Rick Williams

The nonmedical use of prescription ADHD medications: results from a national Internet panel

BackgroundEmerging evidence suggests that nonmedical use (NMU) of prescription attention deficit/hyperactivity disorder (ADHD) medications is rising, but many previous investigations have used clinical or regionally based samples or limited their investigations to stimulants rather than to medications specifically used to treat ADHD. Using an Internet-based epidemiological survey, this paper advances understanding of the prevalence and correlates of NMU of medications used to treat ADHD, sources of diverted medications, motivations for use, and consumption patterns.MethodsThe study used a self-administered Internet survey of civilian, noninstitutionalized adults (N = 4,297) aged 18 to 49 in the United States. National-level estimates were created using propensity scoring methods and weighting procedures using data from three nationally representative probability surveys: a random-digit dialed telephone survey, the current U.S. Census, and the National Survey on Drug Use and Health (NSDUH).ResultsPast-year prevalence of NMU of ADHD medications was approximately 2%, with 4.3% reported among those aged 18 to 25 and 1.3% among those aged 26 to 49. Most respondents reporting NMU used on multiple occasions. Receipt of medications for ADHD was a significant correlate of past-year NMU, though most nonmedical users never had a prescription. Among persons who had never been prescribed medication to treat ADHD, friends or family members were the most common source. Productivity was the most frequently endorsed reason for NMU. Alcohol was the substance most commonly used in combination with ADHD drugs.ConclusionBecause most prescription ADHD medications currently are highly regulated, policy options for supply-side reduction of nonmedical use may include identifying those medications with lower abuse liability for inclusion on insurance formularies. Patient and physician education programs also may be useful tools to heighten awareness of intentional and unintentional diversion of ADHD medications for nonmedical purposes.

Product-limit survival functions with correlated survival times

A simple variance estimator for product-limit survival functions is demonstrated for survival times with nested errors. Such data arise whenever survival times are observed within clusters of related observations. Greenwoods formula, which assumes independent observations, is not appropriate in this situation. A robust variance estimator is developed using Taylor series linearized values and the between-cluster variance estimator commonly used in multi-stage sample surveys. A simulation study shows that the between-cluster variance estimator is approximately unbiased and yields confidence intervals that maintain the nominal level for several patterns of correlated survival times. The simulation study also shows that Greenwoods formula underestimates the variance when the survival times are positively correlated within a cluster and yields confidence intervals that are too narrow. Extension to life table methods is also discussed.

Pharmacokinetics and safety of a single intravenous dose of myo -inositol in preterm infants of 23–29 wk

Background:Myo-inositol given to preterm infants with respiratory distress has reduced death, increased survival without bronchopulmonary dysplasia, and reduced severe retinopathy of prematurity in two randomized trials. Pharmacokinetic (PK) studies in extremely preterm infants are needed before efficacy trials.Methods:Infants born in 23–29u2009wk of gestation were randomized to a single intravenous (i.v.) dose of inositol at 60 or 120u2009mg/kg or placebo. Over 96u2009h, serum levels (sparse sampling population PK) and urine inositol excretion were determined. Population PK models were fit using a nonlinear mixed-effects approach. Safety outcomes were recorded.Results:A single-compartment model that included factors for endogenous inositol production, allometric size based on weight, gestational age strata, and creatinine clearance fit the data best. The central volume of distribution was 0.5115 l/kg, the clearance was 0.0679 l/kg/h, endogenous production was 2.67u2009mg/kg/h, and the half-life was 5.22u2009h when modeled without the covariates. During the first 12u2009h, renal inositol excretion quadrupled in the 120u2009mg/kg group, returning to near-baseline value after 48u2009h. There was no diuretic side effect. No significant differences in adverse events occurred among the three groups (P > 0.05).Conclusion:A single-compartment model accounting for endogenous production satisfactorily described the PK of i.v. inositol.

Safety and pharmacokinetics of multiple dose myo-inositol in preterm infants

Background:Preterm infants with respiratory distress syndrome (RDS) given inositol had reduced bronchopulmonary dysplasia (BPD), death and severe retinopathy of prematurity (ROP). We assessed the safety and pharmacokinetics of daily inositol to select a dose providing serum levels previously associated with benefit, and to learn if accumulation occurred when administered throughout the normal period of retinal vascularization.Methods:Infants ≤ 29u2009wk GA (n = 122, 14 centers) were randomized and treated with placebo or inositol at 10, 40, or 80u2009mg/kg/d. Intravenous administration converted to enteral when feedings were established, and continued to the first of 10u2009wk, 34u2009wk postmenstrual age (PMA) or discharge. Serum collection employed a sparse sampling population pharmacokinetics design. Inositol urine losses and feeding intakes were measured. Safety was prospectively monitored.Results:At 80u2009mg/kg/d mean serum levels reached 140u2009mg/l, similar to Hallman’s findings. Levels declined after 2u2009wk, converging in all groups by 6u2009wk. Analyses showed a mean volume of distribution 0.657 l/kg, clearance 0.058 l/kg/h, and half-life 7.90u2009h. Adverse events and comorbidities were fewer in the inositol groups, but not significantly so.Conclusion:Multiple dose inositol at 80u2009mg/kg/d was not associated with increased adverse events, achieves previously effective serum levels, and is appropriate for investigation in a phase III trial.

Chronic Effects of Neurotrauma Consortium (CENC) multicentre study interim analysis: Differences between participants with positive versus negative mild TBI histories

ABSTRACT Objectives: Compare characteristics and outcomes of combat-exposed military personnel with positive versus negative mild traumatic brain injury (mTBI) histories. Setting: Recruitment was from registration lists and ambulatory clinics at four veterans administration hospitals. Participants: Consented veterans and service members completing initial evaluation by September 2016 (n = 492). Design: Observational with cross-sectional analyses. Main measures: Multimodal assessments including structured interviews, record review, questionnaires, neuroendocrine labs and neurocognitive and sensorimotor performance. Results: In unadjusted comparisons to those absent lifetime mTBI, the mTBI positive group (84%) had greater combat exposure, more potential concussive events, less social support and more comorbidities, including asthma, sleeping problems and post-traumatic stress disorder. They also fared worse on all sensory and pain symptom scores and self-reported functional and global outcomes. They had poorer scores on Wechsler Adult Intelligence Scale-IV coding (processing speed), TMT-B (visual-motor integration and executive function) and two posturography subtests, but were otherwise equal to TBI negative participants on neurocognitive and sensorimotor testing and neuroendocrine levels. Conclusions: Although differences in characteristics exist which were not adjusted for, participants with historical mTBI have greater symptomatology and life functioning difficulties compared with non-TBI. Performance measures were less dissimilar between groups. These findings will guide further research within this accruing cohort.

Erratum: Pharmacokinetics and safety of a single intravenous dose of myo-inositol in preterm infants of 23-29 wk (Pediatric Research (2013) 74 (721-729) DOI:10.1038/pr.2013.162)

Dale L. Phelps, Robert M. Ward, Rick L. Williams, Kristi L. Watterberg, Abbot R. Laptook, Lisa A. Wrage, Tracy L. Nolen, Timothy R. Fennell, Richard A. Ehrenkranz, Brenda B. Poindexter, C. Michael Cotten, Mikko K. Hallman, Ivan D. Frantz III, Roger G. Faix, Kristin M. Zaterka-Baxter, Abhik Das, M. Bethany Ball, T. Michael O’Shea, Conra Backstrom Lacy, Michele C. Walsh, Seetha Shankaran, Pablo J. Sánchez, Edward F. Bell and Rosemary D. Higgins ; for the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network