Hepatotoxicidade induzida por azatioprina em portadora da síndrome de Vogt-Koyanagi-Harada / Azathioprine-induced hepatotoxicity in a Vogt-Koyanagi-Harada syndrome patient

Este relato teve como objetivo apresentar um caso de hepatotoxicidade colestática induzida por azatioprina em portadora da síndrome de Vogt-Koyanagi-Harada. À admissão, apresentava icterícia +3/+4, acolia fecal e colúria, além de aumento de marcadores hepáticos, sendo compatível com síndrome colestática, cuja etiologia foi confirmada após exclusão de outras causas possíveis e retirada da azatioprina. A paciente evoluiu, após 1 semana de retirada do fármaco, com diurese livre de coloração menos escura e evacuação presente, sem acolia. Além disso, houve melhora nos exames que precederam a alta hospitalar

This report aimed at presenting a case of azathioprine-induced cholestatic hepatotoxicity in a patient with Vogt-Koyanagi-Harada syndrome. On admission, she presented with jaundice +3/+4, acholic feces, and choluria, as well as increased hepatic markers, all consistent with cholestatic syndrome, the etiology of which was confirmed after other possible causes were ruled out and azathioprine was discontinued. After 1 week of the drug discontinuation, the patient progressed with free diuresis of lighter color and defecation, with no acholia. In addition, tests performed before discharge were improved.

Role of rosemary leaves extract as a protective agent against azathioprine-induced toxicity in rats

Rosemary is widely found along the coasts of the Mediterranean Sea. Its leaves or extract were found to have a high antioxidant and anti-inflammatory activity. It is also used as an antispasmodic, analgesic, anti-rheumatic and expectorant. These actions are mainly due to its content of essential oils. Azathioprine [AZA] is an immunosuppressive drug. It is widely used in many diseases. A major drawback is the occurrence of side-effects, especially acute pancreatitis. This work was done to study the effect of dietary supplement of rosemary leaves as a strategy for amelioration of the side-effects of azathioprine. Thirty-two adult male albino rats were used in this study. They were equally divided into four groups. Group I: control group, group II: rosemary group, the animals were given a daily oral dose of rosemary leaves extract. Group III: azathioprine group, the animals were given a single dose of AZA intraperitoneally. Group IV: rosemary azathioprine group: the rats were given daily doses of rosemary leaves extract then azathioprine in the last day of the experiment as in the previous regimen. The experiment continued for ten days. Blood samples were taken from all groups and examined for tumour necrosis factor alpha, serum amylase enzyme, C-reactive protein and renal function tests [serum urea and creatinine]. Rosemary significantly decreased the levels of tumour necrosis factor alpha, serum amylase enzyme and serum urea and C-reactive protein in rosemary AZA group compared to AZA group. The aqueous rosemary leaves extract has the ability to ameliorate the biochemical pathways of the side-effects of azathioprine, so it is advisable to give it concomitantly to patients treated by azathioprine

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.

effect of azathioprine on the pulp tissue of rat offsprings

12 adult pregnant female albino rats were used in this study. They were divided into two groups: Control group included 4 female pregnant rats, experimental group included 8 female pregnant rats. They were given 0.6 mg/day of azathioprine orally, from the first week of pregnancy until delivery. After parturition, the drug was stopped at once and the offsprings were sacrificed at 7, 21 and 35 days after birth. The jaws were dissected, decalcified and prepared for routine light microscopic examination using [H and E] stain. The results obtained from the experimental group were compared with those of the control group. The results showed mild to severe dilatation of the blood vessels with some degree of inflammation in the pulp tissue. There was extravasated red bloods cells and hemorrhage in the pulp. Edematous pulp tissue with abscesses formation were also observed