Addition of cetuximab to weekly infusional 5-FU/FA plus irinotecan is safe and first data suggest a promising activity. The 5-FU dose of 1500 mg/m(2) is recommended for further studies.

Cetuximab is a monoclonal antibody directed against the epidermal growth factor receptor and is indicated in the treatment of squamous cell carcinoma of the head and neck. The population pharmacokinetics of cetuximab were characterized by nonlinear mixed effects modeling (NONMEM V) using a total of 912 concentrations from 143 patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck enrolled in 2 phase I/II studies. Cetuximab pharmacokinetics were best described by a 2-compartment model with Michaelis-Menten-type saturable elimination. Population estimates (between-subject variability, percent coefficient of variation) of the pharmacokinetic parameters were V(max) 4.38 mg/h (15.4%), K(m) 74 mug/mL, central compartment volume V(1) 2.83 L (18.6%), peripheral compartment volume 2.43 L (56.4%), and intercompartmental clearance 0.103 L/h (97.2%). Ideal body weight and white blood cell count were identified as predictors of V(max) and total body weight as a predictor of V(1). Clinical dose adjustments beyond the approved body surface area-based dosing of cetuximab may be warranted in patients with extreme deviations of their actual body weight from ideal body weight. Agreement between simulated and measured concentrations monitored for up to 43 weeks of therapy indicates that cetuximab pharmacokinetic parameters remained constant during prolonged therapy.

This study evaluates polyamidoamine PAMAM "starburst" dendrimers (generation 3, Mr 6909) as a potential delivery vehicle for oligonucleotides. Complexes between dendrimer and phosphorothioate oligonucleotides were observed by agarose gel electrophoresis and were positive, negative, or neutral in charge depending on stoichiometry. Complexes were stable in 50% serum to variations in pH (3, 5, and 10) and ionic strength (0-500 mM). Ultrafiltration and gel filtration characterization indicated that the dendrimer:oligonucleotide complexes were primarily < 100 kD, although some larger complexes were formed at oligonucleotide excess. Use of dendrimers resulted in a 50-fold enhancement in cell uptake of oligonucleotide as determined by flow cytometry, and enhanced cytosolic and nuclear availability, as shown by confocal microscopy. These data support the further evaluation of dendrimers for oligonucleotide delivery in cell culture and in vivo.

Timely intervention for acute cyanide poisoning could entail administration of an antidote in the prehospital setting based on a presumptive diagnosis. Results of this placebo-controlled study in healthy volunteers corroborate previous studies and French postmarketing experience in cyanide-exposed patients in suggesting that the safety profile of hydroxocobalamin is consistent with prehospital or hospital use.

The tissue penetration and distribution of antibiotics is of great importance, since most of the infections occur in the tissue. At the infection site, the free, unbound fraction of the antibiotic is responsible for the antiinfective effect. These free extracellular concentrations can be measured by microdialysis. It was the aim of the study to correlate free levels of the beta-lactam antibiotic piperacillin in blood with those in tissue. In vivo microdialysis sampling was used to study the tissue distribution patterns of piperacillin in anesthetized rats after single dose iv administration of the drug. The pharmacokinetics of piperacillin in plasma were consistent with a two-compartment body model. Comparisons between calculated free concentrations in the peripheral compartment and measured free extracellular concentrations revealed excellent agreement. Microdialysis is a suitable method to evaluate unbound drug concentrations in the tissues. In case of piperacillin, predictions of the concentration time profiles of free drug in the peripheral compartment can be made on the basis of plasma data.