OBJECTIVE: To assess evidence from randomized controlled trials (RCTs) on the safety of isotonic versus hypotonic intravenous (IV) maintenance fluids in hospitalized children. METHODS:We searched PubMed, Embase, Cochrane Library, and clinicaltrials.gov (up to April 11, 2013) for RCTs that compared isotonic to hypotonic maintenance IV fluid therapy in hospitalized children. Relative risk (RR), weighted mean differences, and 95% confidence intervals (CIs) were calculated based on the effects on plasma sodium (pNa). The risk of developing hyponatremia (pNa ,136 mmol/L), severe hyponatremia (pNa ,130 mmol/L), and hypernatremia (pNa .145 mmol/L) was evaluated. We adopted a random-effects model in all meta-analyses. Sensitivity analyses by missing data were also performed.RESULTS: Ten RCTs were included in this review. The meta-analysis showed significantly higher risk of hypotonic IV fluids for developing hyponatremia (RR 2.24, 95% CI 1.52 to 3.31) and severe hyponatremia (RR 5.29, 95% CI 1.74 to 16.06). There was a significantly greater fall in pNa in children who received hypotonic IV fluids (-3.49 mmol/L versus isotonic IV fluids, 95% CI -5.63 to -1.35). No significant difference was found between the 2 interventions in the risk of hypernatremia (RR 0.73, 95% CI 0.22 to 2.48). None of the findings was sensitive to imputation of missing data.CONCLUSIONS: Isotonic fluids are safer than hypotonic fluids in hospitalized children requiring maintenance IV fluid therapy in terms of pNa. Pediatrics 2014;133:105-113

PurposeThe primary objective of this sub-study, undertaken as an extension to the previously reported phase I study, was to explore the feasibility, tolerability and pharmacokinetics (PK) of belinostat when administered by the oral route. Preliminary PD studies were also performed to enable comparison of the biologic effects of the oral and intravenous formulations. Patients and MethodsOral belinostat was administered in a range of doses and schedules (once, twice, or thrice daily), on either day 1 or days 1 -5, of the second or a subsequent treatment cycle in 15 patients who were included in the phase I trial of intravenous belinostat.Serial blood samples were collected for pharmacokinetic and pharmacodynamic (histone acetylation) analyses, and the results compared with corresponding analyses following intravenous administration. ResultsA total mean daily AUC of 2767 1453 ng hr/ml (8.7 4.6 M hr) resulted from a dose of 1000 mg/m 2 once daily (qd). There was no clear evidence of drug accumulation on twice daily dosing (bid) however a trend towards accumulation was apparent when belinostat was given three times daily (tid). Mean half life (T½) of a single dose of 1000 mg/m 2 was 1.5 hr ( 0.3 hr) and peak levels were reached in an average of 1.9hrs ( 0.3 hr). The half life was found to be independent of dose, but a trend towards increasing half life following multiple dosing was observed. Histone H4 4 hyperacetylation in PBMCs estimated after oral dosing was comparable to that achieved after intravenous administration. ConclusionsHigh doses of oral belinostat, up to 1000 mg/m 2 bid for 5 consecutive days, have been tolerated in this small study. An oral formulation could lead to enhanced drug exposure and, more importantly, prolonged effects on the intended drug target. Future trials are required to establish the optimal dose and schedule of oral administration of belinostat.

Purpose: BMS-214662 is a potent and selective inhibitor of the farnesyl transferase enzyme with in vitro and in vivo antitumor activity. The aims of this study were to characterize the toxicities and to determine the pharmacokinetic profiles of BMS-214662 when administered in combination with cisplatin, and to determine the constitutive farnesyltransferase activity as a surrogate pharmacodynamic end point.Experimental Design: Twenty-nine patients with advanced solid malignancy, refractory to conventional therapy, and with adequate hematological, renal, and hepatic function were treated with escalating doses of BMS-214662 administered as a 1-h infusion, followed after an interval of 30 min by 75 mg/m 2 cisplatin administered as a 4-h infusion and repeated every 21 days. Blood and urine samples for pharmacokinetic and pharmacodynamic analyses were collected during the first cycle of treatment only.Results: Dose-limiting toxicities occurred in 4 of 9 patients enrolled at the 225 mg/m 2 BMS-214662 dose cohort, and included elevation of hepatic transaminases, nausea, vomiting, diarrhea, and renal failure. There was no apparent pharmacokinetic interaction between the two drugs at the recommended dose levels, and a dose-dependent inhibition of farnesyltransferase activity was observed, which returned to control levels within 24 h of drug administration. There were no objective responses, but disease stabilization was observed in 15 patients, including 4 patients with stable disease after 6 cycles of treatment.Conclusions: A dose of 200 mg/m 2 of BMS-214662 administered as a 1-h infusion with 75 mg/m 2 cisplatin over 4 h is the recommended dose for additional studies.