ATO is administered as a 2-hour intravenous infusion in doses of 0.15 mg/kg/day for up to 60 days, until remission is documented. Further consolidation therapy resumes after a 3-week break. The primary mechanism of elimination is by enzymatic methylation to metabolites that have uncertain biological effects. Peak concentrations of ATO in plasma reach 5—7 jjM with rapid conversion to metabolites. Little drug appears in the urine. No dose reductions are indicated for hepatic or renal dysfunction.
Pharmacological doses of ATO are well tolerated. Patients may experience reversible side effects including hyperglycemia, hepatic enzyme elevations, fatigue, dysesthesias, and lighthead-edness. Ten percent or fewer of patients will experience a leukocyte maturation syndrome similar to that seen with ATRA. O2, glucocorticoids, and temporary discontinuation of ATO lead to full reversal of this syndrome. Another important and potentially dangerous side effect is lengthening of the QT interval on the electrocardiogram in 40% of patients. The basis for this conduction defect appears to be enhanced Ca2+ flux and an inhibition of K+ channels in myocardial tissue by
As2O3, which leads to atrial or ventricular arrhythmias in a small minority of patients. Daily monitoring of the ECG and repletion of serum K+ in patients with hypokalemia are standard measures in ATO therapy.
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