Phase I study of XXXX and @entity1855 given by concurrent iv infusion.

@entity1 @entity137 @entity23198 @entity8253 @entity5 @entity17074 @entity1855 @entity2359 @entity616 @entity5713 @entity460 @entity8270
Overcoming resistance to chemotherapy is an important goal in @entity5 treatment. In many systems, resistance to @entity8253 and @entity17074 correlates with a diminished intracellular content of drug. In @entity23198 and @entity8270 , an active outward transport of @entity8253 and vinca alkaloids occurs. @entity460 channel blockers, such as @entity1855 , inhibit this active outward transport and increase intracellular content of @entity5713 and @entity8253 in cells resistant to vinca alkaloids and @entity8253 , respectively. We report a phase I trial of @entity5713 (1.5 mg/m2 daily as iv continuous infusion X 5 days) in 17 @entity1 and concurrent @entity1855 in escalating doses. @entity1855 was administered as a loading dose (0.02-0.1 mg/kg) followed by a maintenance infusion (0.036-0.18 mg/kg/hour) for 5 1/2 days with continuous cardiac monitoring. There was no apparent augmentation of @entity5713 @entity137 when @entity5713 and @entity1855 were given concurrently. ECG change was the dose-limiting @entity137 . At 0.12 mg/kg/hour, five of nine @entity1 developed first-degree @entity616 (mean P-R interval, 0.32 seconds; range, 0.23-0.52 seconds). Junctional rhythms were noted in two of 17 @entity1 . Reversible nonspecific T-wave changes were seen in four of 17 @entity1 . Blood pressure and left ventricular ejection fractions (ultrasonic) were not altered. Five of 17 @entity1 had wbc count nadirs less than 2000/mm3, and two of 17 @entity1 had platelet count nadirs less than 100,000/mm3. Four @entity1 experienced @entity2359 . A mean @entity5713 concentration of 2.2 ng/ml (0.55 nM) and a mean @entity1855 concentration of 290 ng/ml (0.45 microM) were achieved with the concurrent 5-day infusion. The tolerable levels of @entity1855 obtained appear to be less than those which were reported to inhibit @entity5713 efflux in vitro. Additional in vitro experiments at the tolerable doses of @entity5713 and @entity1855 are recommended.
