Uso de azatioprina en enfermedad de Crohn ¿En qué estamos? / Current state of the use of azathioprine in Crohn’s disease

Crohn´s disease (CD) is an intestinal pathology that may have a torpid and disabling course. One of the purposes of the pharmalogical therapy is to prevent progression of the disease and keep the patient in clinical remission. Thiopurines (azathioprine (AZT)/6-mercaptopurine (6-MP)) correspond to a group of drugs so far recommended in all current consensus for maintaining remission of the disease. Recent publications have questioned its effectiveness as a maintenance treatment. We reviewed the literature to date and the aforementioned publications trying to clarify the current status of the use of AZT/6-MP in CD. We emphasize the importance of thiopurine therapy guided by levels of its metabolites, 6-thioguanines and 6-metilmercaptopurines and usefulness of Allopurinol in selected cases. It is still pending to determine whether thiopurines have the potential to modify the disease at an early stage. Further studies are needed before conclusions can modify our clinical behavior to continue using AZT/6-MP in patients with CD.

La enfermedad de Crohn (EC) es una enfermedad intestinal que puede tener un curso tórpido e invalidan. Uno de los objetivos del tratamiento farmacológico es evitar la progresión de la enfermedad y mantener al paciente en remisión. Las tiopurinas (azatioprina (AZT)/6-mercaptopurina (6-MP) corresponden a un grupo de fármacos hasta ahora recomendados en todos los consensos para mantener la remisión de esta enfermedad. Publicaciones recientes han cuestionado su efectividad como tratamiento de mantención. Revisamos la literatura disponible hasta la fecha y las mencionadas publicaciones, intentando esclarecer el estatus actual del uso de AZT/6-MP en EC. Recalcamos la importancia de realizar la terapia con tiopurinas guiada según los niveles de sus metabolitos 6-tioguaninas y 6-metilmercaptopurinas y la utilidad del uso de alopurinol en casos seleccionados. Conclusión: Está pendiente determinar si las tiopurinas tienen el potencial de modificar la enfermedad tempranamente. Se requieren mayores estudios antes de sacar conclusiones que modifiquen nuestra conducta clínica en lo que respecta a seguir usando AZT/6-MP en pacientes con EC.

Toxicity of azathioprine: why and when? analysis of the prevalence of polymorphism in Joinville, SC, Brazil / Toxicidade da azatioprina: por que e quando? análise da prevalência de polimorfismo em Joinville, SC

CONTEXT: The use of thiopurine drugs such as azathioprine and 6-mercaptopurine has become quite common in the treatment of inflammatory bowel disease, transplantation and acute leukemias. Despite their effectiveness, these drugs are capable of causing drug-induced toxicity with the risk of death by myelosuppression. It is now known that these complications occur because of genetic polymorphisms of the thiopurinemethyltransferase (TPMT) enzyme, responsible for its metabolism. OBJECTIVE: To assess the prevalence of thiopurine methyltransferase polymorphisms in the population of Joinville, SC, Brazil. METHODS: We analyzed the frequency of four main allelic variants of the TPMT gene in 199 blood donors from Joinville, from February to April 2010. RESULTS: The normal allele ("wild-type") was found in 93.9% of subjects studied. TPMT variants were detected in 12 subjects (6.03%). CONCLUSIONS: From this study, it was estimated at 6% the risk of toxicity by the administration of azathioprine and 6-mercaptopurine to patients in Joinville.

CONTEXTO: A utilização de drogas tiopurinas como a azatioprina e a 6-mercaptopurina tem se tornado bastante frequente no tratamento de doenças inflamatórias intestinais, transplantes e leucemias agudas. Apesar de sua efetividade, estas drogas são capazes de causar toxicidade droga-induzida com risco de morte através de mielossupressão. Sabe-se hoje que estas complicações ocorrem em decorrência de polimorfismos genéticos da enzima tiopurina metiltransferase (TPMT), responsável por sua metabolização. OBJETIVOS: Avaliar a prevalência do polimorfismo do gene da TPMT na população de Joinville, SC. MÉTODOS: Foi analisada a frequência das quatro principais variantes alélicas do gene da TPMT em 199 doadores de sangue da cidade de Joinville, SC, no período de fevereiro a abril de 2010. RESULTADOS: O alelo normal ("selvagem") foi encontrado em 93,9% dos indivíduos estudados. Variantes da TPMT foram detectadas em 12 sujeitos (6,03%). CONCLUSÕES: A partir do presente estudo, pode-se estimar em cerca de 6% o risco de toxicidade na administração de azatioprina e 6-mercaptopurina a pacientes em Joinville.

Monitoração terapêutica da azatioprina: uma revisão: [revisão] / Therapeutic drug monitoring of azathioprine: a review: [review]

Os nucleotídeos de tioguanina (6-TGN), metabólitos ativos da azatioprina (AZA) e da 6-mercaptopurina (6-MP), atuam como antagonistas das purinas, inibindo as sínteses de DNA, RNA e a protéica, e induzindo à citotoxicidade/imunossupressão. A enzima geneticamente determinada, tiopurina metiltransferase (TPMT), está envolvida no metabolismo desses agentes e, hipoteticamente, determina a resposta clínica às tiopurinas. A baixa atividade dessa enzima diminui a metilação das tiopurinas, resultando em potencial sobredose, enquanto altos níveis de TPMT levam à superprodução do metabólito tóxico 6-metilmercaptopurina (6-MMP) e à não-efetividade terapêutica da AZA e da 6-MP. Várias mutações no gene da TPMT têm sido identificadas e correlacionadas com fenótipos de baixa atividade. Neste artigo, também se discute a monitoração terapêutica desses fármacos por meio da medida dos níveis de 6-TGN intra-eritrocitários, os quais se correlacionam com imunossupressão e mielotoxicidade. Já a 6-MMP está diretamente relacionada com hepatotoxicidade. Esses ensaios estão associados ao uso de doses adequadas dessa droga, resultando num melhor controle da doença e menor uso de corticosteróides.

Thioguanine nucleotides (6-TGN), active metabolites of azathioprine (AZA) and 6-mercaptopurine (6-MP), act as purine antagonists, inhibiting DNA, RNA, and protein synthesis and inducing cytotoxicity and immunosuppression. The genetically determined thiopurine methyltransferase enzyme (TPMT) is involved in the metabolism of these agents and, theoretically, determines the clinical response to thiopurines. Low activity of this enzyme decreases the methylation of thiopurines, what results in potential overdosing, whereas high TPMT status leads to overproduction of toxic metabolite 6-methilmercaptopurine (6-MMP) and ineffectiveness of AZA and 6-MP. Several mutations in the TPMT gene have been identified and correlated with low activity phenotypes. In this study, we also discuss the therapeutic monitoring of these drugs by means of red blood cell 6-TGN levels, which correlate with immunosuppression and mielotoxicity. 6-MMP is directly connected with hepatotoxicity. These metabolites assays are associated with the use of appropriate doses of this drug, what results in a better control of the disease and a decreased use of corticosteroids.

Efecto de la quimioterapia usada para el tratamiento de la leucemia linfoblástica aguda sobre la odontogénesis en ratas: estudio preliminar / Chemotherapy effect used for the acute lymphoblastic leukemia upon rats odontogenesis

El objetivo del proyecto es evaluar las alteraciones del patrón de formación del molar inferior de rata tras la aplicación de 6-Mercaptopurina y Vincristina, usadas en la quimioterapia para el tratamiento de la leucemia linfoblástica aguda en niños. La fase preliminar busca obtener un patrón normal de odontogénesis para las condiciones del estudio y verificar que los animales toleren las dosis calculadas, para pasar a la fase experimental del proyecto. Se sacrificaron dos animales de la especie ratus Norvegicus en los días 13,15,17,19,21,23,25 y 27 de vida. Los cortes teñidos con Hematoxilina-Eosina y observados bajo microscopio de luz muestran el patrón normal de odontogénesis del segundo y tercer molar inferior. Para la tolerancia a las drogas se realizó un ensayo exploratorio clínico de casos. Se dividieron los animales en tres grupos de 5 individuos. Al primero se le administraron 0.1 mg/kg de Vincristina intraperitoneal, 2.5 mg/kg de 6-Mercaptopurina vía oral al segundo, ambos en cuatro dosis y el tercero se dejó como control. Se compararon los incrementos de peso y talla con el grupo control. Los animales toleraron el esquema y este se puede usar en la segunda fase.

The purpose of this project is to evaluate the effect of Vincristrine and 6-Mercaptopurine on the odontogenesis of second and third inferior rat molars. These drugs are used for the treatment of Acute Lymphoblastic Leukemia. This first stage was carried out to describe normal odontogenesis and to test the calculated doses of this drugs in order to go up to the second phase.Two rats were sacrificed at ages of 13, 15, 17, 19, 21, 23, 25 and 27 days. Mandibles were processed for histologycal observation under light microscope. Odontogenic pattern of the second and the third inferior molars were described. A total of 15 animals were used to test drug tolerance. Five rats received four doses of 0.1 mg/kg Vincristine intra-peritoneal injections. Five of them received four oral doses of 0..3 mg/kg 6-Mercaptopurine, whereas the others were used as controls. Weight an body length increments were compared between groups. This scheme of drug application was weighted by the hole group and can be used at the experimental phase of this project.