No abstract

Propofol abuse in academic anesthesiology likely has increased over the last 10 yr. Much of the mortality is in residents. Most programs have no pharmacy accounting or control of propofol stocks. This may be of concern, given that all programs reporting deaths from propofol abuse were centers in which there was no pharmacy accounting for the drug.

T(peak) is a useful pharmacodynamic parameter and can be used to link separate pharmacokinetic and pharmacodynamic studies. This addresses a common difficulty in clinical pharmacology simulation and control problems, where there is usually a wide choice of pharmacokinetic models but only one or two published pharmacokinetic-pharmacodynamic models. The results will be immediately applicable to target-controlled anesthetic infusion systems, where linkage of separate pharmacokinetic and pharmacodynamic parameters into a single model is inherent in several target-controlled infusion designs.

The current recommended rectal acetaminophen dose of 10-15 mg/kg yields peak serum concentrations less than the antipyretic serum concentration of 10-20 microg/ml. Based on the observed kinetics, the authors recommend that the initial dose should be approximately 40 mg/kg.

Single oral 10 mg doses of diazepam and demethyldiazepam were given on different occasions to 16 healthy subjects. The subjects included four poor hydroxylators of debrisoquin and three poor hydroxylators of mephenytoin. There was a correlation between the total plasma clearance of diazepam and demethyldiazepam (rs = 0.83; p less than 0.01). There was no relationship between benzodiazepine disposition and debrisoquin hydroxylation. Poor hydroxylators of mephenytoin had less than half the plasma clearance of both diazepam (p = 0.0008) and demethyldiazepam (p = 0.0001) compared with extensive hydroxylators of mephenytoin. The plasma half-lives were longer in poor hydroxylators than they were in extensive hydroxylators of mephenytoin for both diazepam (88.3 +/- SD 17.2 and 40.8 +/- 14.0 hours; p = 0.0002) and demethyldiazepam (127.8 +/- 23.0 and 59.0 +/- 16.8 hours; p = 0.0001). There was no significant difference in volume of distribution of the benzodiazepines between the phenotypes. This study shows that the metabolism of both diazepam (mainly demethylation) and demethyldiazepam (mainly hydroxylation) is related to the mephenytoin, but not to the debrisoquin, hydroxylation phenotype.

Background Although, especially in the United States, there has been a recent surge of legalized cannabis for either recreational or medicinal purposes, surprisingly little is known about clinical dose-response relationships, pharmaco- and toxicodynamic effects of cannabinoids such as Δ9-tetrahydrocannabinol (THC). Even less is known about other active cannabinoids. Methods To address this knowledge gap, an online extraction, high-performance liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) method for simultaneous quantification of 11 cannabinoids and metabolites including THC, 11-hydroxy-Δ9-tetrahydrocannabinol (11OH-THC), 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH), 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid glucuronide (THC-C-gluc), cannabinol (CBN), cannabidiol (CBD), cannabigerol (CBG), cannabidivarin (CBDV), Δ9-tetrahydrocannabivarin (THCV), and 11-nor-9-carboxy-Δ9-tetrahydrocannabivarin (THCV-COOH) was developed and validated in human urine and plasma. Results In contrast to atmospheric pressure chemical ionization (APCI), electrospray ionization (ESI) was associated with extensive ion suppression in plasma and urine samples. Thus, the APCI assay was validated showing a lower limit of quantification (LLOQ) ranging from 0.39 to 3.91 ng/mL depending on study compound and matrix. The upper limit of quantitation (ULOQ) was 400 ng/mL except for THC-C-gluc with a ULOQ of 2000 ng/mL. The linearity was r> 0.99 for all analyzed calibration curves. Acceptance criteria for intra- and inter-batch accuracy (85%-115%) and imprecision (<15%) were met for all compounds. In plasma, the only exceptions were THCV (75.3%-121.2% inter-batch accuracy) and CBDV (inter-batch imprecision, 15.7%-17.2%). In urine, THCV did not meet predefined acceptance criteria for intra-batch accuracy. Conclusions This assay allows not only for monitoring THC and its major metabolites, but also of major cannabinoids that are of interest for marijuana research and clinical practice.

Purpose: This in vivo study was designed to determine the optimal doses and schedules of vandetanib, a dual epidermal growth factor receptor (EGFR)-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in combination with irinotecan in a murine xenograft model of human colon cancer. Experimental Design: HT-29 tumor-bearing nude mice were treated with two doses of vandetanib (12.5 and 25 mg/kg/d) with or without irinotecan (100 mg/kg) using either sequential or concurrent schedules for 30 days. Tumor size was measured using standard variables, whereas the antiangiogenic response was evaluated using dynamic contrast-enhanced magnetic resonance imaging. Additionally, effects on EGFR-dependent signal transduction pathways and proliferation were assessed using immunohistochemistry. These pharmacodynamic end points were then evaluated for associations with antitumor efficacy and/or to plasma/tumor concentrations of vandetanib. Results: The greatest antitumor efficacy was observed in the groups receiving the highest dose of vandetanib given continuously (concurrent schedule), alone or in combination with irinotecan. These dosing schedules resulted in significant effects on tumor vasculature, with decreased volume transfer constants, area under the curve, and permeability surface factor as well as increased gadolinium clearance after 30 days of treatment. In addition, these groups showed the greatest inhibition of EGFR signaling. Interestingly, tumor concentrations of vandetanib were increased by irinotecan in the concurrent schedule, possibly due to decreased tumor perfusion in this group. Conclusions: These data suggest that higher, sustained concentrations of vandetanib (versus intermittent), alone and in combination with irinotecan, result in optimal antitumor efficacy in this model and may have implications for the design of future clinical studies with this drug.

Aims Population pharmacokinetic models of Δ9‐tetrahydrocannabinol (THC) have been developed for THC plasma and blood concentration data. Often, only the metabolites of THC are measurable when blood samples are obtained. Therefore, we performed a population pharmacokinetic analysis of THC, 11‐OH‐THC and THCCOOH plasma concentration data from a Phase I clinical trial of THC smoking. Methods Frequently obtained plasma THC, 11‐OH‐THC and THCCOOH concentration data were obtained over 168 h from 6 subjects who smoked low (15.8 mg) and high dose (33.8 mg) THC cigarettes on 2 occasions. Bayesian estimates of the THC pharmacokinetic model from each individual for each dose were fixed prior to the sequential pharmacokinetic analysis of the metabolites. Results A 3‐compartment model of THC was developed that has a steady‐state volume of distribution (VdSS) of 3401 ± 788 L and a clearance of 0.72 ± 0.10 L/min. 11‐OH‐THC was characterized by 50 ± 6% of the THC being directly cleared to a 3‐compartment model with a VdSS of 415.2 ± 4.3 L and clearance of 0.78 ± 0.05 L/min. The THCCOOH model shared the central compartment of the 11‐OH‐THC model with a VdSS of 29.1 ± 0.05 L and a clearance of 0.12 ± 0.02 L/min. First order kinetics were observed for THC and THCCOOH between the low and high doses, but a nonlinear pattern was observed for 11‐OH‐THC. Conclusion We describe the pharmacokinetics of THC, 11‐OH‐THC and THCCOOH including inter‐ and intraindividual variability of the parameter estimates of the model.