Most individuals with cystic fibrosis (CF) carry one or two mutations that result in a maturation defect of the full-length protein. One such mutation, deltaF508, results in a mutant membrane glycoprotein that fails to progress to the apical membrane, where the wild-type protein normally functions as a cyclic AMP-regulated chloride channel. 4-Phenylbutyrate (Buphenyl), an orally bioavailable short chain fatty acid, modulates heat shock protein expression and restores maturation of the deltaF508 protein in vitro and in vivo. We performed a randomized, double-blind, placebo-controlled, dose-escalation and safety study of Buphenyl in 19 adults with CF (homozygous deltaF508) to test the hypothesis that Buphenyl would be safe, well-tolerated, and associated with an increase in chloride transport in nasal epithelia. Three dose levels (20, 30, or 40 g divided t.i.d.) of drug or placebo were given for 1 week. Serial measurements of chloride transport by nasal potential difference (NPD) testing and metabolic safety testing were performed. A maximum tolerated dose of 20 g was defined based on minimal adverse reactions, the safety profile, and a statistically significant induction of chloride transport that was maximal by day 3. This short-term phase I/II study demonstrates proof of principle that modulation of deltaF508 CFTR biosynthesis and trafficking is a viable therapeutic approach for cystic fibrosis.
Purpose: Weekly administration of docetaxel has demonstrated comparable efficacy together with a distinct toxicity profile with reduced myelosuppression, although pharmacokinetic data with weekly regimens are lacking. The comparative pharmacokinetics of docetaxel during weekly and once every 3 weeks (3-weekly) administration schedules were evaluated.Experimental
The World Wide Web-based antimicrobial approval program led to improved communication, more-efficient antimicrobial administration, increased user satisfaction, and significant cost savings. Integrated tools, such as this World Wide Web-based antimicrobial approval program, will effectively enhance antimicrobial stewardship programs.
AKI was common in children receiving vancomycin. Higher doses of vancomycin were associated with increased odds of AKI. The risks and benefits of higher vancomycin dosing should be considered for each patient. Patients should be monitored closely for AKI, especially with higher doses, extended durations of therapy, or concomitant use of nephrotoxic medications.
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