Aminophylline for methotrexate-induced neurotoxicity

Transient encephalopathy following high-dose methotrexate treatment in childhood acute lymphoblastic leukemia

“…27 The acute onset and reversibility have suggested a vascular etiology, such as intracranial vasculitis, emboli, or vascular occlusion, 12 possibly exacerbated or initiated by metabolic disturbances. 13,16,27 For example, it has been proposed that neurotoxicity may result from altered neurotransmitter levels secondary to inhibition of tetrahydrobiopterin synthesis, 13,28 or from increased adenosine 29 or homocysteine 16 levels. Homocysteine, which is increased in patients treated with MTX, causes direct vascular endothelium injury and may, therefore, result in ischemia-mediated neurotoxicity.…”

Molecular therapeutics. Methotrexate and its mechanism of action

“…This provides further evidence that the antiinflammatory effects of MTX are mediated, at least in part, by adenosine. More support for the hypothesis that MTX enhances adenosine release in humans was provided by Bernini et a1 (91), who reported that high-dose MTX increases adenosine concentrations in the cerebrospinal fluid of children treated for childhood leukemia. Thus, MTX treatment does lead to local increases in adenosine concentration in both animals and humans, and the evidence is consistent with the notion that agents that promote adenosine release by alternative mechanisms are also antiinflammatory in in vitro and animal models.…”

“…Similar toxic reactions are seen in children treated with higher doses of MTX for leukemia. Bernini and colleagues (91) showed that the severe CNS toxicity observed in MTX-treated leukemia patients was associated with dramatic elevations in cerebrospinal fluid adenosine concentrations and was completely reversed by administration of an adenosine receptor antagonist (aminophylline). These observations suggest that the well-established CNS effects of adenosine are responsible for the CNS toxicity experienced by some patients.…”

Methotrexate Induced Acute Encephalopathy-Occurrence on Re-challenge and Response to Aminophylline

“…Our patient derived no benefit from dexamethasone and leucovorin. Raised adenosine levels have been implicated in methotrexate encephalopathy which can be pharmacologically antagonized by aminophylline [4,9,11]. We did not have access to adenosine levels, but empiric aminophylline yielded immediate response.…”