Investigation on vibro-impacts of driveline system based on a nonlinear clearance element with time-varying stiffness and oil-squeeze damping

The transient vibro-impacts induced by clearance between the connected rotors in driveline system easily causes serious transient noise and vibration, especially between the gear teeth with backlash. To analyze the transient vibro-impacts of the driveline system excited by a step-down engine torque, a new piecewise nonlinear clearance element with time-varying stiffness and oil squeeze damping is proposed, and an 8 degree-of-freedom lumped parameters model with the new piecewise nonlinear clearance elements is established. The transient vibro-impact phenomena of the vehicle driveline during fast disengagement of the clutch are numerically simulated. Colormaps of angular acceleration and vibro-impact force shows the difference of frequency components from transient impact to stable tooth-meshing. The phase plane reveals the phenomenon of multiple impacts and rebounds in each transient impact, and shows the relationship between the relative contact displacement and velocity. The frequency responses of the angular velocity, angular acceleration and vibro-impact forces with time-varying stiffness and linear stiffness are compared respectively. Compared with the widely used clearance element with piecewise linear stiffness, the new nonlinear clearance element with the piecewise nonlinear time-varying stiffness can better reveal the transient vibro-impact responses between the driving and driven gears. Lastly, the transient vibro-impact results of driveline system are verified by the vehicle experiments.

Population Pharmacokinetics of Extended-Infusion Piperacillin-Tazobactam in Hospitalized Patients with Nosocomial Infections

ABSTRACTWhile extended infusions of piperacillin-tazobactam (TZP) are increasingly used in practice, the effect of infusion on the pharmacokinetic (PK) profile of TZP has not been widely assessed. To assess its effect on the pharmacokinetic profile of TZP, seven serum samples were collected from 11 hospitalized patients who received 3.375 g TZP intravenously for 4 h every 8 h. Population pharmacokinetic models were fit to the PK data utilizing first-order, Michaelis-Menten (MM), and parallel first-order/MM clearance. A population PK model with first-order clearance was fit to the tazobactam PK data. Monte Carlo simulations (MCSs) were used to determine the most effective administration schedule to ensure that free piperacillin concentrations were above the MIC for at least 50% of the dosing interval (50%fT>MIC) and to quantify the extent of the nonlinear clearance. The model incorporating parallel linear/MM clearance best fit the piperacillin PK data. The MCSs demonstrated that approximately 50% of the administered piperacillin is cleared by the nonlinear clearance mechanism. The results of the MCSs also revealed that more intensive TZP extended infusion dosing schemes (3.375 to 4.5 g intravenously [3-h infusion] every 6 h) than those commonly used in clinical practice were needed to maximize the 50%fT>MIC for MICs of ≥8 mg/liter. This study suggests that extended infusion of TZP is the most effective method of administration for patients with nosocomial infections. Due to the hyperclearance nature of the hospitalized patient populations studied, more intensive TZP dosing regimens may be needed to maximizefT>MIC in certain hospitalized populations.

Lack of Whole-body Pharmacokinetic Differences of Halothane Enantiomers in the Rat

Background Halothane is made and used as a racemate (an equimolar mixture of R- and S- enantiomers). This study was initiated to determine whether there were demonstrable enantiomeric differences in the whole-body pharmacokinetics of halothane that might have significance for studies in which racemate is used. Methods Adult male Wistar rats were exposed to halothane vaporized in the atmosphere of a closed constant volume chamber supplied with O2 commensurate with CO2 production. Concentrations of halothane enantiomers were measured by a specific gas chromatography-mass spectrometry method. Experiments were performed at four initial concentrations of halothane (0.1%, 0.5%, 1.0%, and 1.5% vol/vol). Enantiomeric differences in whole-body pharmacokinetics were assessed indirectly from the relative chamber atmosphere concentrations of halothane enantiomers. Results Concentrations of halothane decreased biphasically. The initial more rapid decrease was interpreted as incorporating absorption, distribution, and clearance; the slower decrease was interpreted as principally incorporating metabolic clearance. The ratio of concentrations of the two halothane enantiomers and of the ratios of the respective areas under the concentration-time curves remained constant without differing from unity at any time at any concentration of halothane. The dose-normalized areas under the concentration-time curves for the concentrations 0.1%, 0.5%, and 1.0% did not differ; that for 1.5% was significantly greater, suggesting nonlinear clearance, but the values did not differ significantly between enantiomers at any concentration. Conclusions As there were no significant differences in concentrations of the two enantiomers in the chamber atmosphere, enantioselectivity was not demonstrated in the whole-body pharmacokinetics of halothane.