Disulfiram effects on responses to intravenous cocaine administration

Disulfiram has been studied as a treatment for cocaine dependence. We report results of a randomized, double-blind, placebo-controlled, within-subject study to examine the interaction of disulfiram with intravenous cocaine. METHODS: Non-treatment-seeking, cocaine-dependent, volunteers participated in serial experiments in which they received disulfiram placebo, 62.5 or 250 mg/day on days 1-6. On days 4-6, participants received a morning disulfiram dose 2 h prior to a scheduled session in which they were administered intravenous cocaine placebo, 0.25 mg/kg (n=9) or 0.5 mg/kg (n=3) over 1 min. Blood, cardiovascular and subjective measures were collected. Seven days of washout occurred between disulfiram conditions. RESULTS: Following active disulfiram treatments and cocaine 0.25 mg/kg administration, plasma cocaine AUC (0-480 min) was increased (p=0.003 and 0.001) and cocaine clearance decreased (p<0.001). Disulfiram treatments also decreased cocaine clearance for the 0.5 mg/kg cocaine dose (p=0.002 and<0.001). Neither disulfiram dose with cocaine altered cardiovascular responses relative to cocaine alone. Following cocaine 0.25 mg/kg, 'any high' (p=0.021 and 0.019), 'cocaine high' (p=0.017 and 0.018) and 'rush' (p=0.013 and 0.047) significantly decreased with either disulfiram dose. CONCLUSIONS: Disulfiram decreased cocaine clearance without toxicity. Cocaine 'high' and 'rush' were diminished. Disulfiram may be a promising pharmacotherapy in selected cocaine dependent individuals.     

Comparison of dose calculation algorithms for treatment planning in external photon beam therapy for clinical situations

A study of the performance of five commercial radiotherapy treatment planning systems (TPSs) for common treatment sites regarding their ability to model heterogeneities and scattered photons has been performed. The comparison was based on CT information for prostate, head and neck, breast and lung cancer cases. The TPSs were installed locally at different institutions and commissioned for clinical use based on local procedures. For the evaluation, beam qualities as identical as possible were used: low energy (6 MV) and high energy (15 or 18 MV) x-rays. All relevant anatomical structures were outlined and simple treatment plans were set up. Images, structures and plans were exported, anonymized and distributed to the participating institutions using the DICOM protocol. The plans were then re-calculated locally and exported back for evaluation. The TPSs cover dose calculation techniques from correction-based equivalent path length algorithms to model-based algorithms. These were divided into two groups based on how changes in electron transport are accounted for ((a) not considered and (b) considered). Increasing the complexity from the relatively homogeneous pelvic region to the very inhomogeneous lung region resulted in less accurate dose distributions. Improvements in the calculated dose have been shown when models consider volume scatter and changes in electron transport, especially when the extension of the irradiated volume was limited and when low densities were present in or adjacent to the fields. A Monte Carlo calculated algorithm input data set and a benchmark set for a virtual linear accelerator have been produced which have facilitated the analysis and interpretation of the results. The more sophisticated models in the type b group exhibit changes in both absorbed dose and its distribution which are congruent with the simulations performed by Monte Carlo-based virtual accelerator.     

A virtual-accelerator-based verification of a Monte Carlo dose calculation algorithm for electron beam treatment planning in homogeneous phantoms

By introducing Monte Carlo (MC) techniques to the verification procedure of dose calculation algorithms in treatment planning systems (TPSs), problems associated with conventional measurements can be avoided and properties that are considered unmeasurable can be studied. The aim of the study is to implement a virtual accelerator, based on MC simulations, to evaluate the performance of a dose calculation algorithm for electron beams in a commercial TPS. The TPS algorithm is MC based and the virtual accelerator is used to study the accuracy of the algorithm in water phantoms. The basic test of the implementation of the virtual accelerator is successful for 6 and 12 MeV (gamma < 1.0, 0.02 Gy/2 mm). For 18 MeV, there are problems in the profile data for some of the applicators, where the TPS underestimates the dose. For fields equipped with patient-specific inserts, the agreement is generally good. The exception is 6 MeV where there are slightly larger deviations. The concept of the virtual accelerator is shown to be feasible and has the potential to be a powerful tool for vendors and users.     

Failure to rescue as a center-level metric in pediatric trauma

BackgroundFailure to rescue is defined as death after a complication and has been used to evaluate quality of care in adult trauma patients, but there are no published studies on failure to rescue in pediatric trauma. The aim of this study was to define the relationship among rates of mortality, complications, and failure to rescue at centers caring for pediatric (<18 years of age) trauma patients in a nationally representative database.MethodsWe performed a retrospective cohort study of the 2015 and 2016 National Trauma Data Bank. We included patients <18 years of age with an Injury Severity Score of ≥9. We excluded centers with <50 pediatric patients or that reported no complications. We calculated the complication, failure to rescue, mortality, and precedence rates by center and divided centers into tertiles of mortality. We compared complication and failure-to-rescue rates between high and low tertiles of mortality using the Kruskal-Wallis test.ResultsOf 62,190 patients from 284 centers, 2,204 patients had at least 1 complication for an overall complication rate of 4% (center level 0%–15%), and 120 patients died after a complication for an overall failure-to-rescue rate of 5% (center level 0%–67%). High-mortality centers had both higher failure-to-rescue rates (10% vs 0.6%, P < .001) and higher complication rates (5% vs 4%, P = .001) than lower-mortality hospitals. The overall precedence rate was 15% with a median rate of 0% (interquartile range 0%–25%).ConclusionBoth complication and failure-to-rescue rates are low in the pediatric injury population, but both complication and failure-to-rescue rates are higher at higher-mortality centers. The low overall complication rates and precedence rates likely limit the utility of failure to rescue as a valid center-level metric in this population, but further investigation into individual failure-to-rescue cases may reveal important opportunities for improvement.     

A brief overview of the clinical pharmacology of "club drugs"

Four different "club drugs" are reviewed: MDMA (methylenedioxymethamphetamine, "Ecstasy"), GHB (gamma-hydroxybutyrate), ketamine, and Rohypnol (flunitrazepam). The neurobiology, clinical pharmacology, and treatment issues for each are discussed.     

Drug interactions between opioids and antiretroviral medications: interaction between methadone, LAAM, and nelfinavir

Understanding drug interactions between antiretrovirals and opiate therapies may decrease toxicities and enhance adherence, with improved HIV outcomes in injection drug users. We report results of a clinical pharmacology study designed to examine the interaction of the protease inhibitor, nelfinavir, with methadone and LAAM (N = 48). Nelfinavir decreased methadone exposure, but no withdrawal was observed over the five day study period. LAAM and dinorLAAM concentrations were decreased, while norLAAM concentrations were increased, with minimal overall change in LAAM/metabolite exposure. Methadone and LAAM did not affect nelfinavir concentrations, but methadone decreased M8 metabolite exposure. While no toxicities were observed, clinicians should be aware of the potential for drug interactions when patients require treatment with nelfinavir and these opiate medications.     

The pharmacokinetics of methadone following co-administration with a lamivudine/zidovudine combination tablet in opiate-dependent subjects

Methadone pharmacokinetics were determined in an open-label, within subject study in 16 methadone-maintained, non-HIV-infected subjects prior to and following administration of one lamivudine 150-mg/zidovudine 300-mg combination tablet to determine whether this antiretroviral therapy alters methadone serum concentrations. No significant differences in the mean area under the serum concentration-time curve (AUC(0-24h); 8,753 +/- 4,280 vs. 8,641 +/- 4,431 microg-h/L),oralclearance(CL/F;9.9 +/- 4.9vs. 10.3 +/- 5.5 L/h),oral volume of distribution (Vd/F; 647 +/- 465 vs. 481 +/- 305 L), maximum serum concentration (Cmax; 514 +/- 223 vs. 5,510 +/- 237 microg/L), or terminal elimination half-life (t 1/2; 55.3 +/- 61.0 vs. 35.0 +/- 17.5 h) were detected. These results suggest that methadone dose change is not likely to be necessary for patients treated with lamivudine/zidovudine combination pharmacotherapy.     

Attention Deficit Hyperactivity Disorder and Cocaine Abuse

Recent research has shown that comorbid cocaine abuse and attention deficit hyperactivity disorder (ADHD) occur frequently in clinical populations. These patients are challenging, both diagnostically and clinically, but may respond to combined standard treatment for ADHD and cocaine abuse.