigated using different cancerous cell lines (e.g., Caco-2, MDA, and HepG-2) results showed that 6-MP-loaded-nanofibrous mats have an anti-cancer effect, with a high selective index for breast cancer. We observed that viability of a cancer cell was dropped to about 10%, using nanofibers containing 2%PCL/4%PMMA/1%6-MP. Conclusion: Overall, the PCL: PMMA ratio and sandwich configuration imparts a tight control on long-term release profile and initial burst of 6-MP for anticancer treatment purposes.


Assuntos
Anti-Infecciosos , Nanofibras , Antibacterianos , Células CACO-2 , Humanos , Mercaptopurina , Poliésteres , Polimetil Metacrilato , Engenharia Tecidual , Tecidos Suporte
3.
Ther Drug Monit ; 43(5): 617-623, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34521801

RESUMO

BACKGROUND: In inflammatory bowel disease (IBD), conventional thiopurine users cease treatment in 60% of cases within 5 years, mostly because of adverse events or nonresponse. In this study, the authors aimed to investigate the role of 6-thioguanine nucleotide (TGN) measurements, geno/phenotyping of thiopurine S-methyltransferase (TPMT), and their mutual relationship with TG therapy in IBD. METHODS: An international retrospective, multicenter cohort study was performed at 4 centers in the Netherlands (Máxima Medical Centre) and the United Kingdom (Guy's and St. Thomas' Hospital, Queen Elizabeth Hospital, and East Surrey Hospital). RESULTS: Overall, 526 6-TGN measurements were performed in 316 patients with IBD. The median daily dosage of TG was 20 mg/d (range 10-40 mg/d), and the median duration of TG use was 21.1 months (SD, 28.0). In total, 129 patients (40.8%) had a known TPMT status. In the variant-type and wild-type TPMT genotype metabolism groups, median 6-TGN values were 1126 [interquartile range (IQR) 948-1562] and 467.5 pmol/8 × 10E8 red blood cells (RBCs) (IQR 334-593). A significant difference was observed between the 2 groups (P = 0.0001, t test). For TPMT phenotypes, in the slow, fast, and normal metabolism groups, the median 6-TGN values were 772.0 (IQR 459-1724), 296.0 (IQR 200-705), and 774.5 pmol/8 × 10E8 RBCs (IQR 500.5-981.5), with a significant difference observed between groups (P < 0.001, analysis of variance). CONCLUSIONS: Our findings indicated that TPMT measurements at TG initiation can be useful but are not necessary for daily practice. TPMT genotypes and phenotypes are both associated with significant differences in 6-TGN levels between metabolic groups. However, the advantage of TG remains that RBC 6-TGN measurements are not crucial to monitor treatments in patients with IBD because these measurements did not correlate with laboratory result abnormalities. This presents as a major advantage in countries where patients cannot access these diagnostic tests.


Assuntos
Imunossupressores , Doenças Inflamatórias Intestinais , Metiltransferases , Tioguanina , Adulto , Azatioprina , Feminino , Genótipo , Nucleotídeos de Guanina , Humanos , Imunossupressores/farmacocinética , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/genética , Masculino , Mercaptopurina , Metiltransferases/genética , Pessoa de Meia-Idade , Fenótipo , Estudos Retrospectivos , Tioguanina/farmacocinética , Tionucleotídeos
4.
Aliment Pharmacol Ther ; 54(9): 1124-1133, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34563096

RESUMO

INTRODUCTION: Thiopurine S-methyltransferase (TPTM) is a well known biomarker for thiopurine-induced leucopenia, which has limited value in Asia. Instead, NUDT15 C415T is a promising predictor in Asia. AIMS: To explore whether an optimised strategy based on NUDT15 C415T genotypes affects thiopurine-induced leucopenia, as well as efficacy in Chinese patients with Crohn's disease. METHODS: Patients with Crohn's disease and indications for thiopurines were included from two hospitals in China. They were randomly assigned to either the intervention or the control group. In the intervention group, those with genotype CC received a standard dose (control group), those with CT genotype received 50% of the standard dose, those with TT genotype received alternative drugs. The primary endpoint was thiopurine-induced leucopenia (<3.5 × 109 /L). Secondary outcomes were the incidence of other adverse events and the efficacy for maintaining steroid-free remission at week 36. RESULTS: The rate of thiopurine-induced leucopenia was lower in the intervention group (n = 52) than in the control group (n = 66) (23.7% vs 32.4%, P = 0.049, RR = 0.73, 95% CI 0.53-1.00). In CT subgroup, the incidence of leucopenia in the intervention group (n = 10) was significantly lower than in the control group (n = 28) (31.3% vs 65.1%, RR = 0.48, 95% CI 0.28-0.84). Neither other adverse events nor treatment efficacy was significantly different between the two groups during follow-up. CONCLUSIONS: Among Chinese patients with Crohn's disease, dose optimisation by NUDT15 C415T reduced the rate of thiopurine-induced leucopenia, without significant influence on efficacy. Using 50% dose reduction for heterozygotes, and alternative drugs for homozygotes, are practicable strategies. Clinical trial number: NCT02929706.


Assuntos
Anemia , Doença de Crohn , Leucopenia , Azatioprina , Doença de Crohn/tratamento farmacológico , Doença de Crohn/genética , Genótipo , Humanos , Leucopenia/induzido quimicamente , Mercaptopurina/efeitos adversos , Pirofosfatases/genética
6.
Expert Opin Drug Metab Toxicol ; 17(10): 1187-1198, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34452592

RESUMO

INTRODUCTION: Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurines (mercaptopurine (MP) and tioguanine (TG)), chemotherapeutic agents used in the treatment of acute lymphoblastic leukemia (ALL). Polymorphisms in TPMT gene encode diminished activity enzyme, enhancing accumulation of active metabolites, and partially explaining the inter-individual differences in patients' clinical response. AREAS COVERED: This review gives an overview on TPMT gene and function, and discusses the pharmacogenomic implications of TPMT variants in the prevention of severe thiopurine-induced hematological toxicities and the less known implication on TG-induced sinusoidal obstruction syndrome. Additional genetic and non-genetic factors impairing TPMT activity are considered. Literature search was done in PubMed for English articles published since1990, and on PharmGKB. EXPERT OPINION: To titrate thiopurines safely and effectively, achieve the right degree of lymphotoxic effect and avoid excessive myelosuppression, the optimal management will combine a preemptive TPMT genotyping to establish a safe initial dose with a close phenotypic monitoring of TPMT activity and/or of active metabolites during long-term treatment. Compared to current ALL protocols, replacement of TG by MP during reinduction phase in TPMT heterozygotes and novel individualized TG regimens in maintenance for TPMT wild-type subjects could be investigated to improve outcomes while avoiding risk of severe hepatotoxicity.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Metiltransferases/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Animais , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/farmacocinética , Genótipo , Humanos , Mercaptopurina/administração & dosagem , Mercaptopurina/efeitos adversos , Mercaptopurina/farmacocinética , Metiltransferases/metabolismo , Terapia de Alvo Molecular , Polimorfismo Genético , Leucemia-Linfoma Linfoblástico de Células Precursoras/enzimologia , Tioguanina/administração & dosagem , Tioguanina/efeitos adversos , Tioguanina/farmacocinética
8.
Spectrochim Acta A Mol Biomol Spectrosc ; 262: 120104, 2021 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-34218180

RESUMO

In this study, we designed a dual colorimetric and fluorometric sensor by using nitrogen and phosphor doped carbon dots (N, P-CDs) and Ag nanoprisms (AgNPrs) to detect 6-mercaptopurine (6-MP). For this purpose, we applied the AgNPrs/I- mixture to establish a shape transformation based colorimetric method for the detection of 6-MP. The assay mechanism of colorimetric method was based on etching and protecting effect of I- and 6-MP on the AgNPrs. In the presence of I-, as an etching agent, the solution color altered from blue to purple and the position of AgNPrs' local surface plasmon resonance (LSPR) peak shifted to the blue wavelengths. This phenomenon was assigned to the morphological change of AgNPrs. In the presence of 6-MP, AgNPrs were protected from etching by I-, so the LSPR peak position and solution color of AgNPrs remained unchangeable. Furthermore, the fluorescence intensity of N, P-CDs decreased with adding AgNPrs/I- due to the spectral overlap between etched AgNPrs and N, P-CDs. The CDs' quenched fluorescence was restored in the presence of 6-MP, as a result of the protecting effect of 6-MP on the AgNPrs. These facts have been applied to develop a dual sensor for the determination of 6-MP at the range of 10-500 nM and 30-500 nM by colorimetric and fluorometric detection methods. The detection limits were obtained 10 and 4 nM for fluorometric and colorimetric methods, respectively. The developed sensor was utilized for dual signal analysis of 6-MP in human serum samples with satisfactory results.


Assuntos
Colorimetria , Pontos Quânticos , Carbono , Fluorometria , Humanos , Mercaptopurina , Prata
10.
J Pharm Sci ; 110(10): 3484-3490, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34102205

RESUMO

The likelihood of reoccurrence of acute lymphoblastic leukemia is influenced by the cerebral concentration of the therapeutic agent 6-mercaptopurine (6-MP) during treatment. Therefore, it is important to understand the blood-brain barrier (BBB) transport mechanism of 6-MP. The purpose of this study was to characterize this mechanism using human induced pluripotent stem cell-derived microvascular endothelial cells (hiPS-BMECs). The permeability coefficient of 6-MP across hiPS-BMECs monolayer in the basal-to-apical direction (B-to-A) was significantly greater than that in the opposite direction (A-to-B). The inhibition profiles of 6-MP transport in the A-to-B direction were different from those in the B-to-A direction. Transport in the A-to-B direction was mainly inhibited by adenine (an inhibitor of equilibrative nucleobase transporter 1; ENBT1), while transport in the B-to-A direction was significantly reduced by inhibitors of multidrug resistance-associated proteins (MRPs), especially zaprinast (an MRP5 inhibitor). Immunocytochemical analyses demonstrated the expression of ENBT1 and MRP5 proteins in hiPS-BMECs. We confirmed that the cellular uptake of 6-MP is decreased by ENBT1 inhibitors in hiPS-BMECs and by knockdown of ENBT1 in hCMEC/D3 cells. These results suggest that ENBT1 and MRP5 make substantial contributions to the transport of 6-MP in hiPS-BMECs and hCMEC/D3 cells.


Assuntos
Células-Tronco Pluripotentes Induzidas , Mercaptopurina , Transporte Biológico , Barreira Hematoencefálica , Encéfalo , Células Endoteliais , Humanos
11.
Talanta ; 232: 122379, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34074387

RESUMO

In this paper, Fe3O4@ppy-Pt core-shell nanoparticles (NPs) could be produced and utilized for the development of a novel electrochemical sensor to detect 6-mercaptopurine (6-MP). 6-MP determination was examined by cyclic voltammetry (CV), chronoamperometry (CHA), linear sweep voltammetry (LSV), and differential pulse voltammetry (DPV) at Fe3O4@ppy-Pt core-shell NPs modified screen printed electrode (Fe3O4@ppy-Pt/SPE) in phosphate buffered solution (PBS). The outcomes obtained from DPV demonstrated that the Fe3O4@ppy-Pt/SPE proved a linear concentration range among 0.04 and 330.0 µM having a detection limit of 10.0 nM for 6-MP. Also, modified electrode was satisfactorily utilized to detect 6-MP in the presence of 6-thioguanine (6-TG). This sensor showed two separate oxidative peaks at 530 mV for 6-MP and at 730 mV for 6-TG with a peak potential separation of 200 mV which was large enough for simultaneous detection of the two anticancer drugs. In addition, the proposed sensor presented long-term stability, good repeatability, and excellent reproducibility. Finally, the modified electrode demonstrated satisfactory outcomes while used in real samples, proposing the appropriate potential of Fe3O4@ppy-Pt/SPE in the case of clinical diagnosis, biological samples and pharmaceutical compounds analysis.


Assuntos
Nanopartículas , Polímeros , Técnicas Eletroquímicas , Eletrodos , Mercaptopurina , Platina , Pirróis , Reprodutibilidade dos Testes , Tioguanina
12.
Brasília; CONITEC; jun. 2021.
Não convencional em Português | BRISA/RedTESA | ID: biblio-1293255

RESUMO

INTRODUÇÃO: A retocolite ulcerativa (RCU), ou colite ulcerativa, é uma doença caracterizada pela ocorrência de episódios de inflamação restrita à mucosa do cólon, podendo envolver o reto e se estender por outras partes proximais do cólon. Os pacientes apresentam diarreia, podendo ser associada com a presença de sangue. Os sintomas incluem dor abdominal, urgência, incontinência e tenesmo, que apresentam de forma gradual e progressiva, podendo estender-se por várias semanas. Febre, fadiga, perda de peso, dispneia, palpitação, anemia e deficiência de ferro podem ocorrer. A RCU pode ser dividida em fase ativa e estádio de remissão. A fase ativa é caracterizada pela presença de sintomas e lesões ativas da mucosa e a remissão é caracterizada pela resolução dos sintomas e desaparecimento de achados na mucosa. A doença ocorre gradualmente, seguida de períodos de remissão espontânea e recaídas subsequentes. A incidência da doença é semelhante entre homens e mulheres, sendo que a idade de início é entre 30 e 40 anos. O tratamento da RCU consiste em aminossalicilatos orais e por via retal, corticoides, imunossupressores e medicamentos biológicos, e é feito d


Assuntos
Humanos , Proctocolite/tratamento farmacológico , Azatioprina/efeitos adversos , Corticosteroides/efeitos adversos , Janus Quinases/antagonistas & inibidores , Mercaptopurina/efeitos adversos , Sistema Único de Saúde , Brasil , Análise Custo-Benefício
13.
Sci Rep ; 11(1): 9676, 2021 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-33958640

RESUMO

NUDT15 and TPMT variants are strong genetic determinants of thiopurine-induced hematological toxicity. Despite the impact of homozygous CRIM1 on thiopurine toxicity, several patients with wild-type NUDT15, TPMT, and CRIM1 experience thiopurine toxicity, therapeutic failure, and relapse of acute lymphoblastic leukemia (ALL). Novel pharmacogenetic interactions associated with thiopurine intolerance from hematological toxicities were investigated using whole-exome sequencing for last-cycle 6-mercaptopurine dose intensity percentages (DIP) tolerated by pediatric ALL patients (N = 320). IL6 rs13306435 carriers (N = 19) exhibited significantly lower DIP (48.0 ± 27.3%) than non-carriers (N = 209, 69.9 ± 29.0%; p = 0.0016 and 0.0028 by t test and multiple linear regression, respectively). Among 19 carriers, 7 with both heterozygous IL6 rs13306435 and CRIM1 rs3821169 showed significantly decreased DIP (24.7 ± 8.9%) than those with IL6 (N = 12, 61.6 ± 25.1%) or CRIM1 (N = 94, 68.1 ± 28.4%) variants. IL6 and CRIM1 variants showed marked inter-ethnic variability. Four-gene-interplay models revealed the best odds ratio (8.06) and potential population impact [relative risk (5.73), population attributable fraction (58%), number needed to treat (3.67), and number needed to genotype (12.50)]. Interplay between IL6 rs13306435 and CRIM1 rs3821169 was suggested as an independent and/or additive genetic determinant of thiopurine intolerance beyond NUDT15 and TPMT in pediatric ALL.


Assuntos
Medula Óssea/efeitos dos fármacos , Receptores de Proteínas Morfogenéticas Ósseas/genética , Interleucina-6/genética , Mercaptopurina/efeitos adversos , Metiltransferases/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Pirofosfatases/genética , Adolescente , Criança , Pré-Escolar , Grupos Étnicos/genética , Feminino , Humanos , Lactente , Masculino , Farmacogenética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , República da Coreia , Sequenciamento Completo do Exoma , Adulto Jovem
14.
Cancer Chemother Pharmacol ; 88(2): 271-279, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33928426

RESUMO

PURPOSE: 6-mercaptopurine(6MP)/methotrexate maintenance therapy is essential to reduce relapse of childhood acute lymphoblastic leukemia (ALL). Common germline variants in TPMT cause low activity of thiopurine methyltransferase (TPMT) and higher 6MP metabolite (TGN) levels. Higher levels of TGNs incorporated into DNA (DNA-TG) and low TPMT activity have previously been associated with a lower relapse risk. We explored if TPMT geno- or phenotype was associated with DNA-TG levels and relapse rate in NOPHO ALL2008. METHODS: TPMT genotype, repeated phenotyping, and DNA-TG measurements were collected in 918 children with non-high risk ALL (NOPHO ALL2008 maintenance therapy study). Maintenance therapy started with 6MP at 50 and 75 mg/m2 for TPMT heterozygous and wildtype patients and was adjusted to a target WBC of 1.5 - 3.0 × 109/L. RESULTS: Of 918 patients, 78 (8.5%) were TPMT heterozygous and 903 had at least one TPMT measurement (total 3063). Mean TPMT activities were higher with wildtype than heterozygous TPMT (N = 752, 16.6 versus 9.6 U/mL ery., p < 0.001). The 5-year cumulative incidence of relapse was 6.4% and 6.0% for TPMT heterozygous and wildtype patients, and there was no association between genotype and relapse rate (N = 918, hazard ratio = 1.01, 95% confidence interval [CI] 0.40 - 2.54, p = 0.98). Although TPMT heterozygous patients had higher DNA-TG (N = 548, median 760.9 [interquartile range (IQR) 568.7 - 890.3] versus 492.7 [IQR 382.1 - 634.6] fmol/µg, p < 0.001), TPMT activity was not associated with relapse rate (N = 813; hazard ratio = 0.98 per one U/mL ery. increase in TPMT activity, 95% CI 0.91 - 1.06, p = 0.67). CONCLUSION: TPMT geno- and phenotype were not associated with relapse in non-high risk NOPHO ALL2008.


Assuntos
Metiltransferases/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , DNA/genética , Feminino , Genótipo , Humanos , Lactente , Masculino , Mercaptopurina/uso terapêutico , Metotrexato/uso terapêutico , Fenótipo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Recidiva
15.
Neurochem Res ; 46(7): 1781-1793, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33864170

RESUMO

Increasing evidences indicate that the enteric nervous system (ENS) and enteric glial cells (EGC) play important regulatory roles in intestinal inflammation. Mercaptopurine (6-MP) is a cytostatic compound clinically used for the treatment of inflammatory bowel diseases (IBD), such as ulcerative colitis and Crohn's disease. However, potential impacts of 6-MP on ENS response to inflammation have not been evaluated yet. In this study, we aimed to gain deeper insights into the profile of inflammatory mediators expressed by the ENS and on the potential anti-inflammatory impact of 6-MP in this context. Genome-wide expression analyses were performed on ENS primary cultures exposed to lipopolysaccharide (LPS) and 6-MP alone or in combination. Differential expression of main hits was validated by quantitative real-time PCR (qPCR) using a cell line for EGC. ENS cells expressed a broad spectrum of cytokines and chemokines of the C-X-C motif ligand (CXCL) family under inflammatory stress. Induction of Cxcl5 and Cxcl10 by inflammatory stimuli was confirmed in EGC. Inflammation-induced protein secretion of TNF-α and Cxcl5 was partly inhibited by 6-MP in ENS primary cultures but not in EGC. Further work is required to identify the cellular mechanisms involved in this regulation. These findings extend our knowledge of the anti-inflammatory properties of 6-MP related to the ENS and in particular of the EGC-response to inflammatory stimuli.


Assuntos
Anti-Inflamatórios/farmacologia , Expressão Gênica/efeitos dos fármacos , Interleucina-1beta/genética , Mercaptopurina/farmacologia , Neurônios/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genética , Animais , Células Cultivadas , Sistema Nervoso Entérico/citologia , Inflamação/induzido quimicamente , Interleucina-1beta/metabolismo , Interleucina-1beta/farmacologia , Lipopolissacarídeos , Camundongos , Ratos , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
16.
Cancer Chemother Pharmacol ; 88(1): 53-60, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33754188

RESUMO

PURPOSE: Methotrexate (MTX)/6-Mercaptopurine (6MP)-based maintenance therapy is crucial to cure childhood acute lymphoblastic leukemia (ALL). Cytotoxicity is mediated by incorporation of thioguanine nucleotides (TGN) into DNA (DNA-TG) with higher levels in leucocytes being associated with reduced relapse risk. To further understand the dynamics of DNA-TG formation, we measured DNA-TG levels in leucocyte subsets during maintenance therapy and in the months following its discontinuation. METHODS: DNA-TG levels were measured in leucocytes (DNA-TGTotal), polymorph nucleated granulocytes (neutrophils, eosinophils, basophils [DNA-TGPMN]) and mononucleated cells (lymphocytes, monocytes [DNA-TGMNC]) in 1013 samples from 52 patients on ALL maintenance therapy (951 samples during therapy and 62 samples after therapy discontinuation, respectively). RESULTS: Median DNA-TGTotal, DNA-TGPMN and DNA-TGMNC during maintenance therapy were 539, 563 and 384 fmol/µg DNA, respectively. DNA-TGPMN displayed more pronounced fluctuation than DNA-TGMNC (range 0-3084 [interquartile range IQR 271-881] versus 30-1411 [IQR 270-509] fmol/µg DNA). DNA-TGTotal was more strongly correlated with DNA-TGPMN (rS = 0.95, p < 0.0001) than DNA-TGMNC (rS = 0.73, p < 0.0001). DNA-TGPMN correlated less with DNA-TGMNC (rS = 0.64, p < 0.0001) and to a much lesser extent with absolute neutrophil count (rS = 0.35, p < 0.0001). Following discontinuation of therapy, DNA-TGPMN was rapidly eliminated, and not measurable beyond day 22 after discontinuation, whereas DNA-TGMNC was slowly eliminated, and five patients demonstrated a measurable DNA-TGMNC more than 365 days after therapy discontinuation. CONCLUSION: Fluctuations in DNA-TGTotal are predominantly caused by corresponding fluctuations in DNA-TGPMN, thus DNA-TGTotal measures recent TGN incorporation in these short-lived cells. Measurement of DNA-TGTotal at 2-4 weeks intervals provides a reliable profile of DNA-TG levels.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , DNA/metabolismo , Leucócitos/efeitos dos fármacos , Nucleotídeos/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Tioguanina/metabolismo , Adolescente , Antimetabólitos Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Contagem de Leucócitos/métodos , Masculino , Mercaptopurina/uso terapêutico , Metotrexato/uso terapêutico , Neutrófilos/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo
17.
JCO Oncol Pract ; 17(6): e901-e907, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33729828

RESUMO

PURPOSE: Hypoglycemia has been observed in children receiving acute lymphoblastic leukemia (ALL) therapy, and it can negatively affect patient outcomes. We documented a 4%-6% prevalence of hypoglycemia among patients in the two clinics in this study. We aim to reduce morning hypoglycemia in children on chemotherapy for ALL at two community pediatric oncology clinics (A and B) by 50% in 9 months. METHODS: We used the Institute for Healthcare Improvement (IHI) Model for Improvement as the framework. Prolonged hours of fasting for procedural sedation, gaps in the caregivers' knowledge of hypoglycemia risk, and a lack of awareness of the new mercaptopurine administration guidelines were the most likely contributing factors for hypoglycemia. We developed a hypoglycemia prevention educational program for staff and caregivers followed by a knowledge assessment tool. RESULTS: Each month, the average number of patients seen in both clinics was 43. The monthly average of blood glucose tests in these patients was 94. After implementing the intervention, the percentage of caregivers who received hypoglycemia education reached 88%. Of those, 78% scored ≥ 75% in the knowledge reassessment resurvey. The combined average hypoglycemic episodes in the two clinics decreased by 46%. A higher reduction in hypoglycemic episodes was observed in clinic A (75%) compared with clinic B (17%). CONCLUSION: Implementing hypoglycemia education led to a significant drop in hypoglycemic episodes among children on ALL therapy. Despite using a similar approach, one of the two clinics showed a more than fourfold improvement compared with the other.


Assuntos
Hipoglicemia , Leucemia-Linfoma Linfoblástico de Células Precursoras , Doença Aguda , Criança , Jejum , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemia/epidemiologia , Hipoglicemia/prevenção & controle , Mercaptopurina , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico
18.
Angew Chem Int Ed Engl ; 60(21): 11847-11851, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-33769676

RESUMO

Hydrogels are widely used in various biomedical applications, as they cannot only serve as materials for biofabrication but also as depots for the administration of drugs. However, the possibilities of formulation of water-insoluble drugs in hydrogels are rather limited. Herein, we assembled recombinant spider silk gels using a new processing route with aqueous-organic co-solvents, and the properties of these gels could be controlled by the choice of the co-solvent. The presence of the organic co-solvent further enabled the incorporation of hydrophobic drugs as exemplarily shown for 6-mercaptopurine. The developed gels showed shear-thinning behaviour and could be easily injected to serve, for example, as drug depots, and they could even be 3D printed to serve as scaffolds for biofabrication. With this new processing route, the formulation of water-insoluble drugs in spider silk-based depots is possible, circumventing common pharmaceutical solubility issues.


Assuntos
Portadores de Fármacos/química , Fibroínas/química , Fluoresceínas/química , Hidrogéis/química , Mercaptopurina/química , Solventes/química , Sequência de Aminoácidos , Animais , Dimetil Sulfóxido/química , Liberação Controlada de Fármacos , Interações Hidrofóbicas e Hidrofílicas , Proteínas Recombinantes/química , Aranhas/química , Água/química
19.
Talanta ; 226: 122067, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33676643

RESUMO

The preparation of boron-carbon-oxygen (BCO)-based heterostructure needs commonly high temperature, high pressure and/or auxiliary strong oxidant. And the BCO-based probe for the sensing application is still rare owing to their few active groups, low quantum yield or missing specificity. Exploring BCO-based heterostructured probe via simple routes and application in sensing, therefore, is highly challenging. Herein, we proposed a novel boron-carbon-phosphorus-oxygen (BCPO) nanodot with phosphate tunable near-ultraviolet emission performance and narrow full width at half maximum by a facile, green and gentle synthesis process. The BCPO not only exhibits a distinctive colorimetric response to 6-mercaptopurine (6-MP), but also displays 6-MP-sensitive photoluminescence quenching. Thus, dual detection channels for 6-MP based on BCPO probe have been developed, and the mechanism has been speculated. Enrichment-electron of the 6-MP can be adsorbed at the boron vacancy orbits of the BCPO by the chemical action. The formation of 6-MP/BCPO complexes trigger the efficient photoluminescence quenching and light-absorbing enhancing of the BCPO, owing to the synergistic effect of the acceptor-excited photo-induced electron/energy transfer, inner filter effect and p/π-π conjugated stacking. Furthermore, the presence of ClO- anion efficaciously sparks the release of the 6-MP molecule from the 6-MP/BCPO complexes, thereby a rapid photo-switch of the BCPO for the 6-MP has been developed. Thus, this study can not only guide the further rational design of the BCPO probe, but also inspire the in-depth application of the BCPO and other nanomaterial-based probes.


Assuntos
Carbono , Pontos Quânticos , Boro , Mercaptopurina , Fosfatos
20.
Expert Rev Clin Pharmacol ; 14(4): 491-501, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33682590

RESUMO

Background: Prevalence and impact of thiopurine S-methyltransferase (TPMT) and Nudix hydrolase (NUDT15) minor allele frequencies in South Asian population is unclear.Methods: We searched PubMed and Embase with keywords-TPMT and NUDT15 combined with South Asian countries. We included studies reporting frequency of TPMT and NUDT15 polymorphisms. We estimated the pooled prevalence of TPMT and NUDT15 polymorphisms and their impact on pooled odds ratio of adverse events with thiopurines.Results: We included 26 studies in our analysis. The pooled prevalence of NUDT15 and TPMT polymorphisms was 16.5% (95% CI: 13.09-20.58) and 4.57% (95% CI: 3.66-5.68), respectively. In patients with adverse effects, the pooled prevalence of NUDT15 and TPMT polymorphism was 49.51% (95% C.I. 21.69-77.64) and 9.47% (95% C.I. 5.39-16.11), respectively. The odds ratio (OR) of adverse events with presence of TPMT polymorphisms was 3.65 (95% C.I., 1.43-9.28). The pooled OR for adverse events in presence of NUDT15 polymorphism was 12.63 (95% C.I., 3.68-43.26).Conclusion: NUDT15 were reported more frequently than the TPMT polymorphisms in South Asian population and were more frequently associated with adverse events. These findings may have implications for preemptive testing amongst South Asian population and immigrants prior to starting thiopurines.


Assuntos
Metiltransferases/genética , Pirofosfatases/genética , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Azatioprina/administração & dosagem , Azatioprina/efeitos adversos , Azatioprina/metabolismo , Humanos , Imunossupressores/metabolismo , Mercaptopurina/administração & dosagem , Mercaptopurina/efeitos adversos , Mercaptopurina/metabolismo , Metiltransferases/metabolismo , Polimorfismo Genético , Pirofosfatases/metabolismo
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