Novel treatment for the management of ifosfamide neurotoxicity: Rationale for the use of methylene blue

Abstract

Objective. To provide an overview of the proposed pathophysiology of ifosfamide encephalopathy and the role of methylene blue for the treatment and prevention of this toxicity. Data Source. A Medline search using the terms ‘‘ifosfamide encephalopathy’’ and ‘‘methylene blue’’ was conducted for the period of 1990-2001. The reference lists from retrieved articles were reviewed Data Extraction. The author reviewed the retrieved material and included animal and pharmacokinetic data related to ifosfamide and the pathophysiology of ifosfamide neurotoxicity. Additionally, preclinical data and case reports describing the clinical use and rationale for methylene blue were included. Data Synthesis. Encephalopathy is a unique toxicity described with ifosfamide, but not with cyclophosphamide. Ifosfamide undergoes a secondary ‘‘deactivation’’ metabolic pathway to yield dechloroethylated metabolites and chloroacetalde-hyde. Chloroacetaldehyde is a metabolite that contributes to both the nephrotoxicity and neurotoxicity described with ifosfamide. Chloroacetaldehyde (or a dechloroethylated metabolite) may exert neurotoxic effects by one or more of the following mechanisms: (a) direct neurotoxic damage, (b) depletion of central nervous system (CNS) glutathione level, or (c) inhibition of mitochondrial oxidative phosphorylation resulting in impaired fatty acid metabolism. The biochemical derangements described with this acute toxicity appear to mimic a neonatal mitochondrial disorder, for which methylene blue has been used. Methylene blue has been shown to restore and maintain mitochondrial respiration and therefore can be used to correct or prevent acute neurotoxic effects. Methylene blue has been used to treat moderate to severe cases of ifosfamide neurotoxicity and has also been used prophylactically to prevent encephalopathy in high-risk conditions with the use of oral and bolus iv ifosfamide regimens. Methylene blue may be useful in the treatment of grade III or IV neurotoxicity or in those patients with recurrent neurological symptoms associated with ifosfamide administration. The use of prophylactic or concurrent administration of methylene blue with ifosfamide requires further clinical evaluation.