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 ≤ 29 wk GA (n = 122, 14 centers) were randomized and treated with placebo or inositol at 10, 40, or 80 mg/kg/d. Intravenous administration converted to enteral when feedings were established, and continued to the first of 10 wk, 34 wk 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 80 mg/kg/d mean serum levels reached 140 mg/l, similar to Hallman's findings. Levels declined after 2 wk, converging in all groups by 6 wk. Analyses showed a mean volume of distribution 0.657 l/kg, clearance 0.058 l/kg/h, and half-life 7.90 h. Adverse events and comorbidities were fewer in the inositol groups, but not significantly so. CONCLUSION: Multiple dose inositol at 80 mg/kg/d was not associated with increased adverse events, achieves previously effective serum levels, and is appropriate for investigation in a phase III trial.

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 23-29 wk of gestation were randomized to a single intravenous (i.v.) dose of inositol at 60 or 120 mg/kg or placebo. Over 96 h, 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 2.67 mg/kg/h, and the half-life was 5.22 h when modeled without the covariates. During the first 12 h, renal inositol excretion quadrupled in the 120 mg/kg group, returning to near-baseline value after 48 h. 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.

Estimating model-adjusted risks, risk differences, and risk ratios from complex survey data.

There is increasing interest in estimating and drawing inferences about risk or prevalence ratios and differences instead of odds ratios in the regression setting. Recent publications have shown how the GENMOD procedure in SAS (SAS Institute Inc., Cary, North Carolina) can be used to estimate these parameters in non-population-based studies. In this paper, the authors show how model-adjusted risks, risk differences, and risk ratio estimates can be obtained directly from logistic regression models in the complex sample survey setting to yield population-based inferences. Complex sample survey designs typically involve some combination of weighting, stratification, multistage sampling, clustering, and perhaps finite population adjustments. Point estimates of model-adjusted risks, risk differences, and risk ratios are obtained from average marginal predictions in the fitted logistic regression model. The model can contain both continuous and categorical covariates, as well as interaction terms. The authors use the SUDAAN software package (Research Triangle Institute, Research Triangle Park, North Carolina) to obtain point estimates, standard errors (via linearization or a replication method), confidence intervals, and P values for the parameters and contrasts of interest. Data from the 2006 National Health Interview Survey are used to illustrate these concepts.

Evaluation of the effect of doxasozin and zonisamide on voluntary ethanol intake in mice that experienced chronic intermittent ethanol exposure and stress.

The comorbidity between alcohol use disorder and post-traumatic stress disorder represents a serious health care burden with few effective treatment options. The current study was designed to evaluate the effect of an alpha 1 receptor antagonist (doxazosin) and a novel anticonvulsant (zonisamide) in a model of alcohol (ethanol) dependence and stress exposure. The main dependent variable was voluntary ethanol intake in mice that experienced chronic intermittent ethanol (CIE) exposure and forced swim stress (FSS) alone, and in combination. Adult male and female C57BL/6J mice had access to a single bottle of 15% (v/v) ethanol for 1-hr in the home cage, 3-hr into the dark phase of the light/dark cycle. Once stable ethanol intake was established (~4 weeks), mice were separated into four groups (CTL, CIE, FSS, CIE + FSS). Mice in the FSS condition received 10-min FSS exposure 4-hr prior to drinking sessions (remaining mice were not disturbed). During baseline and the first two test cycles, all mice received vehicle (saline) injections (IP) 30-min before ethanol access. As previously observed, FSS increased ethanol drinking in dependent (CIE-exposed) mice but not in nondependent control (CTL) mice. In the following test cycles mice were evaluated for ethanol intake after administration of doxazosin, zonisamide or their combination. Results indicated that the three doses of doxazosin evaluated significantly reduced voluntary ethanol intake in all mice. Zonisamide had a more modest effect and may require a more prolonged treatment regime. The combined administration of both compounds was not more effective than each drug alone. This study suggests that doxazosin is reliable at reducing voluntary ethanol intake in mice independently of their history of ethanol dependence and stress exposure.

Modeling cholinesterase activity for human dietary risk assessment of carbamate insecticides.

This article demonstrates statistical models to quantify the interaction between a carbamate insecticide and acetylcholinesterase. Carbamates are a class of chemicals that inhibit the activity of acetylcholinesterase in humans, an enzyme involved in the regulation of the neurotransmitter acetylcholine. Following exposure to a carbamate insecticide, we specifically address (1) if acetylcholinesterase activity recovers to its level of preexposure activity; (2) the level of inhibition of acetylcholinesterase activity; (3) the recovery time of acetylcholinesterase activity to its preexposure level for a typical individual; and (4) the upper percentiles of the recovery time of acetylcholinesterase activity across individuals. A nonlinear mixed-effects model is fitted to data from a repeated measures experiment conducted with human volunteers randomly assigned to a control and four dose groups. Repeated measurements were taken prior to exposure and at 1, 2, 4, 6, 8, and 21 hours after exposure to the carbamate aldicarb. It was found that full recovery did occur. Inhibition at 1 hour was estimated with maximum inhibition most likely occurring prior to 1-hour postexposure. In addition, recovery was rapid even for sensitive individuals. Given this information, the potential effect from exposure to a carbamate consumed in the diet during a day can be quantitatively assessed.

Breastfeeding attitudes and reported problems in a national sample of WIC participants.

Recent reports indicate that breastfeeding rates continue to be dramatically lower among WIC participants, compared with other US mothers. The WIC Infant Feeding Practices Study was a nationally representative 1-year longitudinal study of WIC participants that obtained information about attitudes regarding infant feeding and about infant-feeding practices. Hispanic mothers were most likely to agree with statements about benefits of breastfeeding, and Black mothers were most likely to agree with statements about barriers. Concern about insufficient milk was common in all ethnic groups. Perceived benefits were associated with breastfeeding initiation (P < .05), longer breastfeeding duration (P < .01), and later formula initiation (P < .01); for barriers, the opposite pattern was found. Breastfeeding mothers who reported concern about insufficient milk breastfed for shorter durations (P < .001) and initiated formula earlier (P < .01). These results suggest possible messages that should be communicated as part of a re-energized WIC breastfeeding promotion campaign. In particular, maternal anxiety about insufficient breast milk must be addressed.

The VA/DoD Chronic Effects of Neurotrauma Consortium: An Overview at Year 1.

This federally funded program identifies gaps in research and provides support services for scientific, clinical, and translational research projects focused on the long-term effects of mild traumatic brain injury in veterans and active-duty service members.

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

BACKGROUND: Emerging 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. METHODS: The 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). RESULTS: Past-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. CONCLUSION: Because 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.

Prenatal developmental toxicity evaluation of 2',3'-dideoxyinosine (ddI) and 2',3'-didehydro-3'-deoxythymidine (d4T) co-administered to Swiss Albino (CD-1) mice.

BACKGROUND: In pregnant women, antiretroviral drugs improve maternal health and reduce vertical transmission of human immunodeficiency virus to the infant. However, few nonclinical studies have examined the potential for adverse drug interactions. METHODS: On gestational days (GD) 6-16, mice were dosed with vehicle, ddI (360, 1440, or 2,880 mg/kg/day, p.o.), d4T (60, 240, or 480), or ddI/d4T combinations (360/60, 1,440/240, or 2,880/480). Daily doses were divided into two equal parts that were administered >or=6-hr apart. Body weight, clinical signs, and feed consumption were monitored. Pregnancies (22-24/group) were confirmed at necropsy. Maternal liver and gravid uterine weights (GUW), uterine implants (resorption, live or dead fetus), fetal body weight, gender, and morphologic anomalies (external, visceral, skeletal) were recorded. RESULTS: Maternal body weight, clinical signs, and GUW were unaffected. Maternal weight change corrected for GUW was greater than controls at 60 and 480 d4T. Relative feed consumption during treatment was increased relative to controls at 1,440 and 2,880 ddI and 2,880/480 ddI/d4T. Relative maternal liver weight was elevated above controls at 240 and 480 d4T and 2,880/480 ddI/d4T, and above the constituent dose of ddI at 1,440/240 and 2,880/480 ddI/d4T. Liver weight was not affected by ddI and there was no significant drug interaction. Prenatal mortality and morphologic anomalies were not increased. Fetal body weight showed only a decreasing trend for ddI/d4T, no effect for ddI or d4T, and no statistically significant drug interaction. CONCLUSIONS: In pregnant mice, ddI/d4T combinations were not associated with well-defined developmental toxicity or adverse drug interactions.

Project IMPACT: results from a pilot validity study of a new observational database.

OBJECTIVE: The objective of this study was to evaluate the accuracy of the information contained in the Project IMPACT database. Project IMPACT is a comprehensive database system developed to measure and describe the care of intensive care patients. This database is being used by a large group of hospitals to help clinicians improve the care of these patients. Data on patient demographics, diagnoses, treatment, and outcomes are entered into the Project IMPACT database by staff at participating hospitals. This pilot study was a first step in assessing the accuracy of these data to determine the usefulness of the Project IMPACT database for measuring intensive care unit (ICU) performance and patient outcomes. DESIGN: The design of the pilot study was the independent abstraction of selected data items from a random sample of ICU patient records from two hospitals participating in Project IMPACT. The abstracted data were compared with the data existing in the Project IMPACT database for agreement. SETTING: Abstraction was performed onsite at the two pilot hospitals by a trained abstractor who was not affiliated with either hospital. PATIENTS: Patients whose records were abstracted included 45 randomly selected ICU patients at each of the two pilot hospitals. MEASUREMENTS AND MAIN RESULTS: Comparison of the Project IMPACT data with the independently abstracted data indicated good agreement (80% or above) on discrete items, such as type of ICU patient. Poorer agreement (under 80%) was seen for continuous items (e.g., 24-hr urine output) and coded items requiring judgment (e.g., reason for ICU admission). CONCLUSIONS: The pilot study showed good internal validity for most of the abstracted variables. High agreement rates were observed, regardless of method of original data capture (electronic download or manual entry), although agreement was higher for some data items that had been electronically downloaded into the Project IMPACT database. The results suggest that Project IMPACT is a valuable resource for ICUs to collect and evaluate information about treatment and patient outcomes.