RESUMO
BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) deficiency is the main known cause of life-threatening fluoropyrimidine (FP)-induced toxicities. We conducted a meta-analysis on individual patient data to assess the contribution of deleterious DPYD variants *2A/D949V/*13/HapB3 (recommended by EMA) and clinical factors, for predicting G4-5 toxicity. METHODS: Study eligibility criteria included recruitment of Caucasian patients without DPD-based FP-dose adjustment. Main endpoint was 12-week haematological or digestive G4-5 toxicity. The value of DPYD variants *2A/p.D949V/*13 merged, HapB3, and MIR27A rs895819 was evaluated using multivariable logistic models (AUC). RESULTS: Among 25 eligible studies, complete clinical variables and primary endpoint were available in 15 studies (8733 patients). Twelve-week G4-5 toxicity prevalence was 7.3% (641 events). The clinical model included age, sex, body mass index, schedule of FP-administration, concomitant anticancer drugs. Adding *2A/p.D949V/*13 variants (at least one allele, prevalence 2.2%, OR 9.5 [95%CI 6.7-13.5]) significantly improved the model (p < 0.0001). The addition of HapB3 (prevalence 4.0%, 98.6% heterozygous), in spite of significant association with toxicity (OR 1.8 [95%CI 1.2-2.7]), did not improve the model. MIR27A rs895819 was not associated with toxicity, irrespective of DPYD variants. CONCLUSIONS: FUSAFE meta-analysis highlights the major relevance of DPYD *2A/p.D949V/*13 combined with clinical variables to identify patients at risk of very severe FP-related toxicity.
Assuntos
Antineoplásicos , Deficiência da Di-Hidropirimidina Desidrogenase , Humanos , Fluoruracila/efeitos adversos , Di-Hidrouracila Desidrogenase (NADP)/genética , Heterozigoto , Genótipo , Capecitabina/efeitos adversosRESUMO
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 adversosRESUMO
PURPOSE: Metastatic breast cancer (mBC) patients with DPYD genetic variants linked to loss of dihydropyrimidine dehydrogenase (DPD) activity are at risk of severe capecitabine-associated toxicities. However, prospective DPYD genotyping has not yet been implemented in routine clinical practice. Following a previous internal review in which two patients underwent lengthy hospitalisations whilst receiving capecitabine, and were subsequently found to be DPD deficient, we initiated routine DPYD genotyping prior to starting capecitabine. This study evaluates the clinical application of routine DPYD screening at a large cancer centre in London. METHODS: We reviewed medical records for consecutive patients with mBC who underwent DPYD genotyping before commencing capecitabine between December 2014 and December 2017. Patients were tested for four DPYD variants associated with reduced DPD activity. RESULTS: Sixty-six patients underwent DPYD testing. Five (8.4%) patients were found to carry DPYD genetic polymorphisms associated with reduced DPD activity; of these, two received dose-reduced capecitabine. Of the 61 patients with DPYD wild-type, 14 (23%) experienced grade 3 toxicities which involved palmar-plantar erythrodysesthesia (65%), and gastrointestinal toxicities (35%); no patient was hospitalised due to toxicity. CONCLUSIONS: Prospective DPYD genotyping can be successfully implemented in routine clinical practice and can reduce the risk of severe fluoropyrimidine toxicities.
Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Capecitabina/administração & dosagem , Di-Hidrouracila Desidrogenase (NADP)/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama Masculina/tratamento farmacológico , Neoplasias da Mama Masculina/genética , Neoplasias da Mama Masculina/patologia , Capecitabina/efeitos adversos , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Polimorfismo Genético , Estudos RetrospectivosRESUMO
BACKGROUND: Rejuvenation of stored red blood cells (RBCs) increases levels of adenosine 5'-triphosphate (ATP) and 2,3-diphosphoglycerate (2,3-DPG) to those of fresh cells. This study aimed to optimize and validate the US-approved process to a UK setting for manufacture and issue of rejuvenated RBCs for a multicenter randomized controlled clinical trial in cardiac surgery. STUDY DESIGN AND METHODS: Rejuvenation of leukoreduced RBC units involved adding a solution containing pyruvate, inosine, phosphate, and adenine (Rejuvesol, Zimmer Biomet), warming at 37°C for 60 minutes, then "manual" washing with saline adenine glucose mannitol solution. A laboratory study was conducted on six pools of ABO/D-matched units made the day after donation. On Days 7, 21, and 28 of 4 ± 2°C storage, one unit per pool was rejuvenated and measured over 96 hours for volume, hematocrit, hemolysis, ATP, 2,3-DPG, supernatant potassium, lactate, and purines added (inosine) or produced (hypoxanthine) by rejuvenation. Subsequently, an operational validation (two phases of 32 units each) was undertaken, with results from the first informing a trial component specification applied to the second. Rejuvenation effects were also tested on crossmatch reactivity and RBC antigen profiles. RESULTS: Rejuvenation raised 2,3-DPG to, and ATP above, levels of fresh cells. The final component had potassium and hemolysis values below those of standard storage Days 7 and 21, respectively, containing 1.2% exogenous inosine and 500 to 1900 µmoles/unit of hypoxanthine. The second operational validation met compliance to the trial component specification. Rejuvenation did not adversely affect crossmatch reactivity or RBC antigen profiles. CONCLUSION: The validated rejuvenation process operates within defined quality limits, preserving RBC immunophenotypes, enabling manufacture for clinical trials.
Assuntos
Preservação de Sangue/métodos , Eritrócitos/fisiologia , Medicina Regenerativa/métodos , Rejuvenescimento/fisiologia , 2,3-Difosfoglicerato/metabolismo , Trifosfato de Adenosina/sangue , Tipagem e Reações Cruzadas Sanguíneas , Perda Sanguínea Cirúrgica/prevenção & controle , Preservação de Sangue/normas , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Criopreservação/métodos , Contagem de Eritrócitos , Transfusão de Eritrócitos/normas , Eritrócitos/citologia , Hemólise/fisiologia , Humanos , Imunofenotipagem , Manufaturas , Purinas/sangue , Controle de Qualidade , Ensaios Clínicos Controlados Aleatórios como Assunto , Medicina Regenerativa/normasRESUMO
BACKGROUND: Autosomal dominant tubulointerstitial kidney disease (ADTKD) caused by mutations in the UMOD gene (ADTKD-UMOD) is considered rare and often remains unrecognised. We aimed to establish the prevalence of genetic kidney diseases, ADTKD and ADTKD-UMOD in adult chronic kidney disease (CKD) patients, and to investigate characteristic features. METHODS: We sent questionnaires on family history to all patients with CKD stages 3-5 in our tertiary renal centre to identify patients with inherited renal disease. Details on clinical and family history were obtained from patient interviews and clinical records. Sanger sequencing of the UMOD gene was performed from blood or saliva samples. RESULTS: 2027 of 3770 sent questionnaires were returned. 459 patients reported a family history, which was consistent with inherited kidney disease in 217 patients. 182 non-responders with inherited kidney diseases were identified through a database search. Of these 399 individuals, 252 had autosomal dominant polycystic kidney disease (ADPKD), 28 had ADTKD, 25 had Alports, and 44 were unknown, resulting in 11% of CKD 3-5 patients and 19% of end-stage renal disease patients with genetic kidney diseases. Of the unknown, 40 were genotyped, of whom 31 had findings consistent with ADTKD. 30% of unknowns and 39% of unknowns with ADTKD had UMOD mutations. Altogether, 35 individuals from 18 families were found to have ten distinct UMOD mutations (three novel), making up 1% of patients with CKD 3-5, 2% of patients with end-stage renal disease, 9% of inherited kidney diseases and 56% with ADTKD. ADTKD-UMOD was the most common genetic kidney disease after ADPKD with a population prevalence of 9 per million. Less proteinuria and haematuria, but not hyperuricaemia or gout were predictive of ADTKD-UMOD. The main limitations of the study are the single-centre design and a predominantly Caucasian population. CONCLUSIONS: The prevalence of genetic kidney diseases and ADTKD-UMOD is significantly higher than previously described. Clinical features poorly predicted ADTKD-UMOD, highlighting the need for genetic testing guided by family history alone.
Assuntos
Nefrite Intersticial/genética , Rim Policístico Autossômico Dominante/genética , Insuficiência Renal Crônica/genética , Inquéritos e Questionários , Uromodulina/genética , Idoso , Feminino , Testes Genéticos/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Nefrite Intersticial/diagnóstico , Nefrite Intersticial/epidemiologia , Rim Policístico Autossômico Dominante/diagnóstico , Rim Policístico Autossômico Dominante/epidemiologia , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/epidemiologiaRESUMO
Familial juvenile hyperuricaemic nephropathy (FJHN) is a diagnosis that is easily missed. It has taken a long time to clarify the pathophysiology and prevalence of this disease entity which has been shown to be genetically identical to medullary cystic kidney disease (MCKD) type II. The initial suspicion that uric acid was the noxious agent has been replaced by the recognition that a mutant uromodulin (UMOD) is the real culprit-although the exact mechanisms of pathogenicity remain uncertain. The mutation has been traced to the UMOD gene in chromosome 16. The disease is characterised by the classic triad of autosomal dominant inheritance, progressive renal failure beginning in the third to fifth decade of life and gout. Phenotypically similar but genotypically distinct entities have been described over the last 10 years, making a clinical diagnosis difficult. These include mutations in the renin, hepatocyte nuclear factor 1-ß and mucin 1 genes. UMOD-associated kidney disease has been proposed as a logical diagnostic label to replace FJHN, but given all these other mutations, an over-arching diagnostic term of 'autosomal dominant tubulointerstitial kidney disease' (ADTKD) has been recently adopted. Allopurinol has been suggested as a therapeutic agent, but unfortunately this was based on non-randomised uncontrolled trials with small patient numbers.
Assuntos
Gota/genética , Hiperuricemia/genética , Nefropatias/genética , Rim Policístico Autossômico Dominante/genética , Insuficiência Renal/etiologia , Uromodulina/deficiência , Adolescente , Cromossomos Humanos Par 16/genética , Análise Mutacional de DNA , Éxons/genética , Gota/complicações , Gota/epidemiologia , Gota/terapia , Fator 1-beta Nuclear de Hepatócito/genética , Humanos , Hiperuricemia/complicações , Hiperuricemia/epidemiologia , Hiperuricemia/terapia , Nefropatias/complicações , Nefropatias/epidemiologia , Nefropatias/terapia , Mucina-1/genética , Mutação , Fenótipo , Rim Policístico Autossômico Dominante/diagnóstico , Rim Policístico Autossômico Dominante/terapia , Prevalência , Insuficiência Renal/genética , Renina/genética , Ácido Úrico/metabolismo , Uromodulina/genética , Uromodulina/metabolismoRESUMO
BACKGROUND: The best-known cause of intolerance to fluoropyrimidines is dihydropyrimidine dehydrogenase (DPD) deficiency, which can result from deleterious polymorphisms in the gene encoding DPD (DPYD), including DPYD*2A and c.2846A>T. Three other variants-DPYD c.1679T>G, c.1236G>A/HapB3, and c.1601G>A-have been associated with DPD deficiency, but no definitive evidence for the clinical validity of these variants is available. The primary objective of this systematic review and meta-analysis was to assess the clinical validity of c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity. METHODS: We did a systematic review of the literature published before Dec 17, 2014, to identify cohort studies investigating associations between DPYD c.1679T>G, c.1236G>A/HapB3, and c.1601G>A and severe (grade ≥3) fluoropyrimidine-associated toxicity in patients treated with fluoropyrimidines (fluorouracil, capecitabine, or tegafur-uracil as single agents, in combination with other anticancer drugs, or with radiotherapy). Individual patient data were retrieved and analysed in a multivariable analysis to obtain an adjusted relative risk (RR). Effect estimates were pooled by use of a random-effects meta-analysis. The threshold for significance was set at a p value of less than 0·0167 (Bonferroni correction). FINDINGS: 7365 patients from eight studies were included in the meta-analysis. DPYD c.1679T>G was significantly associated with fluoropyrimidine-associated toxicity (adjusted RR 4·40, 95% CI 2·08-9·30, p<0·0001), as was c.1236G>A/HapB3 (1·59, 1·29-1·97, p<0·0001). The association between c.1601G>A and fluoropyrimidine-associated toxicity was not significant (adjusted RR 1·52, 95% CI 0·86-2·70, p=0·15). Analysis of individual types of toxicity showed consistent associations of c.1679T>G and c.1236G>A/HapB3 with gastrointestinal toxicity (adjusted RR 5·72, 95% CI 1·40-23·33, p=0·015; and 2·04, 1·49-2·78, p<0·0001, respectively) and haematological toxicity (adjusted RR 9·76, 95% CI 3·03-31·48, p=0·00014; and 2·07, 1·17-3·68, p=0·013, respectively), but not with hand-foot syndrome. DPYD*2A and c.2846A>T were also significantly associated with severe fluoropyrimidine-associated toxicity (adjusted RR 2·85, 95% CI 1·75-4·62, p<0·0001; and 3·02, 2·22-4·10, p<0·0001, respectively). INTERPRETATION: DPYD variants c.1679T>G and c.1236G>A/HapB3 are clinically relevant predictors of fluoropyrimidine-associated toxicity. Upfront screening for these variants, in addition to the established variants DPYD*2A and c.2846A>T, is recommended to improve the safety of patients with cancer treated with fluoropyrimidines. FUNDING: None.
Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/farmacocinética , Di-Hidrouracila Desidrogenase (NADP)/genética , Gastroenteropatias/genética , Doenças Hematológicas/genética , Neoplasias/tratamento farmacológico , Polimorfismo Genético , Capecitabina/efeitos adversos , Capecitabina/farmacocinética , Di-Hidrouracila Desidrogenase (NADP)/metabolismo , Fluoruracila/efeitos adversos , Fluoruracila/farmacocinética , Gastroenteropatias/induzido quimicamente , Gastroenteropatias/diagnóstico , Predisposição Genética para Doença , Doenças Hematológicas/induzido quimicamente , Doenças Hematológicas/diagnóstico , Humanos , Análise Multivariada , Neoplasias/diagnóstico , Neoplasias/genética , Razão de Chances , Farmacogenética , Fenótipo , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Tegafur/efeitos adversos , Tegafur/farmacocinéticaAssuntos
Aldeído Oxidase/deficiência , Artrite Juvenil/tratamento farmacológico , Azatioprina , Transtornos da Insuficiência da Medula Óssea , Deficiência de IgA/diagnóstico , Erros Inatos do Metabolismo da Purina-Pirimidina , Ácido Úrico , Xantina Desidrogenase/deficiência , Aldeído Oxidase/genética , Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Antirreumáticos/farmacocinética , Artrite Juvenil/imunologia , Azatioprina/administração & dosagem , Azatioprina/efeitos adversos , Azatioprina/farmacocinética , Transtornos da Insuficiência da Medula Óssea/sangue , Transtornos da Insuficiência da Medula Óssea/induzido quimicamente , Transtornos da Insuficiência da Medula Óssea/terapia , Transfusão de Eritrócitos/métodos , Humanos , Tolerância Imunológica/genética , Testes Imunológicos/métodos , Masculino , Testes Farmacogenômicos/métodos , Erros Inatos do Metabolismo da Purina-Pirimidina/diagnóstico , Erros Inatos do Metabolismo da Purina-Pirimidina/genética , Erros Inatos do Metabolismo da Purina-Pirimidina/fisiopatologia , Sulfurtransferases/genética , Ácido Úrico/sangue , Ácido Úrico/urina , Xantina , Xantina Desidrogenase/genética , Adulto JovemRESUMO
BACKGROUND: Renal hypouricaemia is a heterogeneous inherited disorder characterized by impaired tubular uric acid transport with severe complications, such as acute kidney injury and nephrolithiasis. Type 1 is caused by a loss-of-function mutation in the SLC22A12 gene (OMIM #220150), while type 2 is caused by defects in the SLC2A9 gene (OMIM #612076). CASE-DIAGNOSIS/TREATMENT: The cases of two children, a 12- and a 14-year-old boy with acute kidney injury (proband 1: urea 9.4 mmol/l, creatinine 226 µmol/l; proband 2: urea 11.7 mmol/l, creatinine 202 µmol/l) are described. Both are offspring of nonconsanguineous couples in the UK. The concentrations of serum uric acid were consistently below the normal range (0.03 and 0.04 mmol/l) and expressed as an increase in the fractional excretion of uric acid (46 and 93 %). CONCLUSIONS: A sequencing analysis of the coding region of uric acid transporters SLC22A12 and SLC2A9 was performed. Analysis of genomic DNA revealed two unpublished missense transitions, p.G216R and p.N333S in the SLC2A9 gene. No sequence variants in SLC22A12 were found. Our findings suggest that homozygous and/or compound heterozygous loss-of-function mutations p.G216R and p.N333S cause renal hypouricaemia via loss of uric acid absorption and do lead to acute kidney injury.
Assuntos
Injúria Renal Aguda/genética , Proteínas Facilitadoras de Transporte de Glucose/genética , Erros Inatos do Transporte Tubular Renal/complicações , Erros Inatos do Transporte Tubular Renal/genética , Cálculos Urinários/complicações , Cálculos Urinários/genética , Injúria Renal Aguda/metabolismo , Adolescente , Criança , Análise Mutacional de DNA , Humanos , Masculino , Mutação de Sentido Incorreto , Erros Inatos do Transporte Tubular Renal/metabolismo , Ácido Úrico/metabolismo , Cálculos Urinários/metabolismoRESUMO
Inosine triphosphate pyrophosphatase (ITPase) catalyzes the conversion of inosine triphosphate (ITP) to the correspondent monophosphate. The ITPA c.94C>A and g.IVS2+21A>C allelic variants are associated with decreased red cell enzyme activity. The ITPA c.94C>A [P32T] sequence variant is associated with an increased risk of adverse drug reactions in patients treated with the thiopurine drug azathioprine. The aim of this study was to explore the molecular mechanisms of ITPase deficiency. ITPA mRNA was extracted from peripheral blood leukocytes (PBL), Epstein-Barr virus transformed lymphoblast cell cultures, reticulocytes, and cultured fibroblast from patients with known ITPA genotypes. ITPA mRNA was reversed transcribed, sequenced and the relative amounts of misspliced transcripts quantitated from three independent experiments. The ITPA g.IVS2+21A>C sequence variant resulted in missplicing of exon 3. The ITPA c.94C>A allelic variant resulted in missplicing of exons 2 and 3 representing, in PBL samples, 61% of the total mRNA expressed in ITPA c.94C>A homozygotes. We proposed that the ITPA c.94C>A allelic variant destroys an exonic splicing silencing (ESS) element in exon 2, resulting in the activation of two nearby upstream 5' splice sites and missplicing of the exons 2 and 3 cassette causing structural changes to the enzyme and contributing to ITPase deficiency.
Assuntos
Alelos , Hipersensibilidade a Drogas/genética , Variação Genética , Pirofosfatases/genética , Splicing de RNA , Sequência de Bases , Células Cultivadas , Fibroblastos/metabolismo , Humanos , Dados de Sequência Molecular , Pirofosfatases/biossíntese , Pirofosfatases/deficiência , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
Thiopurines are often the mainstay of treatment for many patients with inflammatory bowel disease. As such, a general understanding of the evidence behind their use and of their metabolism is extremely useful in clinical practice. This review gives a practical overview of thiopurine metabolism, the importance of thiopurine S-methyltransferase testing prior to the start of therapy and the monitoring of thioguanine nucleotide levels while on treatment, guiding a personalised approach to optimising thiopurine therapy.
RESUMO
Fluoropyrimidines, including 5-fluororacil (5FU) and its pro-drug Capecitabine, are the common treatment for colorectal, breast, neck and head cancers-either as monotherapy or in combination therapy. Adverse reactions (ADRs) to the treatment are common and often result in treatment discontinuation or dose reduction. Factors contributing to ADRs, including genetic variation, are poorly characterized. We performed exome array analysis to identify genetic variants that contribute to adverse reactions. Our final dataset consisted of 504 European ancestry individuals undergoing fluoropyrimidine-based therapy for gastrointestinal cancer. A subset of 254 of these were treated with Capecitabine. All individuals were genotyped on the Illumina HumanExome Array. Firstly, we performed SNP and gene-level analyses of protein-altering variants on the array to identify novel associations the following ADRs, which were grouped into four phenotypes based on symptoms of diarrhea, mucositis, and neutropenia and hand-and-foot syndrome. Secondly, we performed detailed analyses of the HLA region on the same phenotypes after imputing the HLA alleles and amino acids. No protein-altering variants, or sets of protein-altering variants collapsed into genes, were associated with the main outcomes after Bonferroni correction. We found evidence that the HLA region was enriched for associations with Hand-and-Foot syndrome (p = 0.023), but no specific SNPs or HLA alleles were significant after Bonferroni correction. Larger studies will be required to characterize the genetic contribution to ADRs to 5FU. Future studies that focus on the HLA region are likely to be fruitful.
Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Exoma , Fluoruracila/efeitos adversos , Neoplasias Gastrointestinais/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Polimorfismo de Nucleotídeo Único , Idoso , Biomarcadores/análise , Feminino , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/patologia , Genótipo , Antígenos HLA/genética , Humanos , Masculino , Análise em Microsséries , Pessoa de Meia-IdadeRESUMO
Thiopurines, available as azathioprine, mercaptopurine, and thioguanine, are immunomodulating agents primarily used to maintain corticosteroid-free remission in patients with inflammatory bowel disease. To provide a state-of-the-art overview of thiopurine treatment in inflammatory bowel disease, this clinical review critically summarises the available literature, as assessed by several experts in the field of thiopurine treatment and research in inflammatory bowel disease.
Assuntos
Azatioprina/uso terapêutico , Imunossupressores/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Mercaptopurina/uso terapêutico , Neoplasias/epidemiologia , Tioguanina/uso terapêutico , Azatioprina/farmacologia , Quimioterapia Combinada , Fármacos Gastrointestinais/uso terapêutico , Humanos , Imunossupressores/farmacologia , Infliximab/uso terapêutico , Mercaptopurina/farmacologia , Fatores de Risco , Tioguanina/farmacologiaRESUMO
BACKGROUND: Thioguanine (TG) is efficacious in inflammatory bowel disease (IBD), but its toxicity, particularly nodular regenerative hyperplasia (NRH) of the liver, has limited its use. We assessed the long-term clinical outcomes and safety of TG in patients whom were intolerant or refractory to conventional immunomodulators. METHODS: This is a retrospective, single-centre study of IBD patients treated with TG from 2001-2013. Response was defined as clinical remission (Harvey-Bradshaw Index < 5 for Crohn's disease (CD), Simple Clinical Colitis Activity Index < 4 for ulcerative colitis (UC)) without corticosteroids or, if receiving anti-tumour-necrosis-factor (anti-TNF) therapy, absence of dose escalation. We recorded TG failure, withdrawal and adverse events. Patients were monitored with biochemistry, liver biopsy and/or magnetic resonance imaging (MRI). RESULTS: 54 patients (47 CD and 7 UC) whom received TG (mean dose: 27 mg/d (range: 20-40 mg/d)) as monotherapy (n = 36) or concomitantly with anti-TNF (n = 18) for a median inter-quartile range of 16 (5-37) months (126 patient-years of follow-up). 32 (59%) patients responded to TG at 6 months and 23 (43%) at 12 months. Pancreatitis did not recur amongst the 19 patients with prior thiopurine-induced pancreatitis. 16 (30%) patients ceased TG due to intolerance or toxicity (four serious); NRH was not observed. 6-thioguanine nucleotide concentrations did not correlate with efficacy nor with toxicity. CONCLUSIONS: TG was efficacious and well tolerated in one out of two patients who had previously failed conventional immunomodulators. NRH did not occur.
RESUMO
Genetic defects involving enzymes essential for pyrimidine nucleotide metabolism have provided new insights into the vital physiological functions of these molecules in addition to nucleic acid synthesis. Such aberrations disrupt the haematological, nervous or mitochondrial systems and can cause adverse reactions to analogue therapy. Regulation of pyrimidine pathways is also known to be disrupted in malignancies. Nine genetic defects have now been identified but only one is currently treatable. Diagnosis is aided by the accumulation of specific metabolites. Recently, progress has been made in understanding the molecular mechanisms underlying inborn errors of pyrimidine metabolism, together with the key clinical issues and the implications for the future development of novel drugs and therapeutic strategies.
Assuntos
Saúde , Erros Inatos do Metabolismo da Purina-Pirimidina/metabolismo , Pirimidinas/metabolismo , Transdução de Sinais , Humanos , Erros Inatos do Metabolismo da Purina-Pirimidina/diagnóstico , Erros Inatos do Metabolismo da Purina-Pirimidina/genética , Erros Inatos do Metabolismo da Purina-Pirimidina/terapia , Pirimidinas/antagonistas & inibidoresRESUMO
Hereditary xanthinuria (HX) is a rare inherited disorder caused by a deficiency of xanthine dehydrogenase/oxidase (XDH/XO). Missing XDH/XO activity leads to undetectable levels of uric acid excessively replaced by xanthine in serum/urine. The allopurinol loading test has been traditionally used to differentiate between HX types I and II. Final confirmation of HX has been based on the biopsy finding of the absent XDH/XO activity in the small intestine or liver. We present the clinical, biochemical, ultrasound and molecular genetics findings in three new patients with HX and suggest a simple three-step approach to be used for diagnosis, typing and confirmation of HX. In the first step, the diagnosis of HX is determined by extremely low serum/urinary uric acid excessively replaced by xanthine. Second, HX is typed using urinary metabolomics. Finally, the results are confirmed by molecular genetics. We advocate for this safe and non-invasive diagnostic algorithm instead of the traditional allopurinol loading test and intestinal or liver biopsy used in the past.
Assuntos
Erros Inatos do Metabolismo/diagnóstico , Xantina Desidrogenase/deficiência , Alopurinol/metabolismo , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Metabolômica , Ácido Úrico/sangue , Ácido Úrico/urinaRESUMO
Thiopurines are the cornerstone of treatment for a wide variety of medical disorders, ranging from pediatric leukemia to inflammatory bowel disease. Because of their complex metabolism and potential toxicities, the use of biomarkers to predict risk and response is paramount. Thiopurine S-methyltransferase and thiopurine metabolite levels have emerged as companion diagnostics with crucial roles in facilitating safe and effective treatment. This review serves to update the reader on how these tools are being developed and implemented in clinical practice. A useful paradigm in thiopurine therapeutic strategy is presented, along with fresh insights into the mechanisms underlying these approaches. We elaborate on potential future developments in the optimization of thiopurine therapy.
Assuntos
Mercaptopurina/metabolismo , Metiltransferases/metabolismo , Alopurinol/metabolismo , Alopurinol/uso terapêutico , Biomarcadores/metabolismo , Quimioterapia Combinada , Humanos , Imunossupressores/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/patologia , Leucemia/tratamento farmacológico , Leucemia/metabolismo , Leucemia/patologia , Mercaptopurina/química , Mercaptopurina/uso terapêutico , Metiltransferases/química , Metiltransferases/genéticaRESUMO
Immunomodulator drugs, of which thiopurines can be considered the backbone, are widely used in the treatment of inflammatory bowel disease. They have been shown to be highly effective and safe; however, a significant proportion of patients are deemed to have a poor response or suffer adverse reactions. Knowing how to monitor and optimize thiopurine therapy in these scenarios is crucial to effective management. We discuss the metabolism of thiopurines, the use of enzyme/metabolite testing to guide treatment, as well as strategies to circumvent toxicity and side effects, such as allopurinol coprescription. The indications, use in pregnancy, safety profile and duration of thiopurine therapy are also discussed.
RESUMO
Adverse drug reactions to azathioprine (AZA), the pro-drug of 6-mercaptopurine (6-MP), occur in 15% to 28% of patients and the majority are not explained by thiopurine methyltransferase (TPMT) deficiency. Inosine triphosphate pyrophosphatase (ITPase) deficiency results in the benign accumulation of the inosine nucleotide ITP. 6-MP is activated through a 6-thio-IMP intermediate and, in ITPase deficient patients, potentially toxic 6-thio-ITP is predicted to accumulate. The association between polymorphism in the ITPA gene and adverse drug reactions to AZA therapy was studied in patients treated for inflammatory bowel disease. Sixty-two patients with inflammatory bowel disease suffering adverse drug reactions to AZA therapy were genotyped for ITPA 94C>A and IVS2 + 21A>C polymorphisms, and TPMT*3A, *3C, *2 polymorphisms. Genotype frequencies were compared to a consecutive series of 68 controls treated with AZA for a minimum of 3 months without adverse effect. The ITPA 94C>A deficiency-associated allele was significantly associated with adverse drug reactions [odds ratio (OR) 4.2, 95% confidence interval (CI) 1.6-11.5, P = 0.0034]. Significant associations were found for flu-like symptoms (OR 4.7, 95% CI 1.2-18.1, P = 0.0308), rash (OR 10.3, 95% CI 4.7-62.9, P = 0.0213) and pancreatitis (OR 6.2,CI 1.1-32.6, P = 0.0485). Overall, heterozygous TPMT genotypes did not predict adverse drug reactions but were significantly associated with a subgroup of patients experiencing nausea and vomiting as the predominant adverse reaction to AZA therapy (OR 5.5, 95% CI 1.4-21.3, P = 0.0206). Polymorphism in the ITPA gene predicts AZA intolerance. Alternative immunosuppressive drugs, particularly 6-thioguanine, should be considered for AZA-intolerant patients with ITPase deficiency.
Assuntos
Azatioprina/efeitos adversos , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Imunossupressores/efeitos adversos , Polimorfismo Genético/genética , Pirofosfatases/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Colite Ulcerativa/genética , Doença de Crohn/genética , Feminino , Genótipo , Humanos , Inosina Trifosfato/metabolismo , Masculino , Pessoa de Meia-Idade , Pirofosfatases/deficiência , Inosina TrifosfataseRESUMO
OBJECTIVE: Polymorphisms in the TPMT gene open reading frame (ORF) are associated with reduced TPMT activity. Variable number tandem repeats (VNTR*3 to VNTR*9) in the promoter region of the gene consisting of combinations of Type A, B and C repeat units, may modulate TPMT activity. Here we present the allele frequencies of genetic modifiers of TPMT activity in a British Asian population, as well as the concordance between intermediate TPMT activity and ORF and VNTR genotypes in a predominantly Caucasian population. METHODS: VNTR type and ORF mutations were determined in two selected TPMT activity ranges, intermediate activity (4-8 U, 108 patients), normal (12-15 U, 53 patients) and in 85 British Asians. RESULTS: In British Asians, TPMT*3C was the prevalent mutant allele (four heterozygotes). One patient was heterozygous for TPMT*3A. Overall VNTR frequencies did not differ from Caucasians. Three new VNTR alleles were designated VNTR*6c, VNTR*6d, and VNTR*7c. Forty-one percent of patients with intermediate activity were heterozygous for a TPMT ORF mutation (3A, 2B, 1C). Marked linkage disequilibrium was noted between VNTR*6b - TPMT*3A (D' = 1), VNTR*4b - TPMT*3C (D' = 0.67) and VNTR*6a - TPMT*1 (D' = 1) alleles. As a result, significant differences (P < 0.05) in the distribution of Type A, B or the total number of repeats summed for both alleles, were found between the ORF heterozygous intermediate activity group and the wild-type intermediate or normal activity groups. No significant difference was found between the two wild-type groups. CONCLUSION: Our results suggest that TPMT gene VNTRs do not significantly modulate enzyme activity.