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1.
Medicine (Baltimore) ; 99(18): e20082, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32358392

RESUMO

BACKGROUND: To systematic review the efficacy and safety of 6-thioguanine (6-TG) in the substitute of 6-mercaptopurine (6-MP) in the treatment for patients with childhood acute lymphoblastic leukemia (ALL) in the maintenance phase, and to explore its clinical application value. It provides theoretical guidance for the maintenance treatment of ALL in children from the perspective of evidence-based medicine. METHODS: By means of computer retrieval, Chinese databases were searched: Chinese Biomedical Database (CBM), China national knowledge internet (CNKI), Chongqing Weipu Database (VIP), and Wanfang Database; Foreign databases: PubMed, The Cochrane Library, Embase, and Web of Science were applied to find out randomized controlled trial (RCT) for 6-TG in childhood acute lymphoblastic leukemia. By manual retrieval, documents without electronic edition and related conference papers were retrieved. The retrieval time ranges from the beginning of the establishment of the databases to September 1st, 2019. According to the inclusion, and exclusion criteria by 3 researchers, the literature screening, data extraction, and research methodological quality evaluation were completed. RevMan 5.3 software was applied to evaluate the quality of the included literature, and Stata 12.0 software was used to conduct meta-analysis of the outcome indicators of the included literature. RESULTS: This study systematically evaluated the efficacy and safety of 6-TG in the substitute of 6-MP as a maintenance drug for childhood acute lymphoblastic leukemia. Through the key outcome indicators, this study is expected to draw a scientific, practical conclusion for 6-TG in the treatment of childhood acute lymphoblastic leukemia. This conclusion will provide evidence-based medical direction for clinical treatment. CONCLUSION: The efficacy and safety of 6-TG in the substitute of 6-MP in the maintenance treatment of childhood acute lymphoblastic leukemia will be confirmed through this study. The conclusions will be published in relevant academic journals. REGISTRATION: PROSPERO (registration number is CRD42020150466).


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Tioguanina/uso terapêutico , Adolescente , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Criança , Pré-Escolar , Substituição de Medicamentos , Humanos , Lactente , Mercaptopurina/uso terapêutico , Metástase Neoplásica , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Recidiva , Projetos de Pesquisa , Tioguanina/administração & dosagem , Tioguanina/efeitos adversos
3.
Ann Hematol ; 99(4): 809-818, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32078009

RESUMO

Risk-adapted therapy has significantly contributed to improved survival rates in pediatric acute lymphoblastic leukemia (ALL) and reliable detection of chromosomal aberrations is mandatory for risk group stratification. This study evaluated the applicability of panel-based RNA sequencing and array CGH within the diagnostic workflow of the German study group of the international AIEOP-BFM ALL 2017 trial. In a consecutive cohort of 117 children with B cell precursor (BCP) ALL, array analysis identified twelve cases with an IKZF1plus profile of gene deletions and one case of masked hypodiploidy. Genetic markers BCR-ABL1 (n = 1), ETV6-RUNX1 (n = 25), and rearrangements involving KMT2A (n = 3) or TCF3 (n = 3) were assessed by established conventional techniques such as karyotyping, FISH, and RT-PCR. Comparison of these results with RNA sequencing analysis revealed overall consistency in n=115/117 cases, albeit with one undetected AFF1-KMT2A fusion in RNA sequencing and one undetected ETV6-RUNX1 fusion in conventional analyses. The combined application of RNA sequencing, FISH, and CGH+SNP array reliably detected all genetic markers necessary for risk stratification and will be used as the diagnostic standard workflow for BCP-ALL patients enrolled in the AIEOP-BFM ALL 2017 study. Prospectively, consistent collection of genome-wide CGH+SNP array as well as RNA sequencing data will be a valuable source to elucidate new prognostic lesions beyond established markers of pediatric ALL. In this respect, RNA sequencing identified various gene fusions in up to half of the IKZF1plus (n = 6/12) and B-other (n = 19/36) cases but not in cases with hyperdiploid karyotypes (n = 35). Among these fusions, this study reports several previously undescribed in frame PAX5 fusions, including PAX5-MYO1G and PAX5-NCOA6.


Assuntos
Hibridização Genômica Comparativa , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , RNA Mensageiro/análise , RNA Neoplásico/análise , Análise de Sequência de RNA , Cariótipo Anormal , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Asparaginase/administração & dosagem , Ciclofosfamida/administração & dosagem , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Genes Neoplásicos , Humanos , Fator de Transcrição Ikaros/genética , Hibridização in Situ Fluorescente , Mercaptopurina/administração & dosagem , Metotrexato/administração & dosagem , Proteínas de Neoplasias/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Prednisona/administração & dosagem , Estudos Prospectivos , Fatores de Risco , Transcriptoma , Vincristina/administração & dosagem , Fluxo de Trabalho
4.
Mater Sci Eng C Mater Biol Appl ; 108: 110461, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31924029

RESUMO

A novel bio-responsive co-delivery system based on Poly(DEA)-b-Poly(ABMA-co-OEGMA) (PDPAO, prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization) copolymers was constructed for enhanced cellular internalization and effective combination therapy. Reduction-sensitive 6-mercaptopurine (6MP) based prodrug and pH-sensitive doxorubicin (DOX) based prodrug were grafted onto PDPAO by an azide-alkyne "Click Chemistry" reaction to acquire a pH/reduction-sensitive polymeric prodrug (PDPAO@imine-DOX/cis-6MP), which was able to self-aggregate to form polymeric micelles (M(DOX/6MP)) with an average particle size of 116 ± 2 nm in the water. The resultant micelles could maintain a stable sphere structure and show stability with a small particles' dispersion index in the blood. Importantly, it has been observed that the pH-sensitive surface charge-conversion accompanied pH-triggered DOX release in the biomimetic extracellular acidic environment of tumor tissue and a rapid dual-drug release triggered by pH and GSH in the intracellular environment. The in vitro evaluation of micelles on human cervical cancer (HeLa) and human promyelocytic leukemia (HL-60) cells showed an enhanced cellular uptake because of charge-conversion and exhibited a higher cell-killing performance. Moreover, the graft ratio of DOX and 6MP showed the ability to adjust the cytotoxicity; the micelles with a graft ratio of 2: 1 (M(DOX2/6MP)) displayed the higher cellular inhibition on either HeLa (combination index (CI) = 0.62) or HL-60 (CI = 0.35) cells. Overall, this novel dual-drug-conjugated delivery system might have important potential applications for combination therapy of cancer.


Assuntos
Química Click , Doxorrubicina , Portadores de Fármacos , Mercaptopurina , Neoplasias/tratamento farmacológico , Pró-Fármacos , Preparações de Ação Retardada/síntese química , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacologia , Doxorrubicina/química , Doxorrubicina/farmacologia , Portadores de Fármacos/síntese química , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Células HL-60 , Células HeLa , Humanos , Mercaptopurina/química , Mercaptopurina/farmacologia , Neoplasias/metabolismo , Neoplasias/patologia , Pró-Fármacos/síntese química , Pró-Fármacos/química , Pró-Fármacos/farmacologia
5.
Xenobiotica ; 50(1): 101-109, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31682552

RESUMO

The thiopurine drugs azathioprine and mercaptopurine are effective in the treatment of disorders of immune regulation and acute lymphoblastic leukaemia. Although developed in the 1950s, thiopurines remained relevant in the anti-tumour necrosis factor biologic era, finding widespread use as a co-immunomodulator. Step changes in the management of patients treated with thiopurines have reduced the incidence of severe, sometimes life-threatening toxicity. Testing for thiopurine methyltransferase (TPMT) deficiency directs a safe initial dose for therapy. The introduction of red cell thioguanine nucleotide (TGN) monitoring provides a basis for dose adjustment and the identification of patients with high levels of red cell methylmercaptopurine (MMP) and an increase in the MMP:TGN ratio. These patients are at risk for hepatotoxicity and where TGN levels are sub-therapeutic, non-response to therapy. Switching thiopurine hypermethylators to low-dose thiopurine and allopurinol combination therapy resolves hepatoxicity and increases sub-therapeutic TGN levels to regain clinical response. NUDT15 variants are a common cause of severe myelotoxicity in Asian populations where the frequency of TPMT deficiency is low. There is increasing evidence that testing for NUDT15 and TPMT deficiency in all populations prior to the start of thiopurine therapy is clinically useful and should be the first step in personalising thiopurine therapy.


Assuntos
Hipersensibilidade a Drogas/genética , Erros Inatos do Metabolismo da Purina-Pirimidina/genética , Purinas/uso terapêutico , Azatioprina/efeitos adversos , Azatioprina/uso terapêutico , Eritrócitos , Feminino , Genótipo , Humanos , Masculino , Mercaptopurina/efeitos adversos , Mercaptopurina/análogos & derivados , Mercaptopurina/uso terapêutico , Metiltransferases , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Purinas/efeitos adversos
6.
Ann Hematol ; 99(2): 391-393, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31858188
7.
J Pharm Biomed Anal ; 178: 112870, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31685266

RESUMO

The analysis of 6-thioguanine (6-TG) and 6-methylmercaptopurine (6-mMP) in biological samples is not straight forward and requires pre-treatment of samples. There are no validated published methods for the analysis of azathioprine/6-mercaptopurine (AZA/6-MP) metabolites in dried blood spot (DBS) samples that study the correlation with red blood cells (RBC) concentrations. DBS was prepared by applying fifteen microliters of blood [spiked with analytes or samples obtained from patients] to a Guthrie card which was then dried at room temperature overnight. The sample treatment procedure used protein precipitation followed by a hydrolysis step in which, 6-mMP was converted into 4-amino-5-(methylthio)carbonyl imidazole (AMTCI) then analytes were transferred to a solid phase extraction cartridge. The extracted sample was chromatographed using a reversed phase system (C18) column preceded by a guard column of matching chemistry. The method gave a linear calibration over the range 0.5-15 µmol/L and 3.75-175 µmol/L for 6-TG and 6-mMP, respectively. The method has been applied successfully to the determination of 6-TG and 6-mMP concentrations in DBS finger-prick samples from 27 paediatric patients with IBD who were receiving (AZA/6-MP). Patient 6-TG and 6-mMP RBC concentrations, calculated from whole blood finger prick DBS samples and those measured in RBCs derived from matched venous samples (analyzed using conventional HPLC-UV technique) showed good agreement using the Bland-Altman test. This is the first published method for determining 6-TG and 6-mMP in DBS that studies their correlation with RBCs concentrations. It is applicable to a range of clinical studies such as adherence and pharmacokinetic studies involving AZA/6-MP.


Assuntos
Azatioprina/sangue , Teste em Amostras de Sangue Seco/métodos , Mercaptopurina/sangue , Adolescente , Criança , Cromatografia Líquida/métodos , Eritrócitos/química , Feminino , Humanos , Extração em Fase Sólida , Espectrometria de Massas em Tandem/métodos
8.
J BUON ; 24(5): 2075-2083, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31786878

RESUMO

PURPOSE: To analyze influence of variants in TYMS, MTHFR, SLC19A1 and DHFR genes on 6-mercaptopurine (MP) induced toxicity during maintenance phase of treatment for childhood acute lymphocytic leukemia (ALL). METHODS: One-hundred twenty-seven children with ALL that received maintenance therapy were involved in this study. All patients were treated according to Berlin-Frankfurt-Muenster (BFM) based protocols. Myelotoxicity and hepatotoxicity were evaluated using surrogate markers (median 6-MP dose, number of leukopenic episodes and levels of bilirubin and transaminases on each visit). RESULTS: Higher number of leukopenic episodes, as a surrogate marker of 6-MP myelotoxicity, was found in carriers of TYMS 3R3R and 3R4R genotypes (p=0.067) as well as in TYMS 3R6bp+ (28bp VNTR, 6bp indel) haplotype carriers (p=0.015). Carriers of DHFR CATAG (-680, -675, -556, -464, -317) haplotype were also found to have higher number of leukopenic episodes (p=0.070). SLC19A1 c.80A allele (p=0.079) and TYMS 2R6bp+ (5'UTR VNTR, 6bp indel) haplotype carriers (p=0.078) had fewer leukopenic episodes. No difference in genotype frequencies between the control group of volunteered blood donors and childhood ALL patients was found. CONCLUSIONS: Variants in TYMS, SLC19A1 and DHFR genes are potential biomarkers of myelotoxicity and could be used for 6-MP therapy individualization in maintenance phase of childhood ALL treatment, alongside with well-established TPMT variants.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Proteína Carregadora de Folato Reduzido/genética , Tetra-Hidrofolato Desidrogenase/genética , Timidilato Sintase/genética , Adolescente , Alelos , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Biomarcadores Tumorais/genética , Linhagem da Célula/efeitos dos fármacos , Linhagem da Célula/imunologia , Criança , Pré-Escolar , Feminino , Ácido Fólico/metabolismo , Variação Genética/genética , Humanos , Imunofenotipagem , Lactente , Masculino , Mercaptopurina/administração & dosagem , Mercaptopurina/efeitos adversos , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
9.
Inorg Chem ; 58(23): 16154-16170, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31721562

RESUMO

In this study, two new bis-cyclometalated Pt(II) complexes, [Pt(C^N)(S^N)] [S^N = deprotonated 6-mercaptopurine (6-MP) and C^N = deprotonated 2-phenylpyridine (ppy), 2a; C^N = deprotonated benzo[h]quinoline (bhq), 2b], are synthesized by the reaction of [PtR(SMe2)(C^N)] (R = Me or p-MeC6H4) with 1 equiv of 6-mercaptopurine (6-HMP) at room temperature. The complexes are fully characterized using 1H and 13C NMR spectroscopies, electrospray ionization mass spectrometry, and elemental analysis. Biomolecular interaction of complex 2a with human serum albumin (HSA) is studied by fluorescence, UV-vis, and circular dichroism (CD) spectroscopies. The binding constants (Kb) and number of binding sites (n) are evaluated using the Stern-Volmer equation. The intrinsic fluorescence of protein is quenched by a static quenching mechanism, with a binding constant of Kb ∼ 105 reflecting a high affinity of complex 2a for HSA. The thermodynamic parameters (ΔH°, ΔG°, and ΔS°) indicate that the interaction is a spontaneous process and hydrophobic forces play a main role in the reaction. The displacement experiments demonstrate that the reactive binding sites of HSA to complex 2a are mainly located within its hydrophobic cavity in subdomain IIA (site I). Synchronous fluorescence spectra reveal that complex 2a affected the microenvironment of tryptophan-214 residues in subdomain IIA of HSA. In the case of interaction of complex 2b and HSA, because of overlapping of the emission spectra of complex 2b with HSA, chemometric approaches are applied. The results indicate significant interaction between the tryptophan residue of HSA and complex 2b. Moreover, the binding of Pt(II) complexes 2a and 2b causes a reduction of the α-helix content of HSA, as obtained by far-UV CD spectroscopy. The average binding distance (r) between Pt(II) complexes and HSA is obtained by Förster's resonance energy-transfer theory. Also, a molecular docking simulation reveals that π-π-stacking and hydrophobic interactions between these complexes and HSA are significant. Furthermore, the interactions of platinum complexes, 2, with calf-thymus DNA (CT-DNA) are investigated. The UV-vis results and ethidium bromide competitive studies support an intercalative interaction of both Pt(II) complexes with DNA. The new complexes 2 are also screened for anticancer activities. The results show that complexes 2 exhibit significant anticancer activity against the K562 (chronic myelogenous leukemia) cell line.


Assuntos
Antineoplásicos/farmacologia , DNA/efeitos dos fármacos , Mercaptopurina/farmacologia , Compostos Organoplatínicos/farmacologia , Albumina Sérica Humana/efeitos dos fármacos , Antineoplásicos/síntese química , Antineoplásicos/química , Sítios de Ligação/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , DNA/química , Teoria da Densidade Funcional , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células K562 , Mercaptopurina/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Albumina Sérica Humana/química , Relação Estrutura-Atividade , Termodinâmica
10.
PLoS One ; 14(11): e0225122, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31714926

RESUMO

BACKGROUND: Several antineoplastic drugs have been proposed as new compounds for pulmonary arterial hypertension treatment but many have cardiotoxic side effects. The chemotherapeutic agent 6-mercaptopurine may have an effect in treatment of pulmonary arterial hypertension but at the same time, its effects on the afterload adaption of the right ventricle is unpredictable due to interaction with multiple downstream signalling pathways in the cardiomyocytes. We investigated the direct cardiac effects of 6-mercaptopurine in rats with isolated right heart failure caused by pulmonary trunk banding (PTB). METHODS: Male Wistar rat weanlings (112±2 g) were randomized to sham operation (sham, n = 10) or PTB. The PTB animals were randomized to placebo (PTB-control, n = 10) and 6-mercaptopurine (7.5 mg/kg/day) groups with treatment start before the PTB procedure (PTB-prevention, n = 10) or two weeks after (PTB-reversal, n = 10). Right ventricular effects were evaluated by echocardiography, cardiac MRI, invasive pressure-volume measurements, and histological and molecular analyses. RESULTS: PTB increased right ventricular afterload and caused right ventricular hypertrophy and failure. 6-mercaptopurine did not improve right ventricular function nor reduce right ventricular remodelling in both prevention and reversal studies compared with placebo-treated rats. CONCLUSION: Treatment with 6-mercaptopurine did not have any beneficial or detrimental effects on right ventricular function or remodelling. Our data suggest that treatment of pulmonary arterial hypertension with 6-mercaptopurine is not harmful to the failing right ventricle.


Assuntos
Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Hipertensão Pulmonar/complicações , Mercaptopurina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Pressão Sanguínea , Modelos Animais de Doenças , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/patologia , Ventrículos do Coração , Hemodinâmica , Masculino , Ratos Wistar , Função Ventricular Direita , Remodelação Ventricular
11.
United European Gastroenterol J ; 7(9): 1156-1163, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31700628

RESUMO

Autoimmune hepatitis is a rare and chronic liver disease that is characterised by increased serum transaminases and immunoglobulin G, inflammatory liver histology and presence of circulating autoantibodies. An autoimmune hepatitis diagnosis justifies life-long treatment in most patients in order to prevent development of cirrhosis and end-stage liver disease. The cornerstone of treatment is steroid induction therapy followed by maintenance therapy with azathioprine, which is effective in most cases. For patients who do not respond to standard treatment, second-line treatment with other immunosuppressants can be effective. Treatment should be aimed at biochemical remission of the disease, which is defined as normalization of transaminases and immunoglobulin G. Patients should be monitored intensively during the first months of treatment in order to monitor side-effects, assess symptoms and individualise treatment. Specialist consultation should be sought in difficult-to-treat patients. Future studies and networking initiatives should result in optimization of current treatment strategies in autoimmune hepatitis.


Assuntos
Azatioprina/uso terapêutico , Glucocorticoides/uso terapêutico , Hepatite Autoimune/tratamento farmacológico , Imunossupressores/uso terapêutico , Alanina Transaminase/metabolismo , Aspartato Aminotransferases/metabolismo , Autoanticorpos/imunologia , Progressão da Doença , Hepatite Autoimune/diagnóstico , Hepatite Autoimune/imunologia , Hepatite Autoimune/metabolismo , Humanos , Imunoglobulina G/imunologia , Quimioterapia de Indução , Quimioterapia de Manutenção , Mercaptopurina/uso terapêutico , Ácido Micofenólico/uso terapêutico , Prednisolona/uso terapêutico
12.
World J Gastroenterol ; 25(38): 5850-5861, 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31636477

RESUMO

BACKGROUND: Thiopurine-induced leukopenia (TIL) is a life-threatening toxicity and occurs with a high frequency in the Asian population. Although nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) variants significantly improve the predictive sensitivity of TIL, more than 50% of cases of this toxicity cannot be predicted by this mutation. The potential use of the 6-thioguanine nucleotide (6TGN) level to predict TIL has been explored, but no decisive conclusion has been reached. Can we increase the predictive sensitivity based on 6TGN by subgrouping patients according to their NUDT15 R139C genotypes? AIM: To determine the 6TGN cut-off levels after dividing patients into subgroups according to their NUDT15 R139C genotypes. METHODS: Patients' clinical and epidemiological characteristics were collected from medical records from July 2014 to February 2017. NUDT15 R139C, thiopurine S-methyltransferase, and 6TGN concentrations were measured. RESULTS: A total of 411 Crohn's disease patients were included. TIL was observed in 72 individuals with a median 6TGN level of 323.4 pmol/8 × 108 red blood cells (RBC), which was not different from that of patients without TIL (P = 0.071). Then, we compared the 6TGN levels based on NUDT15 R139C. For CC (n = 342) and CT (n = 65) genotypes, the median 6TGN level in patients with TIL was significantly higher than that in patients without (474.8 vs 306.0 pmol/8 × 108 RBC, P = 9.4 × 10-5; 291.7 vs 217.6 pmol/8 × 108 RBC, P = 0.039, respectively). The four TT carriers developed TIL, with a median 6TGN concentration of 135.8 pmol/8 × 108 RBC. The 6TGN cut-off levels were 411.5 and 319.2 pmol/8 × 108 RBC for the CC and CT groups, respectively. CONCLUSION: The predictive sensitivity of TIL based on 6TGN is dramatically increased after subgrouping according to NUDT15 R139C genotypes. Applying 6TGN cut-off levels to adjust thiopurine therapies based on NUDT15 is strongly recommended.


Assuntos
Doença de Crohn/tratamento farmacológico , Nucleotídeos de Guanina/sangue , Imunossupressores/efeitos adversos , Leucopenia/diagnóstico , Mercaptopurina/efeitos adversos , Pirofosfatases/genética , Tionucleotídeos/sangue , Adolescente , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Variação Biológica da População/genética , Biomarcadores/sangue , Criança , Doença de Crohn/sangue , Doença de Crohn/imunologia , Feminino , Humanos , Leucopenia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Valor Preditivo dos Testes , Prognóstico , Valores de Referência , Estudos Retrospectivos , Adulto Jovem
13.
Eur J Clin Pharmacol ; 75(12): 1669-1674, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31587102

RESUMO

PURPOSE: Many patients with Crohn's disease (CD) and ulcerative colitis (UC) who have a high 6-methylmercaptopurine/6-thioguanine (6-MMP/6-TGN) ratio receive allopurinol 100 mg in addition to thiopurines to optimize metabolite concentrations. However, some patients do not tolerate allopurinol at this dosage. The aim of this study was to determine the intra-patient effect of reducing the allopurinol dosage from 100 to 50 mg, in terms of metabolite concentrations, enzyme activities, efficacy, and tolerability. METHODS: A prospective non-inferiority one-way crossover study was performed. CD and UC patients with stable disease using a thiopurine and allopurinol 100 mg were switched to 50 mg for 1 month. Primary outcomes were thiopurine metabolite concentrations. Secondary outcomes were enzyme activities of xanthine oxidase, thiopurine methyltransferase and hypoxanthine-guanine phosphoribosyltransferase, disease activity, and tolerability. RESULTS: Twenty-two patients were included. Treatment with allopurinol 50 mg compared with 100 mg resulted in a significant decrease in mean 6-TGN levels (761 to 625 pmol/8 × 108 RBC; p = 0.005) and a significant increase in mean 6-MMP levels (451 to 665 pmol/8 × 108 RBC; p = 0.01). However, the mean metabolite concentrations were still therapeutic. Enzyme activities, disease activity scores, and patient experiences did not alter significantly. Generally, UC patients were more positive about their improved treatment than CD patients. CONCLUSION: Combination therapy with 50 mg allopurinol led to a decrease of 6-TGN levels compared with 100 mg allopurinol. Disease activity, side effects, and patient experience, however, were similar between allopurinol 100 and 50 mg. UC patients seem to benefit and prefer lower doses whereas the contrary is seen in CD patients. TRIAL REGISTRATION: EudraCT trial registry - number 2016-001638-84.


Assuntos
Alopurinol/administração & dosagem , Azatioprina/administração & dosagem , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Mercaptopurina/análogos & derivados , Adulto , Idoso , Alopurinol/efeitos adversos , Colite Ulcerativa/metabolismo , Doença de Crohn/metabolismo , Estudos Cross-Over , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Humanos , Masculino , Mercaptopurina/administração & dosagem , Mercaptopurina/metabolismo , Metiltransferases/metabolismo , Pessoa de Meia-Idade , Estudos Prospectivos , Tioguanina/metabolismo
14.
Mater Sci Eng C Mater Biol Appl ; 105: 110010, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31546426

RESUMO

The absorption and release of 6-mercaptopurine anticancer drug was investigated in biodegradable and biocompatible polymer of polylactic acid (PLA) using molecular dynamics simulation. For this purpose, the amount of mixing energy, radius of gyration, mean squared displacement and radial distribution function were computed and compared in concentrations of 5-36 wt% of 6-mercaptopurine drug. The simulation results show that increasing the concentration of the drug reduces mixing energy and PLA polymer carrier is able to carry 35.8 wt% of 6-mercaptopurine anticancer drug. Based on these results, the amount of 6-mercaptopurine release from PLA carrier 35.8 wt% of it in water environment is zero due to hydrophobic property of PLA and 6-mercaptopurine. Finally, polyethylene glycol (PEG) polymer with different percentages (10-30 wt%) was used to modify PLA carrier. The simulation results show that the rate of drug release increases by increasing the concentration of PEG polymer in the modified PLA carrier and also with increasing the percentage of drug loaded in the carrier and also the optimum weight percentage of PEG in modified PLA carrier for 35.8 wt% of drug concentration is 11 wt% and the rate of drug release is slower and equal to 4.4 molecules/ns.


Assuntos
Antineoplásicos/farmacologia , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Mercaptopurina/farmacologia , Simulação de Dinâmica Molecular , Poliésteres/química , Adsorção , Polietilenoglicóis/química , Polimerização , Solubilidade
15.
Drug Des Devel Ther ; 13: 2729-2744, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496650

RESUMO

Purpose: As a common immunosuppressive and anticancer drug, thiopurine has achieved remarkable clinical success. However, higher inter-individual dose variability and unpredictable toxicity still challenge its use in clinical practices. Some studies indicate that NUDT 15 polymorphisms are associated with this variation, but specific correlation remains controversial. This meta-analysis assessed the association between three polymorphisms of NUDT 15 and thiopurine-induced toxicities. Methods: Three databases were electronically searched: PubMed, Embase, and Web of Science. Only case-control studies and cohort studies were eligible. The overall pooled ORs and corresponding 95% CIs were used to represent the results. Findings: We included 16 studies that focus on NUDT 15 c.415C > T, c.52G > A, and 36_37insGGAGTC polymorphisms in patients treated with thiopurine. Significant associations between NUDT 15 c.415C > T polymorphism and leukopenia were found in all genetic models (TC/TT vs CC, OR: 7.64, 95% CI: (6.19, 9.44), P<0.00001; TT vs CC/TC, OR: 29.66, 95% CI: (12.31, 71.46), P<0.00001; TT vs CC, OR: 45.60, 95% CI: (18.84, 110.37), P<0.00001; TC vs CC, OR: 6.41, 95% CI: (5.19, 7.94), P<0.00001; TT vs TC, OR: 6.38, 95% CI: (2.59, 15.72), P<0.00001), early/late leukopenia (in recessive and co-dominant model), leukopenia (grade 3-4), and severe hair loss in all genetic models. Besides, c.52G > A and 36_37insGGAGTC polymorphisms were also significantly associated with leukopenia. No significant association between NUDT 15 c.415C > T polymorphism and early/late leukopenia in the Chinese population was determined in the co-dominant model (TC vs CC). Implications: NUDT 15 c.415C > T polymorphism could increase the risk of leukopenia, early/late leukopenia, leukopenia (grade 3-4), and severe hair loss. Meanwhile, c.52G > A and c.36_37insGGAGTC mutations also probably increase the risk of leukopenia. Preemptive tests for NUDT 15 polymorphisms are highly recommended to individualize the treatment of thiopurine for a better outcome with less toxicity.


Assuntos
Alopecia/genética , Leucopenia/induzido quimicamente , Leucopenia/genética , Mercaptopurina , Polimorfismo de Nucleotídeo Único/genética , Pirofosfatases/genética , Humanos , Leucopenia/patologia , Índice de Gravidade de Doença
16.
J Mol Model ; 25(10): 304, 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31493060

RESUMO

In this work, the effect of the external electric field (EF) on the drug delivery performance of peptide-based metal-organic framework (MPF) for 6-mercaptopurine (6-MP) drug is investigated by means of the molecular dynamics (MD) simulations. It is found that the strength interaction of drug molecule with MPF is decreased under the influence of the electric field. In other words, the adsorbed drug molecules have more tendencies for the interaction with the porous nanostructure in the absence of EF. According to the radial distribution function (RDF) patterns, the probability of finding drug molecules in terms of the intermolecular distance with respect to the MPF surface is lowest during the high field strength. As the EF strength increases, the spread of drug molecules around MPF results in high dynamics movement and further more diffusion coefficient of drug molecule in the simulation system. This result emphasizes the weak intermolecular interaction of drug molecules with MPF with the application of EF. Assessment of dynamical properties of 6-mercaptopurine in the presence of EF with various strengths reveals that the applied electric field can act as a trigger on liberation behavior of drug from the porous nanostructure.


Assuntos
Eletricidade , Mercaptopurina/farmacologia , Estruturas Metalorgânicas/farmacologia , Simulação de Dinâmica Molecular , Peptídeos/farmacologia , Fatores de Tempo
17.
Aliment Pharmacol Ther ; 50(7): 780-788, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31429097

RESUMO

BACKGROUND: Thiopurines are the most widely used immunosuppressants in IBD although drug-related adverse events (AE) occur in 20%-30% of cases. AIM: To evaluate the safety of thiopurines in elderly IBD patients METHODS: Cohort study including all adult patients in the ENEIDA registry who received thiopurines. Patients were grouped in terms of age at the beginning of thiopurine treatment, specifically in those who started thiopurines over 60 years or between 18 and 50 years of age. Thiopurine-related AEs registered in the ENEIDA database were compared. RESULTS: Out of 48 752 patients, 1888 started thiopurines when over 60 years of age and 15 477 under 50 years of age. Median treatment duration was significantly shorter for those who started thiopurines >60 years (13 [IQR 2-55] vs 32 [IQR 5-82] months; P < .001). Patients starting >60 years had higher rates of all types of myelotoxicity, digestive intolerance and hepatotoxicity. Thiopurines were discontinued due to AEs (excluding malignancies and infections) in more patients starting >60 years (67.2% vs 63.1%; P < .001). Elderly age and female sex were independent risk factors for most AEs. CONCLUSION: In elderly IBD patients, thiopurines are associated with an increased risk of non-infectious, non-neoplastic, AEs.


Assuntos
Azatioprina/efeitos adversos , Imunossupressores/efeitos adversos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Mercaptopurina/efeitos adversos , Adulto , Idoso , Azatioprina/administração & dosagem , Estudos de Coortes , Bases de Dados Factuais , Feminino , Humanos , Imunossupressores/administração & dosagem , Masculino , Mercaptopurina/administração & dosagem , Pessoa de Meia-Idade , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco
18.
Cochrane Database Syst Rev ; 8: CD010233, 2019 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-31425621

RESUMO

BACKGROUND: Crohn's disease (CD) is a chronic relapsing inflammatory condition and maintenance of remission is a major issue as many patients fail to achieve remission with medical management and require surgical interventions. Purine analogues such as azathioprine (AZA) and 6-mercaptopurine (6-MP) have been used to maintain surgically-induced remission in CD, but the effectiveness, tolerability and safety of these agents remains controversial. OBJECTIVES: To assess the efficacy and safety of purine analogues (AZA and 6-MP) for maintenance of surgically-induced remission in CD. SEARCH METHODS: We searched PubMed, MEDLINE, Embase, CENTRAL, and the Cochrane IBD Group Specialized Register from inception to 26 July 2018 (and from inception to 31 July 2019). In addition, we searched reference lists of all included studies and relevant reviews, conference proceedings and trials registers. SELECTION CRITERIA: Randomised controlled trials (RCTs) with a duration of at least three months that enrolled adults and children with surgically-induced remission of CD and compared AZA or 6-MP to no treatment, placebo or any other active intervention were considered for inclusion. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial eligibility, extracted data, assessed the risk of bias and assessed the certainty of the evidence using GRADE. The primary outcome was clinical relapse. Secondary outcomes included endoscopic relapse, radiologic and surgical relapse, adverse events (AEs), serious adverse events (SAEs), withdrawal due to AEs and health-related quality of life. MAIN RESULTS: Ten RCTs with a total of 928 participants were included. Study participants were adults recruited from university clinics and gastroenterology hospitals who received interventions post-surgery for a duration between 12 to 36 months. Most study participants were recruited less than three months after surgery in all except one study where participants were recruited between 6 to 24 months post-surgery. One study was rated as low risk of bias, six studies were rated high risk of bias and three were rated unclear risk of bias.There was moderate certainty evidence that purine analogues are more efficient for preventing clinical relapse than placebo. At 12 to 36 months, 51% (109/215) of AZA/6-MP participants relapsed compared to 64% (124/193) of placebo participants (RR 0.79; 95% CI 0.67 to 0.92; 408 participants; 3 studies; I² = 0%; moderate certainty evidence). The certainty of the evidence regarding the efficacy of AZA or 6-MP for maintaining postoperative clinical remission compared to 5-ASA compounds was low. At 12 to 24 months , 64% (113/177) of purine analogue participants relapsed compared to 59% (101/170) of 5-ASA participants (RR 1.05; 95% CI 0.89 to 1.24; 347 participants; 4 studies; I² = 8%; low certainty evidence). The certainty of evidence that purine analogues are inferior for preventing postsurgical clinical relapse compared to tumour necrosis factor alpha agents (anti-TNF-α) was very low. At 12 to 24 months, 43% (29/67) of AZA participants relapsed compared to 14% (10/72) of anti-TNF-α participants (RR 2.89; 95% CI 1.50 to 5.57; 139 participants; 3 studies; I² = 0%; very low certainty evidence).The effect of purine analogues compounds on AEs compared to placebo or any active treatment was uncertain, as the quality of evidence ranged from very low to low. After 12 to 24 months, 14% (12/87) of purine analogue participants experienced an AE compared to 10% (8/81) of placebo participants (RR 1.36; 95% CI 0.57 to 3.27; 168 participants; 2 studies; I² = 0%; low certainty evidence). The effect of purine analogues on AEs compared to 5-ASA agents was uncertain. After 12 to 24 months, 41% (73/176) of purine analogue participants had an AE compared to 47% (81/171) of 5-ASA participants (RR 0.89; 95% CI 0.74 to 1.07; 346 participants; 4 studies; I² = 15%; low certainty evidence). The effect of purine analogues on AEs in comparison to anti TNF-α agents was uncertain. At 12 to 24 months, 57% (32/56) of AZA participants had an AE compared to 51% (31/61) of anti-TNF-α participants (RR 1.13; 95% CI 0.83 to 1.53; 117 participants; 2 studies; I² = 0%; low certainty evidence). Purine analogue participants were more like than 5-ASA participants to have a SAE (RR 3.39, 95% CI 1.26 to 9.13, 311 participants; 3 studies; I² = 9%; very low certainty evidence), or to withdraw due to an AE (RR 2.21, 95% CI 1.28 to 3.81; 425 participants; 5 studies; I² = 0%; low certainty evidence). Commonly reported AEs across all studies included leucopenia, arthralgia, abdominal pain or severe epigastric intolerance, elevated liver enzymes, nausea and vomiting, pancreatitis, anaemia, nasopharyngitis and flatulence. AUTHORS' CONCLUSIONS: Moderate certainty evidence suggests that AZA and 6-MP may be superior to placebo for maintenance of surgically-induced remission in participants with CD. There was no clear difference in the number of clinical relapses when purine analogues were compared with 5-ASA agents, however this is based on low certainty evidence. There was very low certainty evidence that AZA and 6-MP are more likely to result in more serious adverse events (SAEs) and withdrawals due to an AE (low certainty) when compared to 5-ASA agents. Very low certainty evidence suggests that purine analogues may be inferior to anti-TNF-α agents, however, no firm conclusions can be drawn. Further research investigating the efficacy and safety of AZA and 6-MP in comparison to other active medications in surgically-induced remission of CD is warranted.


Assuntos
Azatioprina/uso terapêutico , Doença de Crohn/tratamento farmacológico , Imunossupressores/uso terapêutico , Quimioterapia de Manutenção/métodos , Mercaptopurina/uso terapêutico , Doença de Crohn/prevenção & controle , Doença de Crohn/cirurgia , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Indução de Remissão/métodos , Prevenção Secundária
19.
Clin Chim Acta ; 499: 24-33, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31449774

RESUMO

BACKGROUND: Therapeutic drug monitoring of azathioprine metabolites is required for pharmacotherapy individualisation in patients with inflammatory bowel disease. Currently mainly hemolysates are used, requiring long sample preparation and showing limited analytes stability. Therefore, a quantitative LC-MS/MS method for determination of 6-thioguanine (6-TG) and 6-methylmercaptopurine (6-MMP) in dried blood spot samples (DBS) was developed. METHODS: Analysis involves liquid extraction from 30 µL blood spot, hydrolysis and quantification with LC-MS/MS. RESULTS: Method met the validation criteria in terms of selectivity, linearity, accuracy, and precision in a range from 50 to 5300 pmol/8 × 108 Ery for 6-TG and from 260 to 5300 pmol/8 × 108 Ery for 6-MMP. Range can be increased to 8000 pmol/8 × 108 Ery. No matrix effect was observed and the recovery was >80%. DBS specific validation parameters were confirmed: spot homogeneity, no influence of blood spot volume (>30 µL) on 6 mm DBS disk, and absence of haematocrit effect. DBS samples were stable for at least one month at temperatures from -20 to 40 °C. Clinical validation confirmed that DBS method and routine clinical method with hemolysate samples give comparable results and enable similar clinical decisions. CONCLUSIONS: The newly developed DBS method is simple and presents an alternative to conventional methods for therapeutic drug monitoring of azathioprine metabolites.


Assuntos
Teste em Amostras de Sangue Seco , Mercaptopurina/análogos & derivados , Tioguanina/sangue , Calibragem , Cromatografia Líquida , Humanos , Mercaptopurina/sangue , Controle de Qualidade , Espectrometria de Massas em Tandem
20.
Int J Mol Sci ; 20(17)2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31438649

RESUMO

The transforming growth factor-beta (TGF-ß) plays an important role in pathological fibrosis and cancer transformation. Therefore, the inhibition of the TGF-ß signaling pathway has therapeutic potential in the treatment of cancer. In this study, the binding modes between 47 molecules with a pyrrolotriazine-like backbone structure and transforming growth factor-beta type 1 receptor (TßR1) were simulated by molecular docking using Discovery Studio software, and their structure-activity relationships were analyzed. On the basis of the analysis of the binding modes of ligands in the active site and the structure-activity relationships, 29,254 new compounds were designed for virtual screening. According to the aforementioned analyses and Lipinski's rule of five, five new compounds (CQMU1901-1905) with potential activity were screened through molecular docking. Among them, CQMU1905 is an attractive molecule composed of 5-fluorouracil (5-FU), 6-mercaptopurine (6-MP), and 5-azacytosine. Interestingly, 5-FU, 6-MP, and 5-azacytidine are often used as anti-metabolic agents in cancer treatment. Compared with existing compounds, CQMU1901-1905 can interact with target proteins more effectively and have good potential for modification, making them worthy of further study.


Assuntos
Receptor do Fator de Crescimento Transformador beta Tipo I/antagonistas & inibidores , Citosina/análogos & derivados , Citosina/química , Citosina/farmacologia , Fluoruracila/química , Fluoruracila/farmacologia , Humanos , Mercaptopurina/química , Mercaptopurina/farmacologia , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade
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