Translational Modeling in Schizophrenia:Predicting Human Dopamine D2 Receptor Occupancy

OBJECTIVES: To assess the ability of a previously developed hybrid physiology-based pharmacokinetic-pharmacodynamic (PBPKPD) model in rats to predict the dopamine D2 receptor occupancy (D2RO) in human striatum following administration of antipsychotic drugs.METHODS: A hybrid PBPKPD model, previously developed using information on plasma concentrations, brain exposure and D2RO in rats, was used as the basis for the prediction of D2RO in human. The rat pharmacokinetic and brain physiology parameters were substituted with human population pharmacokinetic parameters and human physiological information. To predict the passive transport across the human blood-brain barrier, apparent permeability values were scaled based on rat and human brain endothelial surface area. Active efflux clearance in brain was scaled from rat to human using both human brain endothelial surface area and MDR1 expression. Binding constants at the D2 receptor were scaled based on the differences between in vitro and in vivo systems of the same species. The predictive power of this physiology-based approach was determined by comparing the D2RO predictions with the observed human D2RO of six antipsychotics at clinically relevant doses.RESULTS: Predicted human D2RO was in good agreement with clinically observed D2RO for five antipsychotics. Models using in vitro information predicted human D2RO well for most of the compounds evaluated in this analysis. However, human D2RO was under-predicted for haloperidol.CONCLUSIONS: The rat hybrid PBPKPD model structure, integrated with in vitro information and human pharmacokinetic and physiological information, constitutes a scientific basis to predict the time course of D2RO in man.</p

Effect of antiarrhythmic drugs on ventricular conduction of midrange extrasystoles

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The effects of lidocaine and methyl lidocaine on cardiac conduction

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A specific effect of lidocaine and tocainide on ventricular conduction of mid-range extrasystoles

Lidocaine and tocainide had no effect on ventricular conduction of extrasystoles with coupling intervals longer than 500 msec in isolated blood-perfused dog hearts, but caused interval-related increases in conduction time of extrasystoles in the range of 250-400 msec, here called mid-range extrasystoles (MRE). Quinidine, procainamide, disopyramide, and methyl lidocaine increased conduction times of extrasystoles at all coupling intervals, and no additional slowing of MRE was observed. The slowing of MRE specific to lidocaine and tocainide was confirmed in the intact dog heart. During acute myocardial ischemia in the intact dog heart, conduction was slowed and additional slowing of MRE was found. Lidocaine and tocainide caused further slowing of conduction of MRE. This unique effect of lidocaine and tocainide on the conduction of MRE may be important in the suppression of the reentrant arrhythmias. However, lidocaine and tocainide were also found to be arrhythmogenic when extrasystoles were introduced, after acute coronary occlusion, in those animals in which such occlusion alone did not allow demonstration of arrhythmias due to extrasystoles.link_to_subscribed_fulltex

Effect of lidocaine and methyl lidocaine on cardiac conduction

The effects of lidocaine and methyl lidocaine on cardiac conduction were studied using His bundle recordings from isolated blood perfused dog hearts. The input and output characteristic of the atrioventricular (AV) node can be described as consisting of three components, namely, minimal conduction time, fatigue, and the effect of prematurity (ΔCT). Lidocaine (2.5-10.0 mg/kg) increased minimal conduction time but not fatigue. Methyl lidocaine (1.25-5.0 mg/kg) increased both. A dose of 5 mg/kg or less of either drug caused a nonparallel shift of the ΔCT curve to the right. High doses of lidocaine (10 mg/kg) cause ΔCT to become rate-dependent. Lidocaine slowed atrial conduction only slightly. Atrial block prevented the observation of the effect of methyl lidocaine in doses higher than 5.0 mg/kg. Both drugs showed greater effect on atrial conduction at fast heart rate. Lidocaine did not affect ventricular conduction time at slow heart rates and had only minimal effects at fast heart rates. Methyl lidocaine increased ventricular conduction time at all heart rates. The results of this study indicate that lidocaine and methyl lidocaine have entirely different spectra of activity on cardiac conduction, in that their effects on AV nodal conduction do not differ greatly whereas the quaternary analog has a much stronger depressant effect on atrial and ventricular conduction.link_to_subscribed_fulltex

Prediction of the functional refractory period of the atrioventricular node

Based on the new description of AV-nodal conductivity from our laboratory, we developed an equation which describes AV-nodal conduction time in the dog heart at all coupling intervals. This allows us to predict the functional refractory period (FRP) of the AV-node based on the AV-nodal conduction times of only five extra stimuli having relatively long coupling intervals. The equation predicted the FRP within acceptable limits when compared to values obtained by the classical technique in which the full range of extrasystolic intervals must be tested. Changes in FRP after the administration of antiarrhythmic drugs (lidocaine and quinidine) or due to changes in heart rate were predicted accurately. The ease and accuracy of the present method could allow determination of FRP in a short time.link_to_subscribed_fulltex

Effect of digitalis on atrioventricular conduction

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Measurement of Tritium in Gas Phase Soil Moisture and Helium-3 in Soil Gas at the Hanford Townsite and 100 K Area

In 1999, soil gas samples for helium-3 measurements were collected at two locations on the Hanford Site. Eight soil gas sampling points ranging in depth from 1.5 to 9.8 m (4.9 to 32 ft) below ground surface (bgs) in two clusters were installed adjacent to well 699-41-1, south of the Hanford Townsite. Fifteen soil gas sampling points, ranging in depth from 2.1 to 3.2 m (7 to 10.4 ft) bgs, were installed to the north and east of the 100 KE Reactor. Gas phase soil moisture samples were collected using silica gel traps from all eight sampling locations adjacent to well 699-41-1 and eight locations at the 100 K Area. No detectable tritium (&lt;240 pCi/L) was found in the soil moisture samples from either the Hanford Townsite or 100 K Area sampling points. This suggests that tritiated moisture from groundwater is not migrating upward to the sampling points and there are no large vadose zone sources of tritium at either location. Helium-3 analyses of the soil gas samples showed significant enrichments relative to ambient air helium-3 concentrations with a depth dependence consistent with a groundwater source from decay of tritium. Helium-3/helium-4 ratios (normalized to the abundances in ambient air) at the Hanford Townsite ranged from 1.012 at 1.5 m (5 ft) bgs to 2.157 at 9.8 m (32 ft) bgs. Helium-3/helium-4 ratios at the 100 K Area ranged from 0.972 to 1.131. Based on results from the 100 K Area, the authors believe that a major tritium plume does not lie within that study area. The data also suggest there may be a tritium groundwater plume or a source of helium-3 to the southeast of the study area. They recommend that the study be continued by placing additional soil gas sampling points along the perimeter road to the west and to the south of the initial study area

Integrated Monitoring Plan for the Hanford Groundwater Monitoring Project

Groundwater is monitored at the Hanford Site to fulfill a variety of state and federal regulations, including the Atomic Energy Act of 1954; the Resource Conservation and Recovery Act of 1976; the Comprehensive Environmental Response, Compensation, and Liability Act of 1980; and Washington Administrative Code. Separate monitoring plans are prepared for various requirements, but sampling is coordinated and data are shared among users to avoid duplication of effort. The U.S. Department of Energy manages these activities through the Hanford Groundwater Monitoring Project. This document is an integrated monitoring plan for the groundwater project. It documents well and constituent lists for monitoring required by the Atomic Energy Act of 1954 and its implementing orders; includes other, established monitoring plans by reference; and appends a master well/constituent/ frequency matrix for the entire site. The objectives of monitoring fall into three general categories: plume and trend tracking, treatment/ storage/disposal unit monitoring, and remediation performance monitoring. Criteria for selecting Atomic Energy Act of 1954 monitoring networks include locations of wells in relation to known plumes or contaminant sources, well depth and construction, historical data, proximity to the Columbia River, water supplies, or other areas of special interest, and well use for other programs. Constituent lists were chosen based on known plumes and waste histories, historical groundwater data, and, in some cases, statistical modeling. Sampling frequencies were based on regulatory requirements, variability of historical data, and proximity to key areas. For sitewide plumes, most wells are sampled every 3 years. Wells monitoring specific waste sites or in areas of high variability will be sampled more frequently