The A-OCDS predicts both craving and alcohol cue reactivity in adolescent alcoholics

Adolescents with alcohol dependence may experience marked craving and physiologic reactivity in the presence of alcohol cues which could undermine treatment gains. The Adolescent Obsessive Compulsive Drinking Scale (A-OCDS) was developed to help quantify the severity of alcohol craving in adolescents with alcohol use disorders. The A-OCDS is a relatively new instrument, and empirical data are needed to support its value in clinical trials. The present investigation uses data collected as part of a clinical laboratory study examining alcohol craving and cue reactivity in adolescents with and without alcohol dependence. A-OCDS total and subscale scores from adolescent alcoholics (N = 28) were examined regarding their relationship to drinking and several indices of craving and alcohol cue reactivity. In addition, regression analyses were performed to characterize the predictive ability of A-OCDS total scores and drinking indices (drinks per drinking day and percent days abstinent) on two measures of alcohol craving and cue reactivity. Results showed that the A-OCDS total scores, but not drinks per drinking day or percent days abstinent, predicted scores on both indices of craving. The study uses a small but well-defined sample of adolescents with alcohol dependence and supports the construct validity of the A-OCDS and suggests that, as in adults, alcohol craving and drinking behavior are related but separate elements of alcohol dependence. The results are intended to guide future studies in which the A-OCDS may be employed to measure craving and changes in craving over the course of treatment for adolescents with alcohol dependence.     

A prospective study of risk and protective factors for substance use among impoverished women living in temporary shelter settings in Los Angeles County

Alcohol and drug use are significant public health problems facing homeless women, but few prospective studies have examined risk and protective factors for substance use in this population. This 6-month prospective study identified psychosocial, behavioral, and economic predictors of drinking to intoxication, crack use, and marijuana use in a probability sample of 402 women living in temporary shelter settings in Los Angeles County with a simple majority of homeless residents (92% of these women had a history of homelessness). Engaging in sexual risk behavior and having depressive symptoms were risk factors for more frequent intoxication, marijuana use, and crack use. Drinking to intoxication was additionally predicted by perceived HIV susceptibility, lower social support, more avoidant and less active coping, and lower self-esteem. Additional predictors of marijuana use included partner alcohol misuse and less social support, whereas more frequent crack use was additionally predicted by partner alcohol misuse, lack of economic resources, and more avoidant and less active coping. These findings suggest that effective substance use programs may need an integrative approach that addresses other types of risk behaviors, assists women in strengthening their support networks and learning effective coping skills, and provides access to basic services (e.g., housing, health care). For women in relationships, there may be a further need to address issues of partner substance use.     

Human milk research for answering questions about human health

Concerns regarding human milk in our society are diverse, ranging from the presence of environmental chemicals to the health of breastfed infants and the economic value of breastfeeding to society. The panel convened for the Technical Workshop on Human Milk Surveillance and Biomonitoring for Environmental Chemicals in the United States, held at the Hershey Medical Center, Pennsylvania State College of Medicine, on 24--26 September 2004, considered how human milk research may contribute to environmental health initiatives to benefit society. The panel concluded that infant, maternal, and community health can benefit from studies using human milk biomonitoring. Unlike other biological specimens, human milk provides information regarding exposure of the mother and breastfed infant to environmental chemicals. Some of the health topics relevant to this field of research include disorders of growth and development in infants, cancer origins in women, and characterization of the trend of exposure to environmental chemicals in the community. The research focus will determine the design of the study and the need for the collection of alternative biological specimens and the long-term storage of these specimens. In order to strengthen the ability to interpret study results, it is important to identify reference ranges for the chemicals measured and to control for populations with high environmental chemical exposure, because the amount of data on environmental chemical levels in human milk that is available for comparison is extremely limited. In addition, it will be necessary to validate models used to assess infant exposure from breastfeeding because of the variable nature of current models. Information on differences between individual and population risk estimates for toxicity needs to be effectively communicated to the participant. Human milk research designed to answer questions regarding health will require additional resources to meet these objectives.     

Age-related changes in proton T1 values of normal human brain

To determine whether there were age-related changes In the brain tissue of 55 healthy adult volunteers (29 men, 26 women; 18-72 years old) without known brain abnormalities, a standard inversion-recovery technique was optimized for precise and accurate T1 measurement within the constraints of a 15-minute examination. Measurements of water proton T1 were obtained in eight brain regions. T1 increased with age in the genu (P < 0.001) (analysis of variance), frontal white matter (P < 0.05), occipital white matter (P < 0.05), putamen (P < 0.001), and thalamus (P << 0.001). A significant decrease in T1 with age was found in cortical gray matter (P < 0.05). Thus, age-related changes in T1 are present in a healthy population, even if extremes of age are excluded, suggesting that T1 values generally increase with age. However, increases in T1 were also observed in the genu, putamen, and thalamus of a substantial fraction of volunteers less than 35 years old. Aging healthy persons can show subtle, nonsymp- tomatic brain changes, suggesting that brain aging is associated with occult processes that can begin at a relatively early age.     

Desipramine treatment of cocaine-dependent patients with depression: a placebo-controlled trial

OBJECTIVE: The aim of this study was to test the hypothesis that desipramine would be an effective treatment in cocaine abusers with current depressive disorders. METHOD: This was a randomized, 12-week, double-blind, 'placebo-controlled trial of outpatients (N = 111) meeting DSM-III-R criteria for cocaine dependence and major depression or dysthymia (by SCID interview). Participants were treated with desipramine, up to 300 mg per day, or matching placebo. All patients received weekly individual manual-guided relapse prevention therapy. Weekly outcome measures included the Clinical Global Impression Scale, self-reported cocaine use and craving, urine toxicology, and the Hamilton Depression Scale (biweekly). Summary measures of mood and cocaine use outcome were compared between treatment groups with chi2- or t-tests. Dichotomous summary measures of depression response and cocaine response were the primary outcomes. Mixed effect models were also fit to explore the relationship of cocaine use to mood improvement and treatment over weeks in the trial. RESULTS: Desipramine was associated with a higher rate of depression response (51%, 28/55) than placebo (32%, 18/56) (p < 0.05), but treatment groups did not differ in rate of cocaine response. Depression improvement was associated with improvement in cocaine use. Desipramine was associated with more dropouts due to side effects and medical adverse events, while placebo was associated with more dropouts due to psychiatric worsening. CONCLUSIONS: Desipramine was an effective treatment for depression among cocaine-dependent patients. Improvement in mood was associated with improvement in cocaine abuse, but a direct effect of medication on cocaine outcome was not clearly established and rates of sustained abstinence were low. Future research should examine newer antidepressant medications with more benign side effect profiles and combinations of behavioral and pharmacological treatments to maximize effects on cocaine use.     

Influence of coadministration on the pharmacokinetics of azimilide dihydrochloride and digoxin

The influence of coadministration on digoxin and azimilide pharmacokinetics/pharmacodynamics was assessed in a randomized, 3-way crossover study in 18 healthy men. Serial blood and urine samples were obtained for azimilide and digoxin quantitation. Treatment effects on pharmacokinetics were assessed using analysis of variance. The relationship between azimilide blood concentrations and QT(c) prolongation was characterized by an E(max) model. Effects of coadministration on pharmacodynamics were assessed using a mechanistic-based inhibition model. Azimilide pharmacokinetics was unaffected by digoxin, except for a 36% increase in CL(r) (P = .0325), with no change in CL(o). Digoxin pharmacokinetics was unaffected by azimilide, except for a 21% increase in C(max) (P = .0176) and a 10% increase in AUC(tau) (P = .0121). Digoxin coadministration increased the apparent EC(50) with no effect on E(max), consistent with competitive inhibition (K(i) = 0.899 ng/mL). The pharmacokinetic and pharmacodynamic changes observed upon coadministration were small and are not expected to be clinically important.     

A 3-dimensional human embryonic stem cell (hESC)-derived model to detect developmental neurotoxicity of nanoparticles

Nanoparticles (NPs) have been shown to accumulate in organs, cross the blood–brain barrier and placenta, and have the potential to elicit developmental neurotoxicity (DNT). Here, we developed a human embryonic stem cell (hESC)-derived 3-dimensional (3-D) in vitro model that allows for testing of potential developmental neurotoxicants. Early central nervous system PAX6⁺ precursor cells were generated from hESCs and differentiated further within 3-D structures. The 3-D model was characterized for neural marker expression revealing robust differentiation toward neuronal precursor cells, and gene expression profiling suggested a predominantly forebrain-like development. Altered neural gene expression due to exposure to non-cytotoxic concentrations of the known developmental neurotoxicant, methylmercury, indicated that the 3-D model could detect DNT. To test for specific toxicity of NPs, chemically inert polyethylene NPs (PE-NPs) were chosen. They penetrated deep into the 3-D structures and impacted gene expression at non-cytotoxic concentrations. NOTCH pathway genes such as HES5 and NOTCH1 were reduced in expression, as well as downstream neuronal precursor genes such as NEUROD1 and ASCL1. FOXG1, a patterning marker, was also reduced. As loss of function of these genes results in severe nervous system impairments in mice, our data suggest that the 3-D hESC-derived model could be used to test for Nano-DNT.     

Alcohol prevention for school students: Results from a 1-year follow up of a cluster-randomised controlled trial of harm minimisation school drug education

Aims: The Drug Education in Victorian Schools (DEVS) programme taught about licit and illicit drugs over two years (2010–2011), with follow up in the third year (2012). It focussed on minimising harm and employed participatory, critical-thinking and skill-focussed pedagogy. This study evaluated the programme’s residual effectiveness at follow up in reducing alcohol-related risk and harm. Methods: A cluster-randomised, controlled trial was conducted with a student cohort during years eight (13–14?years old), nine (14–15?years old) and 10 (15–16?years old). Schools were randomly allocated to the DEVS programme (14 schools, n?=?1163), or their usual drug education (7 schools, n?=?589). Multi-level models were fitted to the data, which were analysed on an intent-to-treat basis. Statistically significant findings: Over the 3 years, there was a greater increase in intervention students’ knowledge about drugs, including alcohol. Their alcohol consumption did not increase as much as controls. Their alcohol-related harms decreased, while increasing for controls. There were fewer intervention group risky drinkers, and they reduced their consumption compared to controls. Similarly, harms decreased for intervention group risky drinkers, while increasing for controls. Conclusions: Skill-focussed, harm minimisation drug education can remain effective, subsequent to programme completion, in reducing students’ alcohol consumption and harm, even with risky drinkers.     

Molecular mechanism of allosteric modulation at GPCRs: insight from a binding kinetics study at the human A1 adenosine receptor

Background and Purpose

Many GPCRs can be allosterically modulated by small-molecule ligands. This modulation is best understood in terms of the kinetics of the ligand–receptor interaction. However, many current kinetic assays require at least the (radio)labelling of the orthosteric ligand, which is impractical for studying a range of ligands. Here, we describe the application of a so-called competition association assay at the adenosine A₁ receptor for this purpose.

Experimental Approach

We used a competition association assay to examine the binding kinetics of several unlabelled orthosteric agonists of the A₁ receptor in the absence or presence of two allosteric modulators. We also tested three bitopic ligands, in which an orthosteric and an allosteric pharmacophore were covalently linked with different spacer lengths. The relevance of the competition association assay for the binding kinetics of the bitopic ligands was also explored by analysing simulated data.

Key Results

The binding kinetics of an unlabelled orthosteric ligand were affected by the addition of an allosteric modulator and such effects were probe- and concentration-dependent. Covalently linking the orthosteric and allosteric pharmacophores into one bitopic molecule had a substantial effect on the overall on- or off-rate.

Conclusion and Implications

The competition association assay is a useful tool for exploring the allosteric modulation of the human adenosine A₁ receptor. This assay may have general applicability to study allosteric modulation at other GPCRs as well.Table of Links