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1.
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
2.
Clin Dermatol ; 37(3): 240-254, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31178106

RESUMO

Sarcoidosis is a chronic multisystemic, inflammatory disease with specific granulomatous cutaneous lesions. The cutaneous form may be considered a "great imitator," due to its extensive clinical morphology that occurs in upwards of 20% to 35% of patients. Cutaneous lesions may have a variety of presentations including papules, plaques, nodules, infiltrative scars, annular, angiolupoid, psoriasiform, hypopigmented, atrophic, ulcerative lesions, scarring and nonscarring alopecia, erythroderma, and ichthyosiform lesions. The dermatopathology is generally the same for all of the clinical presentations; however, variations in the cutaneous findings cause confusion in following a clinical course, therapeutic approach, or prognosis.


Assuntos
Sarcoidose , Dermatopatias , Pele/patologia , Corticosteroides/administração & dosagem , Hormônio Adrenocorticotrópico/administração & dosagem , Idade de Início , Antimaláricos/uso terapêutico , Fatores Biológicos/uso terapêutico , Diagnóstico Diferencial , Feminino , Humanos , Infliximab/uso terapêutico , Injeções , Masculino , Mercaptopurina/análogos & derivados , Mercaptopurina/uso terapêutico , Metotrexato/uso terapêutico , Prognóstico , Rituximab/administração & dosagem , Sarcoidose/diagnóstico , Sarcoidose/epidemiologia , Sarcoidose/etiologia , Sarcoidose/patologia , Dermatopatias/diagnóstico , Dermatopatias/etiologia , Dermatopatias/patologia , Talidomida/uso terapêutico
3.
Saudi Med J ; 40(6): 610-613, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31219497

RESUMO

Diffuse alveolar hemorrhage is an uncommon and often fatal condition in children that is characterized by distinct histopathological etiologies. Herein, we discuss the case of an 11-year-old girl who presented with acute worsening of hypoxia and left-sided chest pain. The patient had lung biopsy-proven idiopathic pulmonary capillaritis and was being treated with prednisolone every alternate day, azathioprine, and hydroxychloroquine. A contrast-computed tomography (CT) scan of the chest showed an acute left lower-lobe pulmonary embolism. Negative results were obtained on a test for thrombophilia. In children, pulmonary embolism with anti-neutrophil cytoplasmic antibody-negative idiopathic pulmonary capillaritis is a rare clinical condition. The exact cause of thrombus formation in this case is unknown; however, obesity, immobility, and chronic systemic corticosteroid therapy probably played a role.


Assuntos
Capilares , Pulmão/irrigação sanguínea , Embolia Pulmonar/etiologia , Vasculite/complicações , Doença Aguda , Anticorpos Anticitoplasma de Neutrófilos , Dor no Peito/etiologia , Criança , Feminino , Hemorragia/etiologia , Heparina de Baixo Peso Molecular/administração & dosagem , Humanos , Hidroxicloroquina/administração & dosagem , Hipóxia/etiologia , Pneumopatias/etiologia , Mercaptopurina/administração & dosagem , Mercaptopurina/análogos & derivados , Prednisolona/administração & dosagem , Alvéolos Pulmonares , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/tratamento farmacológico , Resultado do Tratamento
4.
Artigo em Inglês | MEDLINE | ID: mdl-30901734

RESUMO

Thiopurines are drugs widely used for the treatment of autoimmune conditions, inflammatory bowel disease or acute lymphoblastic leukemia. Determination of thiopurine methyltransferase activity (TPMT), a major determinant of thiopurines toxicity, has been suggested before implementing thiopurine treatment. An ultraperformance liquid chromatography (UPLC) method was developed and validated for the quantification of TPMT enzyme activity based on the conversion of 6-mercaptopurine (6-MP) to 6-methylmercaptopurine (6-MMP) using S-adenosyl-L-methionine (SAM) as methyl donor in red blood cell lysates (RBC). This method was improved from a previous laborious high performance liquid chromatography (HPLC) method, using a lower volume of injection and with a shorter runtime. After incubation and protein precipitation 6-MMP was separated on a HSS-T3 (2.1 × 50 mm, 1.8 µm) column and monitored by UV detection (290 nm). A change on the organic solvent used to dissolve 6-MP resulted in a reduction of interference by endogenous or non-enzymatic methylated 6-MMP. A full validation of the 6-MMP assay was performed according to the FDA and EMA guidelines. The method was linear from 0.125 to 2 nmol/mL, with acceptable values of accuracy and precision. The method was applied in 106 patients treated with thiopurines whose TPMT activity was previously quantified by HPLC. Evaluation through Bland-Altman plot showed that TPMT activities were in agreement between both methods.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Ensaios Enzimáticos/métodos , Eritrócitos/enzimologia , Metiltransferases/sangue , Metiltransferases/metabolismo , Monitoramento de Medicamentos , Humanos , Limite de Detecção , Modelos Lineares , Mercaptopurina/análogos & derivados , Mercaptopurina/metabolismo , Reprodutibilidade dos Testes , S-Adenosilmetionina/análise , S-Adenosilmetionina/metabolismo
5.
Ther Drug Monit ; 41(1): 75-85, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30507626

RESUMO

BACKGROUND: Concentrations of 6-thioguanine (6TG) nucleotides and 6-methylmercaptopurine (6MMP) nucleotides in RBCs were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). This assay was validated for clinical use and was applied to blood samples from patients taking mercaptopurine (6MP). METHODS: RBCs were hemolyzed and deproteinized using perchloric acid, followed by heating for the hydrolysis of nucleotides, and the resultant base was measured using LC-MS/MS. Precision, recovery, linearity, matrix effect, and limit of quantification was validated for clinical application. Our results were compared with another institution's established LC-MS/MS assay. We measured the concentrations of 6TG and 6MMP in RBCs of pediatric patients with acute lymphoblastic leukemia (ALL), and the clinical impact of those metabolites was investigated. RESULTS: The imprecision coefficient of variations of 6TG and 6MMP were 5.7%-8.1%, and the bias was within 5%. Lower limits of quantification were set at 54 ng/mL for 6TG and 1036 ng/mL for 6MMP. Correlation coefficients for 6TG and 6MMP were 0.997 and 1.0 in a comparison study. For clinical proof-of-concept, 74 blood samples were collected from 37 pediatric ALL patients receiving maintenance therapy. Concentration of 6TG ranged from 16.1 to 880 pmol/8 × 10 RBCs and that of 6MMP from 55 to 20,937 pmol/8 × 10 RBCs. The 6MP metabolites were not correlated with WBC or absolute neutrophil count. On the other hand, the higher 6MMP level was associated with elevated alanine aminotransferase and aspartate aminotransferase. CONCLUSIONS: In this study, an assay for the quantification of 6TG and 6MMP in RBCs was established and applied to pediatric ALL patients. Interindividual variability in 6MP metabolite concentrations was considerable and associated with elevation of liver enzymes, which may be useful in the clinical monitoring of 6MP maintenance therapy in pediatric ALL patients.


Assuntos
Antimetabólitos Antineoplásicos/farmacocinética , Eritrócitos/efeitos dos fármacos , Nucleotídeos/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Tioguanina/farmacocinética , Tioguanina/uso terapêutico , Adolescente , Antimetabólitos Antineoplásicos/sangue , Antimetabólitos Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , Cromatografia Líquida/métodos , Eritrócitos/metabolismo , Feminino , Humanos , Masculino , Mercaptopurina/análogos & derivados , Mercaptopurina/sangue , Mercaptopurina/metabolismo , Nucleotídeos/sangue , Nucleotídeos/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Espectrometria de Massas em Tandem/métodos , Tioguanina/sangue
6.
Turk J Gastroenterol ; 29(6): 650-654, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30381272

RESUMO

BACKGROUND/AIMS: Thiopurines are widely used in the treatment of inflammatory bowel disease, but data are limited. Or aim was to determine the outcome of thiopurine application in children diagnosed with ulcerative colitis (UC). MATERIALS AND METHODS: Forty-eight patients with UC, diagnosed at our center between 2005 and 2016 and applied azathiopurine (AZA), were included in the study. Data were collected retrospectively. The diagnosis of UC was based on the conventional clinical, radiological, histological, and endoscopic assessment. All patients with UC at this intercept were analyzed at the 4- and 6-week and 3-month intervals after remission to determine patient characteristics, thiopurine properties, and its efficacy and toxicity. Determination of remission, relapse, and steroid refractoriness/dependency were guided according to the European Crohn's and Colitis Organisation consensus. RESULTS: Azathiopurine was started at the median 1 month (0-12 months), and it was applied thereafter for maintenance (n=43). Response to remission induction was obtained in 40 (93.7%) patients. The median duration of the AZA treatment was 24 months (5-63). In 34 (85%) of the 40 children, it was well tolerated until the last visit. During the follow-up, adverse events occurred in 6 patients. These are leucopenia, neutropenia, vomiting, diarrhea, and skin rush. CONCLUSION: Thiopurine is an appropriate treatment option for remission in patients with UC. For a long-term follow-up, it is very important to identify patients with UC who have clinical remission with side effects and with thiopurine application.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Imunossupressores/administração & dosagem , Quimioterapia de Indução/métodos , Quimioterapia de Manutenção/métodos , Mercaptopurina/análogos & derivados , Adolescente , Criança , Feminino , Humanos , Masculino , Mercaptopurina/administração & dosagem , Recidiva , Estudos Retrospectivos , Tempo , Resultado do Tratamento
7.
J Pediatr Gastroenterol Nutr ; 67(6): 695-700, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30234756

RESUMO

BACKGROUND: Azathioprine (AZA) is the mainstay of maintenance therapy in pediatric autoimmune hepatitis (AIH). The use of thiopurines metabolites to individualize therapy and avoid toxicity has not, however, been clearly defined. METHODS: Retrospective analysis of children ≤18 years diagnosed with AIH between January 2001 and 2016. Standard definitions were used for treatment response and disease flare. Thiopurine metabolite levels were correlated with the corresponding liver function test. RESULTS: A total of 56 children (32 girls) were diagnosed with AIH at a median age of 11 years (interquartile range [IQR] 9). No difference in 6-thioguanine-nucleotide (6-TG) levels (271[IQR 251] pmol/8 × 10 red blood cell vs 224 [IQR 147] pmol/8 × 10 red blood cell, P = 0.06) was observed in children in remission when compared with those who were not in remission. No correlation was observed between the 6-TG and alanine aminotransferase levels (r = -0.179, P = 0.109) or between 6-methyl-mercaptopurine (6-MMP) and alanine aminotransferase levels (r = 0.139, P = 0.213). The 6-MMP/6-TG ratio was significantly lower in patients who were in remission (2[7] vs 5 (10), P = 0.04). Using a quartile analysis, we found that having a ratio of <4 was significantly associated with being in remission with OR 2.50 (95% confidence interval 1.02-6.10), P = 0.047. Use of allopurinol with low-dose AZA in 6 children with preferential 6-MMP production brought about remission in 5/6 (83.3%). CONCLUSIONS: Thiopurine metabolite levels should be measured in patients with AIH who have experienced a loss of remission. A 6-MMP/6-TG ratio of <4 with the addition of allopurinol could be considered in these patients.


Assuntos
Antimetabólitos/administração & dosagem , Azatioprina/administração & dosagem , Nucleotídeos de Guanina/sangue , Hepatite Autoimune/sangue , Hepatite Autoimune/tratamento farmacológico , Mercaptopurina/análogos & derivados , Tionucleotídeos/sangue , Alopurinol/administração & dosagem , Criança , Feminino , Humanos , Testes de Função Hepática , Quimioterapia de Manutenção/métodos , Masculino , Mercaptopurina/sangue , Estudos Retrospectivos , Resultado do Tratamento
9.
Gastroenterol Hepatol ; 41(10): 629-635, 2018 Dec.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-30107940

RESUMO

INTRODUCTION: Thiopurine therapy can be optimised by determining the concentration of the drug's metabolites. PATIENTS AND METHODS: Retrospective analysis on a prospective database of 31 patients with inflammatory bowel disease who failed therapy with thiopurines. Thiopurine metabolites (6-thioguanine, 6-TGN and 6-methylmercaptopurine, 6-MMP) were measured by high-performance liquid chromatography (Laboratorios Cerba, Barcelona) and treatment was duly adjusted in accordance with the results. Clinical response was reassessed after six months. RESULT: Despite the appropriate theoretical dose of thiopurines being administered, the dose was insufficient in 45.6% of patients (nonadherence to treatment suspected in 6.45%) and 16.2% received an excessive dose or the drug was metabolised by other metabolic pathways. After treatment was optimised based on metabolite levels, only 25.8% (8/31) were prescribed a biological agent, while 74.2% of cases (23/31) were managed through dose optimisation alone. DISCUSSION: Monitoring thiopurine metabolite levels may help clinicians to assess non-responsive patients before adding or switching to another drug (generally a biological agent), thereby avoiding any additional costs or potential toxicity. This strategy may also help to identify patients receiving an insufficient dose and those with an alternative metabolic pathway, who could be candidates for low-dose AZA with allopurinol, as well as patients who are suspected of being non-adherent. In three out of four patients, switching to a biological agent can be avoided.


Assuntos
Azatioprina/uso terapêutico , Monitoramento de Medicamentos/métodos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Mercaptopurina/análogos & derivados , Mercaptopurina/uso terapêutico , Tioguanina/sangue , Adulto , Idoso , Azatioprina/farmacocinética , Biotransformação , Relação Dose-Resposta a Droga , Feminino , Humanos , Doenças Inflamatórias Intestinais/metabolismo , Masculino , Mercaptopurina/sangue , Mercaptopurina/farmacocinética , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
10.
Eur J Gastroenterol Hepatol ; 30(10): 1155-1158, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29975242

RESUMO

OBJECTIVE: Two meta-analyses have found that the risk of relapse in Crohn's disease (CD) was ~40 and 50% 1 and 2 years, respectively, after withdrawal of anti-tumour necrosis factor-α (anti-TNFα). The aim of this study was to evaluate relapse rates in CD when thiopurine therapy was optimized before anti-TNFα withdrawal. PATIENTS AND METHODS: An observational study was conducted including patients with CD in remission with optimized thiopurine therapy before anti-TNFα withdrawal. We defined optimized thiopurine therapy as 6-thioguanine levels of at least 150 nmol/mmol haemoglobin (∼300 pmol×10 red blood cells) and clinical/biochemical remission as Harvey-Bradshaw Index of 5 or less and faecal calprotectin of 200 µg/g or less. RESULTS: We included 33 patients (median age: 31 years, 55% males, and median disease duration: 7 years) followed for a median of 36 months. A total of three (9%) patients relapsed during the first year and six patients (in total 27%) relapsed after 2 years. After 2 years, none of the additional patients relapsed. The disease duration and duration of anti-TNFα treatment and faecal calprotectin levels before inclusion did not predict relapse. Calprotectin levels of at least 180 after 1 year predicted relapse at year 2. CONCLUSION: This study found that 73% of patients with CD maintained remission (>2 years) when thiopurine therapy was optimized before withdrawal of anti-TNFα. Additional prospective evidence is needed to confirm the findings.


Assuntos
Doença de Crohn/tratamento farmacológico , Imunossupressores/administração & dosagem , Mercaptopurina/análogos & derivados , Mercaptopurina/administração & dosagem , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab/uso terapêutico , Adulto , Doença de Crohn/sangue , Fezes/química , Feminino , Fármacos Gastrointestinais/uso terapêutico , Humanos , Infliximab/uso terapêutico , Complexo Antígeno L1 Leucocitário/análise , Masculino , Recidiva , Tioguanina/sangue , Suspensão de Tratamento , Adulto Jovem
11.
Toxicol Appl Pharmacol ; 353: 102-108, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-29935280

RESUMO

BACKGROUND: The aim of our study was to identify the genetic background of thiopurine-induced toxicity in a patient with a wild-type thiopurine methyltransferase genotype and activity. A 38-year-old Caucasian woman presented with cutaneous necrotizing vasculitis pancytopenia one month after starting azathioprine therapy. METHODS: During a routine biochemical follow-up of the patient, undetectable serum uric acid (<10 µl) was observed. A high performance liquid chromatography analysis of urinary purines revealed increased levels of xanthine (137 mmol/mol creatinine). The suspected diagnosis of hereditary xanthinuria, a rare autosomal recessive disorder of the last two steps of purine metabolism, was confirmed by sequence analysis. RESULTS: An analysis of XDH/XO and AOX1 revealed common polymorphisms, while analysis of the MOCOS gene identified a rare homozygous variant c.362C > T. Dysfunction of this variant was confirmed by significantly decreased xanthine dehydrogenase/oxidase activity in the patient's plasma (<2% of control mean activity). CONCLUSIONS: We present a biochemical, enzymatic, and molecular genetic case study suggesting an important association between a hitherto undescribed dysfunction variant in the MOCOS gene and thiopurine-induced toxicity. The identified variant c.362C > T results in slower thiopurine metabolism caused by inhibition of 6-mercaptopurine oxidation (catabolism) to 6-thioxanthine and 6-thiouric acid, which increases the formation of the nucleotide 6-thioguanine, which is toxic. This is the first clinical case to identify the crucial role of the MOCOS gene in thiopurine intolerance and confirm the impact of genetic variability of purine enzymes on different therapeutic outcomes in patients undergoing thiopurine treatment.


Assuntos
Aldeído Oxidase/deficiência , Mercaptopurina/análogos & derivados , Erros Inatos do Metabolismo da Purina-Pirimidina/genética , Sulfurtransferases/genética , Xantina Desidrogenase/deficiência , Adulto , Aldeído Oxidase/genética , Feminino , Humanos , Mercaptopurina/efeitos adversos , Mercaptopurina/metabolismo , Metiltransferases/genética , Polimorfismo Genético/genética , Ácido Úrico/sangue , Xantina/urina , Xantina Desidrogenase/genética , Xantina Oxidase/genética
12.
Inflamm Bowel Dis ; 24(12): 2606-2612, 2018 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-29788244

RESUMO

Background: Up to 20% of patients with inflammatory bowel disease (IBD) who are refractory to thiopurine therapy preferentially produce 6-methylmercaptopurine (6-MMP) at the expense of 6-thioguanine nucleotides (6-TGN), resulting in a high 6-MMP:6-TGN ratio (>20). The objective of this study was to evaluate whether genetic variability in guanine monophosphate synthetase (GMPS) contributes to preferential 6-MMP metabolizer phenotype. Methods: Exome sequencing was performed in a cohort of IBD patients with 6-MMP:6-TGN ratios of >100 to identify nonsynonymous single nucleotide polymorphisms (nsSNPs). In vitro assays were performed to measure GMPS activity associated with these nsSNPs. Frequency of the nsSNPs was measured in a cohort of 530 Caucasian IBD patients. Results: Two nsSNPs in GMPS (rs747629729, rs61750370) were detected in 11 patients with very high 6-MMP:6-TGN ratios. The 2 nsSNPs were predicted to be damaging by in silico analysis. In vitro assays demonstrated that both nsSNPs resulted in a significant reduction in GMPS activity (P < 0.05). The SNP rs61750370 was significantly associated with 6-MMP:6-TGN ratios ≥100 (odds ratio, 5.64; 95% confidence interval, 1.01-25.12; P < 0.031) in a subset of 264 Caucasian IBD patients. Conclusions: The GMPS SNP rs61750370 may be a reliable risk factor for extreme 6MMP preferential metabolism.


Assuntos
Azatioprina/uso terapêutico , Carbono-Nitrogênio Ligases com Glutamina como Doadora de N-Amida/genética , Doenças Inflamatórias Intestinais/enzimologia , Adulto , Estudos de Coortes , Feminino , Nucleotídeos de Guanina/sangue , Humanos , Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/tratamento farmacológico , Masculino , Mercaptopurina/análogos & derivados , Mercaptopurina/sangue , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Tionucleotídeos/sangue , Adulto Jovem
13.
Inflamm Bowel Dis ; 24(4): 892-896, 2018 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-29522107

RESUMO

Background: 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. Methods: 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. Results: 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. Conclusions: 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.


Assuntos
Azatioprina/uso terapêutico , Doenças Inflamatórias Intestinais/metabolismo , Mercaptopurina/análogos & derivados , Mercaptopurina/uso terapêutico , Tioguanina/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Masculino , Mercaptopurina/metabolismo , Pessoa de Meia-Idade , Nova Zelândia , Adulto Jovem
14.
J Pediatr Gastroenterol Nutr ; 67(3): 341-345, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29601433

RESUMO

OBJECTIVES: Thiopurines are commonly used in the maintenance of remission for children with inflammatory bowel diseases (IBDs). Variation in drug metabolism may affect hepatotoxicity or therapeutic effect. We aimed to describe our center's experience with thiopurine optimization through the use of reduced thiopurine dosing in combination with allopurinol upon hepatotoxicity, drug metabolite levels, and clinical outcomes in children with IBD. METHODS: Patients aged 2 to 21 years with IBD treated with the combination of thiopurines/allopurinol between 2008 and 2015 were retrospectively reviewed. Patients previously treated with antitumor necrosis factor therapy were excluded. Demographic data, transaminase levels (aspartate transaminase, alanine transaminase), drug metabolites levels (6-thioguanine [6-TG], 6-methylmercaptopurine), physician global assessment, and corticosteroid use were recorded at baseline, 6, and 12 months. RESULTS: Fifty-two patients (29 girls, 56%) met inclusion criteria. Thirty-two of 52 (62%) remained on the combination for 12 months. In those remaining on the thiopurine/allopurinol combination, median alanine transaminase and aspartate transaminase levels were reduced (P < 0.001) and median 6-TG levels were increased (P < 0.001) at both 6 and 12 months. Corticosteroid use was decreased at both 6 (P < 0.001) and 12 months (P < 0.001) compared to use at baseline. Remission rates also improved at both 6 (P = 0.013) and 12 months (P = 0.003). Twenty of the 52 patients (38%) had discontinued the thiopurine/allopurinol combination within 12 months of initiation with 17 of 52 (33%) initiating antitumor necrosis factor therapy. CONCLUSIONS: Low-dose thiopurines in combination with allopurinol improved hepatotoxicity and increased 6-TG levels in children with IBD. Corticosteroid use was reduced and remission rates improved in those patients remaining on this combination for 1 year. However, approximately 40% of patients required a change in therapy within 12 months.


Assuntos
Alopurinol/uso terapêutico , Azatioprina/uso terapêutico , Imunossupressores/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Mercaptopurina/análogos & derivados , Adolescente , Adulto , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Seguimentos , Depuradores de Radicais Livres/uso terapêutico , Humanos , Masculino , Mercaptopurina/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
15.
Ann Lab Med ; 38(3): 255-260, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29401561

RESUMO

Measurement of thiopurine metabolites is helpful to monitor adverse effects and assess compliance in patients on thiopurine treatment. The purpose of this study was to develop and validate an analytical method for measurement of thiopurine metabolites, thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine nucleotide (6-MMPN), in RBCs. We developed and validated a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantification of 6-TGN and 6-MMPN and evaluated the stability of the thiopurine metabolites in RBC and whole blood states without any preprocessing at various storage conditions. The linear range was 0.1-10 µmol/L and 0.5-100 µmol/L for 6-TGN and 6-MMPN, respectively. The mean extraction recovery at the two concentrations was 71.0% and 75.0% for 6-TGN, and 102.2% and 96.4% for 6-MMPN. Thiopurine metabolites in preprocessed RBC samples were stable at 25°C and 4°C after storage for 4 hours and at -70°C for up to 6 months. However, 6-TGN decreased by 30% compared with the initial concentration when stored at -20°C for 180 days. In whole blood states, 6-TGN decreased by about 20% at four days after storage at 4°C. We validated a reliable LC-MS/MS method and recommend that the patient's whole blood sample be preprocessed as soon as possible.


Assuntos
Mercaptopurina/análogos & derivados , Espectrometria de Massas em Tandem , Tioguanina/sangue , Cromatografia Líquida de Alta Pressão , Eritrócitos/citologia , Eritrócitos/metabolismo , Humanos , Mercaptopurina/sangue , Temperatura Ambiente , Tioguanina/metabolismo
16.
Clin Biochem ; 54: 100-105, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29425801

RESUMO

BACKGROUND: Identification of patients with thiopurine S-methyltransferase (TPMT) deficiency prior to thiopurine drug therapy has become routine clinical practice worldwide. To measure TPMT activity, traditional radiochemical assays have been replaced by chromatographic methods. METHOD: Inspired by the increasing number of isotope labelled sources that may be of benefit for the TPMT assay, a new LC-MS/MS method for TPMT activity was developed and validated. Isotope labelled d3-S-adenosyl-l-methionine (d3-SAM) was selected for the enzymatic methylation of mercaptopurine during sample incubation; d3-6-methylmercaptopurine (d3-6-MMP) with d2-2, 8-hypoxanthine as the internal standard was quantified to ascertain individual TPMT activity. RESULTS: The validation of the analytical part of this method showed good linearity (coefficient of determination 0.9999 in the range of 1-500 ng/mL) with the intra-and inter-day impression CV% between 7.6% and 9.1% and 3.7% and 9.2%, respectively. Recovery ranged from 94.9% to 112.3%. The specificity of the enzymatic reaction was validated by using 108 clinical check samples. After compared with traditional radiochemical assay and genotype results, all homozygous and heterozygous deficiency clinical checks fitted into the nominal groups, inter-batch and intra-batch impression CV% were between 2.3% and 9.7%. CONCLUSION: With the inclusion of isotope labelled substrate, interfering non-enzymatic methylation no longer results in potential false assignment of abnormal patients. Furthermore, the method can be applied to patients who have already been prescribed thiopurine drugs. This new LC-MS/MS is therefore a favourable clinical routine application to test TPMT activity, as it shows excellent performance in identifying patients with TPMT deficiency.


Assuntos
Espectrometria de Massas/métodos , Mercaptopurina/análogos & derivados , Metiltransferases/análise , Cromatografia Líquida/métodos , Humanos , Mercaptopurina/química , Metiltransferases/química
17.
JAMA Neurol ; 75(4): 478-487, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29305608

RESUMO

Importance: Myelin oligodendrocyte glycoprotein antibodies (MOG-Abs) are consistently identified in a range of demyelinating disorders in adults and children. Current therapeutic strategies are largely center specific, and no treatments have been formally evaluated. Objective: To examine the clinical phenotypes, treatment responses, and outcomes of children with relapsing MOG-Ab-associated disease. Design, Setting, and Participants: This study prospectively collected demographic, clinical, and radiologic data from 102 patients from 8 countries of the EU Paediatric Demyelinating Disease Consortium from January 1, 2014, through December 31, 2016. Patients were treated according to local protocols. Main Outcomes and Measures: Annualized relapse rates (ARRs) and Expanded Disability Status Scale (EDSS) scores before and during treatment with disease-modifying drugs (DMDs). Results: A total of 102 children were identified (median [range] age, 7.0 [1.5-7.9] years; male to female ratio, 1.0:1.8; white to other race/ethnicity ratio, 3.6:1.0). Original diagnoses were neuromyelitis optica spectrum disorder (44 patients [43.1%]), acute disseminated encephalomyelitis followed by optic neuritis (20 [19.6%]), multiphasic disseminated encephalomyelitis (20 [19.6%]), and relapsing optic neuritis (18 [17.6%]). In all, 464 demyelinating events were reported. Treated patients had more relapses (median, 3.0; range, 1.0-17.0) than untreated patients (median, 1.0; range 1.0-7.0) (P = .009) and higher EDSS scores (median, 1.5; interquartile range, 0-2.5) than untreated patients (median, 1.0; interquartile range, 0-1.5) (P < .001). Fifty-two children (51.0%) received DMDs: 28 (53.8%) were treated with 1 DMD, 17 (32.7%) with 2, and 7 (13.5%) with 3 or more sequential DMDs. Patients relapsed during all treatments, with a total of 127 relapses on treatment reported. No changes in median ARR and EDSS score were observed between the preinitiation and postinitiation phases of interferon beta and glatiramer acetate treatment (n = 11). The median ARR was reduced from 1.84 to 1.0 with azathioprine (n = 20, P < .001), 1.79 to 0.52 with mycophenolate mofetil (n = 15, P = .003), and 2.12 to 0.67 with rituximab (n = 9, P < .001), although the median EDSS score remained unchanged. An improvement in ARR (from 2.16 to 0.51, P < .001) and EDSS score (from 2.2 to 1.2, P = .01) was observed in the 12 patients treated with regular intravenous immunoglobulins. Conclusions and Relevance: Although commonly used to treat patients with multiple sclerosis, DMDs were not associated with clinical improvement in children with MOG-Ab-associated disease, whereas azathioprine, mycophenolate mofetil, rituximab, and particularly intravenous immunoglobulins were associated with a reduction in relapse frequency. A correct diagnosis of relapsing MOG-Ab-associated disorders is therefore important to optimize immune treatment.


Assuntos
Autoanticorpos/sangue , Fatores Imunológicos/uso terapêutico , Glicoproteína Mielina-Oligodendrócito/imunologia , Neuromielite Óptica , Resultado do Tratamento , Estudos de Coortes , Avaliação da Deficiência , Europa (Continente) , Feminino , Humanos , Cooperação Internacional , Masculino , Mercaptopurina/análogos & derivados , Mercaptopurina/uso terapêutico , Ácido Micofenólico/uso terapêutico , Neuromielite Óptica/sangue , Neuromielite Óptica/tratamento farmacológico , Neuromielite Óptica/imunologia , Recidiva , Rituximab/uso terapêutico
18.
J Crohns Colitis ; 12(5): 546-558, 2018 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-29370346

RESUMO

Background and Aims: The association between thiopurines and colorectal neoplasia risk remains controversial in inflammatory bowel disease [IBD] patients. We performed a systematic review and meta-analysis examining this association. Methods: A comprehensive search of the PubMed, EMBASE and Cochrane Library databases was performed to identify relevant literature. Random-effects models were applied to calculate the pooled odds ratio [OR] and relative risk [RR] with corresponding 95% confidence intervals [CIs] among case-control and cohort studies. Results: Eleven cohort and 16 case-control studies involving 95397 patients were included in this study. Overall, the use of thiopurines was associated with a reduced risk of colorectal neoplasia both in case-control [OR = 0.49, 95% CI: 0.34-0.70] and cohort studies [RR = 0.96, 95% CI: 0.94-0.98]. Moreover, a protective effect of thiopurines against advanced neoplasia [high-grade dysplasia and cancer] [OR = 0.51, 95% CI: 0.31-0.84 for case-control studies; RR = 0.96, 95% CI: 0.94-0.98 for cohort studies] and colorectal cancer [CRC] [OR = 0.56, 95% CI: 0.34-0.93 for case-control studies; RR = 0.96, 95% CI: 0.94-0.98 for cohort studies] was also observed. Furthermore, when the analysis was conducted on patients at a high risk for colorectal neoplasia, the chemopreventive effect was confirmed in patients with long disease duration [> 8 years] but not in those with extensive colitis or primary sclerosing cholangitis. Conclusions: This study demonstrated that thiopurine use was associated with a reduced risk of colorectal neoplasia, advanced neoplasia and CRC in IBD patients, especially those with long disease duration [> 8 years].


Assuntos
Neoplasias Colorretais/epidemiologia , Imunossupressores/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Mercaptopurina/análogos & derivados , Mercaptopurina/uso terapêutico , Neoplasias Colorretais/etiologia , Humanos , Incidência , Doenças Inflamatórias Intestinais/complicações , Fatores de Proteção , Fatores de Risco
19.
Eur J Gastroenterol Hepatol ; 30(2): 167-173, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29120908

RESUMO

BACKGROUND: Patients' beliefs about medicine may either reflect the necessity for treatment or concerns regarding the treatment. We explored the extent to which these beliefs have an effect on thiopurine metabolite levels and premature discontinuation in patients with inflammatory bowel disease (IBD). PATIENTS AND METHODS: Patients enrolled in the 'Thiopurine response Optimization by Pharmacogenetic testing in Inflammatory Bowel Disease Clinics' (TOPIC) trial were asked to complete the Beliefs about Medicine Questionnaire (BMQ) 4 weeks after thiopurine initiation. The BMQ measures perceptions about treatment necessity and concerns. On the basis of the necessity and concern scores, patients can be categorized as accepting, ambivalent, indifferent, or skeptical. The thiopurine discontinuation rates for these belief subgroups were compared by Kaplan-Meier curves. Furthermore, clinical response and metabolite levels were compared between the belief subgroups. RESULTS: A total of 767 patients with IBD started thiopurine treatment, of whom 576 (75%) completed the BMQ. Patients could be classified as accepting (34%), indifferent (17%), ambivalent (34%), or skeptical (15%). Compared with patients in the accepting group (discontinuation rate 22%), patients with an indifferent (35%; P=0.02), ambivalent (37%; P<0.01), or skeptical belief (54%; P<0.01) had higher thiopurine discontinuation rates. No differences were observed in the steady-state thiopurine metabolite levels between the different belief subgroups. CONCLUSION: Patients with a low perceived treatment necessity or high concerns toward IBD treatment were more likely to discontinue thiopurine treatment prematurely. Extra attention toward these patients might prevent premature discontinuation.


Assuntos
Conhecimentos, Atitudes e Prática em Saúde , Imunossupressores/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Adesão à Medicação/psicologia , Mercaptopurina/análogos & derivados , Mercaptopurina/uso terapêutico , Adulto , Feminino , Nucleotídeos de Guanina/sangue , Humanos , Imunossupressores/metabolismo , Masculino , Mercaptopurina/metabolismo , Pessoa de Meia-Idade , Inquéritos e Questionários , Tioinosina/análogos & derivados , Tioinosina/sangue , Tionucleotídeos/sangue , Resultado do Tratamento , Adulto Jovem
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