191 Pulsatile Administration of Leucine Promotes mTOR Signaling and Protein Synthesis in Skeletal Muscle of Continuously Fed Preterm Pigs

Continuous feeding does not elicit an optimal anabolic response but is required for some premature infants. We reported previously that intermittent intravenous pulses of Leu (800 μmol Leu·kg-1·h-1 every 4 h) to continuously fed pigs born at term enhanced skeletal muscle mTOR signaling and protein synthesis (PS). The objective of this study was to determine if the anabolic response of skeletal muscle to intermittent Leu pulses is altered following premature birth. Pigs delivered 10 d preterm by cesarean section were advanced to full oral feeding over four days (195 kcal·kg-1·d-1; 13.5 g protein·kg-1·d-1). Pigs were assigned to 1 of 4 treatments: 1) ALA (continuous feeding; 800 μmol Ala·kg-1·h-1 every 4 h; n = 7); 2) L1× (continuous feeding; 800 μmol Leu·kg-1·h-1 every 4 h; n = 6); 3) L2× (continuous feeding; 1600 μmol Leu·kg-1·h-1 every 4 h; n = 6); and 4) INT (intermittent feeding every 4 h; n = 5). Pigs received a Phe tracer 30 min following the amino acid pulse or intermittent feeding to measure PS in longissimus dorsi muscle. Anabolic signaling downstream of mTOR was determined by immunoblot.ResultsPS was higher in L2× and INT compared to ALA (P < 0.05) but was not different between L2× and INT; PS in L1× was intermediate and not different from other groups. Phosphorylation of 4EBP1 and S6K1 was higher in INT compared to L1× and ALA groups (P < 0.05) but was not different compared to L2×. Phosphorylation of 4EBP1, but not S6K1, was higher in L2× compared to ALA (P < 0.05); phosphorylation of 4EBP1 and S6K1 was not different between L1× and L2×.ConclusionsThese results demonstrate that intravenous Leu enhances mTOR activation and PS in LD muscle of continuously fed preterm pigs. However, the amount required may be higher than in pigs born at term.Source of Research SupportNIH and USDA.

Pharmacokinetic–pharmacodynamic modelling of the hypoglycaemic effect of pulsatile administration of human insulin in rats

The relationship between the plasma insulin (INS) concentration–time course and plasma glucose concentration–time course during and after pulsatile INS administration to rats was characterized using a pharmacokinetic–pharmacodynamic (PK–PD) model. A total INS dose of 0.5 IU/kg was intravenously injected in 2 to 20 pulses over a 2-h period. Compared with the single bolus administration, the area under the effect-time curve (AUE) increased depending on the number of pulses, and the AUEs for more than four pulses plateaued at a significantly larger value, which was similar to that after the infusion of a total of 0.5 IU/kg of INS over 2 h. No increase in plasma INS concentration occurred after pulsatile administration. Two indirect response models primarily reflecting the receptor-binding process (IR model) or glucose transporter 4 (GLUT4) translocation (GT model) were applied to describe the PK–PD relationship after single intravenous bolus administration of INS. These models could not explain the observed data after pulsatile administration. However, the IR-GT model, which was a combination of the IR and GT models, successfully explained the effects of pulsatile administration and intravenous infusion. These results indicate that the receptor-binding process and GLUT4 translocation are responsible for the change in AUE after pulsatile administration.

A randomized phase II trial comparing pulsed erlotinib before or after carboplatin and paclitaxel in patients with stage IIIB or IV non-small cell lung cancer

7619 Background: A randomized phase 3 trial failed to show any improvement in response rate (RR) or overall survival (OS) when erlotinib was added to carboplatin and paclitaxel (TRIBUTE). However, preclinical data suggested that administration of erlotinib before or after chemotherapy may improve efficacy of chemotherapy [Gumerlock et al ASCO 2003, Solit et al Clin Can Res 2005]. We designed this trial to test the hypothesis that administration of pulsed erlotinib prior to or following chemotherapy would improve the response rate in patients with advanced NSCLC. Methods: All patients had chemotherapy naive, stage IIIB or IV NSCLC and were former or current smokers. All patients received carboplatin (AUC 6) and paclitaxel (200 mg/m2). Patients were randomly assigned to one of three arms: erlotinib 150 mg days 1,2, and chemotherapy on day 3; erlotinib 1500 mg days 1, 2 and chemotherapy on day 3; or chemotherapy on day 1 and erlotinib 1500 mg on days 2,3. Patients received up to six 21-day cycles of treatment. The primary endpoint was overall RR (CR+PR) using RECIST. We planned to enroll 29 patients to each arm in a “pick the winner” design comparing arms to the chemotherapy alone arm of TRIBUTE (RR 19%) with a desirable RR of 50%. Results: Eighty-seven patients were randomized to 3 arms. Accrual is complete. The most common grade 3/4 toxicities were neutropenia (39%), fatigue (15%), and anemia (12%). Grade 3/4 rash or diarrhea were uncommon. Conclusions: Treatment with erlotinib before (150 mg on days 1 and 2 or 1500 mg on days 1 and 2) or after (1500 mg on days 2 and 3) administration of carboplatin and paclitaxel failed to improve response rates compared to TRIBUTE. The benefit of pulsatile administration of erlotinib predicted by preclinical models was not evident in this clinical trial. Supported by Genentech, Inc. [Table: see text] [Table: see text]