Phase 1 study of arsenic trioxide, high-dose cytarabine, and idarubicin to down-regulate constitutive signal transducer and activator of transcription 3 activity in patients aged <60 years with acute myeloid leukemia.

BACKGROUND: Constitutive activation of signal transducer and activator of transcription-3 (STAT3) was detected in blasts from approximately 50% of patients with acute myeloid leukemia (AML) and was correlated with an adverse outcome. In vitro treatment of AML blasts with arsenic trioxide (ATO) down-regulated STAT3 activity within 6 hours associated with a reduced viability within 48 hours. METHODS: A phase 1 clinical trial to evaluate the biologically effective dose and/or the maximally tolerated dose (MTD) of ATO in vivo in conjunction with high-dose cytarabine (Hidac) and idarubicin (Ida) in patients with AML aged <60 years was conducted. Data were compared with 117 historic AML patients who had received treatment with Hidac/Ida. RESULTS: In total, 61 patients were enrolled onto 11 different dose levels (from 0.01 to 0.65 mg/kg ideal body weight). The MTD was 0.5 mg/kg. Compared with historic controls, patients who received ATO/Hidac/Ida, although they had similar pretreatment characteristics, had better overall survival (P = .039). CONCLUSIONS: ATO priming may have improved the outcome of patients aged <60 years with AML who received Hidac/Ida. The current data suggested that ATO may enhance the effect of chemotherapy. The authors concluded that further studies of this novel combination are warranted.

An overview of the central control of weight regulation and the effect of antipsychotic medication.

Weight regulation is a complex system necessary for maintaining health. Obesity and cachexia are consequences of dysregulation and cause significant physical morbidity and mortality. In the developed world, obesity is a growing epidemic. A greater understanding of the neuroanatomy of weight regulation has been gained through advances in imaging and neural mapping techniques. The neural connections between key hypothalamic and other central nuclei have been elucidated. Advances in molecular biology have led to the identification and cloning of important peripheral and central weight regulating peptides. Weight gain as a consequence of antipsychotic use is increasingly being recognized as a serious clinical issue. The weight regulation system provides a framework upon which antipsychotics exert their weight-inducing effects. Some studies have sought, with inconsistent results, to establish associations between antipsychotic use and levels of weight regulating mediators. The receptor pharmacology of antipsychotics known to increase weight can be studied with a view to establishing genetic variants contributing to the risk. To date, the 5-HT(2C) receptor 759C/T polymorphism shows most promise. Further studies are required to replicate previous findings and establish new associations.