Somnolence, hypotension, and metabolic acidosis following high-dose teniposide treatment in children with leukemia

Abstract

This report describes an unexpected adverse effect in three children receiving teniposide at 3-5 times the conventional dosage (i.e. 200 mg/m2) plus cytarabine as part of continuation therapy for acute lymphocytic leukemia. Pharmacokinetic studies in each patient had demonstrated high teniposide clearances, and thus the increased dosage requirements were necessary to attain plasma concentrations similar to those expected for patients with average drug clearance. At 3-4 h after the beginning of the 4-h simultaneous infusions of teniposide and cytarabine, these patients experienced somnolence, hypotension, and metabolic acidosis. The adverse events were associated with elevated teniposide plasma concentrations during the infusions compared with those in patients receiving similar doses without toxicity, and clinically significant ethanol concentrations, presumably from the teniposide formulation. Blood concentrations of cremophor and histamine, which are also constituents of the teniposide formulation, were not measured. In addition, concomitant therapy with antiemetic agents in patients who may have been mildly volume-depleted due to emesis may also play a contributory role. Prolonging the infusion time for patients receiving teniposide doses above 500 mg/m2 will avoid excessive teniposide and ethanol plasma concentrations and minimize the risk of this potentially serious side effect.

AraC binds the p75NTRtransmembrane domain to induce neurodegeneration in mature neurons

“…Although the current work has focused on the effect of AraC on mature CGNs, we speculate that mature neurons in other brain regions that express p75 NTR could be also affected by this treatment. Interestingly, AraC treated patients also exhibit somnolence and drowsiness 63,64 , reinforcing the notion that this drug could alter the function of other brain regions besides the cerebellum. Intriguingly, one brain region that express p75 NTR in abundance in adult brain is the basal forebrain 18 , which has been implicated in the homeostatic regulation of sleep [65][66][67] .…”

AraC interacts with p75NTR transmembrane domain to induce cell death of mature neurons

“…Although the current work has focused on the effect of AraC on mature CGNs, we speculate that mature neurons in other brain regions that express p75 NTR could also be affected by this treatment. Interestingly, AraC-treated patients also exhibit somnolence and drowsiness [ 72 , 73 ], reinforcing the notion that this drug could alter the function of other brain regions besides the cerebellum. Intriguingly, one brain region that expresses p75 NTR in abundance in the adult brain is the basal forebrain [ 18 ], which has been implicated in the homeostatic regulation of sleep [ 74 – 76 ].…”