A pharmacodynamic study of the FLT3 inhibitor KW-2449 yields insight into the basis for clinical response.

Internal tandem duplication mutations of FLT3 (FLT3/ITD mutations) are common in acute myeloid leukemia (AML) and confer a poor prognosis. This would suggest that FLT3 is an ideal therapeutic target, but FLT3 targeted therapy has produced only modest benefits in clinical trials. Due to technical obstacles, the assessment of target inhibition in patients treated with FLT3 inhibitors has been limited and generally only qualitative. KW-2449 is a novel multitargeted kinase inhibitor that induces cytotoxicity in Molm14 cells (which harbor an FLT3/ITD mutation). The cytotoxic effect occurs primarily at concentrations sufficient to inhibit FLT3 autophosphorylation to less than 20% of its baseline. We report here correlative data from a phase 1 trial of KW-2449, a trial in which typical transient reductions in the peripheral blast counts were observed. Using quantitative measurement of FLT3 inhibition over time in these patients, we confirmed that FLT3 was inhibited, but only transiently to less than 20% of baseline. Our results suggest that the failure to fully inhibit FLT3 in sustained fashion may be an underlying reason for the minimal success of FLT3 inhibitors to date, and stress the importance of confirming in vivo target inhibition when taking a targeted agent into the clinical setting.

Glucose Response during the Night Is Suppressed by Wheat Albumin in Healthy Participants: A Randomized Controlled Trial.

Postprandial blood glucose excursions are important for achieving optimal glycemic control. In normal-weight individuals, glucose tolerance is diminished in the evening compared to glucose tolerance in the morning. Wheat albumin (WA) has the potential to suppress the postprandial glucose response with a relatively small dose, compared to the dose required when using dietary fiber. In the present study, the effect of WA on glycemic control during the night was investigated after a late evening meal. A randomly assigned crossover trial involving a single oral ingestion in healthy male participants was performed in a double-blind placebo-controlled manner. The participants ingested the placebo (PL) tablets or the WA (1.5 g)-containing tablets 3 min before an evening meal at 22:00 hour, and blood samples were drawn during the night until 07:00 hour using an intravenous cannula. The participants slept from 00:30 hour to 06:30 hour. Glucose response, as a primary outcome during the night, was suppressed significantly by the WA treatment compared to the PL treatment, but the insulin response was not. Plasma glucose-dependent insulinotropic polypeptide concentration during the night was lowered significantly by the WA treatment compared to the PL treatment. In conclusion, WA may be a useful food constituent for glycemic control during the night.

Wheat Albumin Increases the Ratio of Fat to Carbohydrate Oxidation during the Night in Healthy Participants: A Randomized Controlled Trial.

Not only are energy expenditure (EE) and the respiratory quotient (RQ) parameters of the energy nutrient utilization and energy balance, they are also related to the development of obesity. In this study, post-meal night-time energy metabolism was investigated following the oral ingestion of wheat albumin (WA) with a late evening meal. A randomly assigned, double-blind, placebo-controlled crossover trial for a single oral ingestion in healthy participants was completed. The participants ingested the placebo (PL) or WA (1.5 g) containing tablets 3 minutes before the late evening meal at 22:00 hour, and energy metabolism was measured using a whole-room indirect calorie meter until wake-up. The participants were in bed from 00:00 hour until 06:30 hour. Twenty healthy participants completed the trial and were included in the analyses. Night-time RQ and carbohydrate oxidation were significantly lower following the WA treatment as compared with the PL treatment. Although the total EE was not significantly different between treatments, postprandial fat oxidation was significantly higher following the WA treatment as compared with the PL treatment. In conclusion, WA has the potential to shift the energy balance to a higher ratio of fat to carbohydrate oxidation during the night.