Deferoxamine Mesylate

Abstract

Abstract-Iron resulting from hemoglobin degradation is linked to delayed neuronal injury after intracerebral hemorrhage. Extensive preclinical investigations indicate that the iron chelator, deferoxamine mesylate, is effective in limiting hemoglobin-and iron-mediated neurotoxicity. However, clinical studies evaluating the use of deferoxamine in intracerebral hemorrhage are shortcoming. This article reviews the potential role of deferoxamine as a promising neuroprotective agent to target the secondary effects of intracerebral hemorrhage to limit brain injury and improve outcome, and ongoing efforts to translate the preclinical findings into clinical investigations. Key Words: deferoxamine Ⅲ ICH Ⅲ edema Ⅲ neuroprotection A t present, there is no specific treatment for spontaneous intracerebral hemorrhage (ICH) beyond supportive medical care. Therapeutic attempts to target hematoma and its expansion might provide some benefit in carefully selected patients. However, this strategy alone is likely to be of limited usefulness because hematoma expansion often occurs within the first hours after onset. Furthermore, neuronal injury in ICH is not only related to hematoma expansion. Other secondary processes, including apoptosis, necrosis, autophagy, inflammation, and edema formation, have been implicated. 1,2 A potential adjunctive approach to the treatment of ICH might be to target hemoglobin-and iron-mediated neurotoxicity. Iron-Mediated NeurotoxicityHemoglobin degradation products resulting from hemolysis after ICH include the iron-containing heme. Iron plays a role in neuronal injury by catalyzing a sequence of reactions "Haber-Weiss reaction" that yield highly reactive toxic hydroxyl radicals leading to oxidative stress and cell death, activating lipid peroxidation, and exacerbating excitotoxicity. 3,4 The time course for hemoglobin hemolysis and toxicity after ICH is 2 to 3 days. 5,6 This delayed time window can have important therapeutic advantages. Deferoxamine MesylateDeferoxamine has been used in clinical practice for more than 30 years in iron-overloaded patients with acute iron intoxication or overload due to transfusion-dependent anemia. It is a hydrophilic chelator, which chelates Fe ϩϩϩ and hemosiderin forming a stable complex that prevents iron from entering into Haber-Weiss reaction. The drug is relatively well tolerated. Serious adverse effects are uncommon. Hypotension and shock occur in 2% of patients, mostly with rapid intravenous administration at high doses. The infusion rate should not exceed 15 mg/kg per hour, and the total amount administered should not exceed 6000 mg in 24 hours. PharmacokineticsDeferoxamine is rapidly absorbed. Plasma concentrations between 80 and 130 mol/L are recorded 3 minutes after intravenous injections. The drug's serum protein-binding rate is Ͻ10%. It is distributed throughout all body fluids and has a volume of distribution of 0.8 to 1.35 L/kg. The drug is mostly metabolized by oxidative deamination, yielding metabolite B. The drug, its iron chelate complex (ferrioxamin...

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“…However, the potential beneficial effects of deferoxamine may be only partly related to its iron chelating abilities. Deferoxamine also alters iron regulatory genes and proteins binding activity, thereby reducing cellular vulnerability to iron; prevents apoptosis induced by glutathione depletion and OS by activating a signal transduction pathway leading to activation transcription factor 1/cAMP response element-binding protein and hypoxia inducible factor, and the expression of genes known to compensate for OS; inhibits prolyl 4-hydroxylase activity, which may lead to protection from OS-induced cell death; this exerts anti-inflammatory effects by stimulating cyclo-oxygenase; blocks glutamate-mediated excitotoxicity; and exerts anti-phagocytic effects [115].…”