MARIA ELIZABETE MENDES
Projetos de Pesquisa
Unidades Organizacionais
Instituto Central, Hospital das Clínicas, Faculdade de Medicina
LIM/03 - Laboratório de Medicina Laboratorial, Hospital das Clínicas, Faculdade de Medicina
LIM/03 - Laboratório de Medicina Laboratorial, Hospital das Clínicas, Faculdade de Medicina
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article Pharmacokinetics of 6-thioguanine nucleotide and 6-methyl-mercaptopurine in a case of inadvertent combination therapy of azathioprine with allopurinol(2012) PACHECO-NETO, Maurílio; ALVES, Atecla N. L; FORTINI, Alexandre S.; SUMITA, Nairo M.; MENDES, Maria E.; TORRES, Larissa H. L.; DULEY, John A.; NAHAS, William C.; CHOCAIR, Pedro R.Background: Allopurinol was invented originally to improve response to thiopurine drugs, such as azathioprine (AZA) and mercaptopurine, but if they are given in combination then the thiopurine dose must be drastically reduced to about one third of a normal dose. Failure to reduce the thiopurine dose can cause severe toxicity, and has resulted in allopurinol usually being contraindicated for patients taking thiopurines. Case report: We present a case of a 44 year old female patient who received a renal transplant in 2001, with mycophenylate/tacrolimus/prednisolone immunosuppression. In 2004 the patient experienced gout symptoms and was prescribed 100 mg allopurinol per day. In 2008, her mycophenylate was replaced with 150 mg AZA. Within four weeks the patient was hospitalized suffering from severe myelotoxicity, with high blood levels of the AZA metabolite thioguanine nucleotide (6-TGN). AZA was stopped, with recovery of hematological parameters and elimination of AZA metabolites requiring a further two weeks. Discussion: This case demonstrates the risk of rapid-onset myelotoxicity due to AZA/ allopurinol co-therapy without correct dose adjustment of these drugs. The availability of routine analysis of AZA metabolites was useful for rapidly diagnosing the cause of the toxicity and monitoring recovery. Interestingly, the half-life of AZA metabolites after cessation of therapy (5.5 days for 6-TGN, 4 days for 6-MMP) was comparable to values in the absence of allopurinol: this excluded the elevation of 6-TGN being caused by an increased half-life.article A case report of azathioprine-induced recurrent acute pancreatitis associated with high levels of 6-thioguanine nucleotides in a renal transplant recipient(2012) PACHECO-NETO, Maurílio; ALVES, Atecla N. L; FORTINI, Alexandre S.; SUMITA, Nairo M.; MENDES, Maria E.; TORRES, Larissa H. L.; DULEY, John A.; NAHAS, William C.; CHOCAIR, Pedro R.Background: Myelotoxicity is the most common side effect associated with the use of azathioprine (AZA) in transplant recipients, while other side effects – rash, nausea, flu-like symptoms, diarrhea, hepatitis, and pancreatitis – are relatively rare. This is the first report of the evolution in a kidney transplant recipient of recurrent acute pancreatitis related to the use of AZA and high levels of 6-thioguanine nucleotide (6-TGN). Case report: A 57-year-old Brazilian male renal transplant patient remained stable for 30 years on a maintenance immunosuppressive regimen of AZA and prednisone. The patient experienced three episodes of mild acute pancreatitis in 2004, 2007 and 2008, and despite intensive investigation, AZA was not suspected as the causal agent of pancreatitis. In October 2008 the patient was found to have raised levels of erythrocyte 6-TGN, which resolved rapidly when AZA was interrupted. His maintenance immunosuppression regimen was subsequently changed to mycophenolate mofetil/ tacrolimus/ prednisone. Discussion: Despite the classic pharmacogenetic model for thiopurines afforded by thiopurine methyltransferase (TPMT) and highly variable pharmacokinetics, AZA continues to be used empirically, i.e. mg/kg. In transplant recipients, AZA is usually employed as part of polytherapy, which complicates the elucidation of the cause of drug-related side effects. We propose that therapeutic drug monitoring of AZA metabolites is useful for differential diagnosis of the causes of drug-related side effects, such as acute pancreatitis.article Azathioprine-related severe diarrhea induced by high levels of 6-thioguanine nucleotides in renal transplant recipient carrying mutant thiopurine methyltransferase: a case report(2012) PACHECO-NETO, Maurílio; NASSER, Paulo D.; ALVES, Atecla N. L; FORTINI, Alexandre S.; SUMITA, Nairo M.; MENDES, Maria E.; ONO-NITA, Suzane K.; CANÇADO, Eduardo L. R.; TORRES, Larissa H. L.; DULEY, John A.; NAHAS, William C.; CHOCAIR, Pedro R.Introduction: Azathioprine (AZA) is widely used to prevent rejection in organ transplants and treat auto-immune diseases. The major side effects reported for the use of AZA are myelotoxicity, hepatotoxicity, and flu-like symptoms, while there are a few reports of severe diarrhea. Thiopurine methyltransferase (TPMT) is a major catabolic route that has pharmacogenetic importance. We describe here the evolution of a renal transplant recipient carrying a mutant TPMT allele, who developed severe diarrhea related to the use of AZA and high levels of 6-TGN. Case presentation: A 28-year-old Brazilian Caucasian man underwent preemptive renal transplant in 2006 and presented persistent diarrhea. Therapeutic drug monitoring (TDM) of AZA metabolites indicated high levels of red blood cell 6-TGN, and AZA was discontinued in view of the patient’s persistent diarrhea. Normalization of bowel habit was gradual, parallel to the patient’s physical condition. TPMT genotype showed the mutant allele TPMT*1/*3A, genotype associated with low enzymatic activity, high levels of 6-TGN and consequently high susceptibility to side effects. Discussion: AZA has been empirically used for about 50 years, even though the pharmacokinetics is demonstrably variable among individuals. It is known that AZA has a higher selectivity for rapidly multiplying cells, which also implies higher toxicity. So it can be inferred that the high levels of 6-TGN were causing damage to the patient’s intestinal mucosa. This report shows that TDM of AZA may be useful for differential diagnosis of the cause of less frequent adverse events, such as diarrhea.