Exercise increases glucose transport into skeletal muscle via a pathway that is poorly understood. We investigated the role of endogenously produced reactive oxygen species (ROS) in contractionmediated glucose transport. Repeated contractions increased 2-deoxyglucose (2-DG) uptake roughly threefold in isolated, mouse extensor digitorum longus (fast-twitch) muscle. N -Acetylcysteine (NAC), a non-specific antioxidant, inhibited contraction-mediated 2-DG uptake by ∼50% (P < 0.05 versus control values), but did not significantly affect basal 2-DG uptake or the uptake induced by insulin, hypoxia or 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR, which mimics AMP-mediated activation of AMP-activated protein kinase, AMPK). Ebselen, a glutathione peroxidase mimetic, also inhibited contraction-mediated 2-DG uptake (by almost 60%, P < 0.001 versus control values). Muscles from mice overexpressing Mn2+ -dependent superoxide dismutase, which catalyses H 2 O 2 production from superoxide anions, exhibited a ∼25% higher rate of contractionmediated 2-DG uptake versus muscles from wild-type control mice (P < 0.05). Exogenous H 2 O 2 induced oxidative stress, as judged by an increase in the [GSSG]/[GSH + GSSG] (reduced glutathione + oxidized glutathione) ratio to 2.5 times control values, and this increase was substantially blocked by NAC. Similarly, NAC significantly attenuated contraction-mediated oxidative stress as judged by measurements of glutathione status and the intracellular ROS level with the fluorescent indicator 5-(and-6)-chloromethyl-2 ,7 -dichlorodihydrofluorescein (P < 0.05). Finally, contraction increased AMPK activity and phosphorylation ∼10-fold, and NAC blocked ∼50% of these changes. These data indicate that endogenously produced ROS, possibly H 2 O 2 or its derivatives, play an important role in contraction-mediated activation of glucose transport in fast-twitch muscle.

Dosing of antibacterial agents is generally based on point estimates of the effect, even though bacteria exposed to antibiotics show complex kinetic behaviors. The use of the whole time course of the observed effects would be more advantageous. The aim of the present study was to develop a semimechanistic pharmacokinetic (PK)/pharmacodynamic (PD) model characterizing the events seen in a bacterial system when it is exposed to antibacterial agents with different mechanisms of action. Time-kill curve experiments were performed with a strain of Streptococcus pyogenes exposed to a wide range of concentrations of the following antibiotics: benzylpenicillin, cefuroxime, erythromycin, moxifloxacin, and vancomycin. Bacterial counts were monitored with frequent sampling during the experiment. A simultaneous fit of all data was accomplished. The degradation of the drugs was monitored and corrected for in the model, and a link model was used to account for an effect delay. In the final PK/PD model, the total bacterial population was divided into two subpopulations: one growing drug-susceptible population and one resting insusceptible population. The drug effect was included as an increase of the killing rate of bacteria in the susceptible state, according to a maximum-effect (E max ) model. An internal model validation showed that the model was robust and had good predictability. In conclusion, for all drugs, the final PK/PD model successfully described bacterial growth and killing kinetics when the bacteria were exposed to different antibiotic concentrations. The semimechanistic model that was developed might, after further refinement, serve as a tool for the development of optimal dosing strategies for antibacterial agents.The MIC is the most commonly used parameter to describe the efficacy of an antibacterial agent against a bacterial strain. This is an in vitro measure reflecting the efficacy of a constant antibiotic exposure to a specified bacterial inoculum after an incubation period of 16 to 20 h (19). The MIC is an estimate of the susceptibility of a bacterial strain to an antibiotic that can guide the choice of appropriate antibiotic treatment in the clinical setting. However, it is not an optimal pharmacodynamic (PD) marker since it reflects only a point estimate of the effect and does not take the time course of the effect into account. Nevertheless, the pharmacokinetic (PK)/PD relationship for antibiotics has generally been characterized by using point estimates of the pharmacodynamics (e.g., the bacterial load after 24 h of exposure) and the pharmacokinetics. This approach has led to the classification of the antibacterial effect being dependent either on the antibiotic exposure (the maximum concentration in serum/MIC or the area under the concentration-time curve/MIC) or on the time that the antibiotic concentration is kept above the MIC (4, 18). The design of dosing schedules may, however, be further optimized if it is based on models that take the whole time course of the PK/PD relation, i.e., the time cour...

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Bodyweight and age (GA and PNA) were found to be major factors contributing to IIV in gentamicin clearance in neonates. Based on these data, cystatin C and serum creatinine were not correlated with gentamicin clearance and therefore not likely to be predictive markers of renal function in this patient population. Based on predictions from the developed model, preterm neonates do not reach targeted peak and trough gentamicin concentrations after a standard dosage regimen of 4 mg/kg given once daily, suggesting a need for higher loading doses and prolonged dosing intervals in this patient population.