Search

Funder: NIHR MedTech, Funder: in vitro diagnostic Co-operative, Funder: nihr cambridge biomedical research centre, Funder: Wallitt Foundation and Eton College, Funder: Wellcome Trust Collaborative Award, BACKGROUND AND AIMS: Cannabis is a commonly used recreational drug in young adults. The worldwide prevalence in 18- to 25-year-olds is approximately 35%. Significant differences in cognitive performance have been reported previously for groups of cannabis users. However, the groups are often heterogeneous in terms of cannabis use. Here, we study daily cannabis users with a confirmed diagnosis of cannabis use disorder (CUD) to examine cognitive performance on measures of memory, executive function and risky decision-making. METHODS: Forty young adult daily cannabis users with diagnosed CUD and 20 healthy controls matched for sex and premorbid intelligence quotient (IQ) were included. The neuropsychological battery implemented was designed to measure multiple modes of memory (visual, episodic and working memory), risky decision-making and other domains of executive function using subtests from the Cambridge Neuropsychological Test Automated Battery (CANTAB). RESULTS: Our results showed that young adult daily cannabis users with CUD perform significantly poorer on tasks of visual and episodic memory compared with healthy controls. In addition, executive functioning was associated with the age of onset. CONCLUSIONS: Further research is required to determine whether worse performance in cognition results in cannabis use or is a consequence of cannabis use. Chronic heavy cannabis use during a critical period of brain development may have a particularly negative impact on cognition. Research into the persistence of cognitive differences and how they relate to functional outcomes such as academic/career performance is required.

Background: Palliative care encompasses supportive health care for patients at any stage of illness aimed at relieving symptoms, controlling pain, managing stress, offering respite for caregivers, and optimizing the quality of life. Objective: To explore strategies for increasing access to palliative care among individuals living in remote/rural communities, a rapid review was conducted on studies that explored the use of telehealth applications with this population. Methods: From December 2019 to February 2020, the PRISMA methodology was used to gather peer-reviewed studies published in the English language. MedLine, Google Scholar, and EBSCO were searched; no date limitations were set. Given the diversity of study methodologies and outcomes, the findings were synthesized narratively. The Cochrane Collaboration’s tool for assessing the risk of bias was also employed. Lastly, the studies were mapped to clinical guidelines for the various aspects of quality palliative care. Results: The 18 studies found, published between 2004 and 2019, were conducted in seven countries and on five continents. Aims included evaluating feasibility, efficacy, and user satisfaction. Insights draw from a combined pool of 3,313 patients and 250 providers. Most studies involved oncology patients and employed videoconferencing or a web platform/online software with videoconferencing. Three themes emerged: delivery of care, symptom management and quality of life, and patient/caregiver/provider satisfaction levels. Telehealth proved effective for patient and medication monitoring, provider and specialist appointments, and palliative care consultations. Operational benefits included clinician time saved, shorter appointment wait times, and reduced no show rates; implementation challenges also emerged. Statistical improvements in quality of life and symptom management were reported. Nearly two-thirds of the studies reported positive experiences among patients, caregivers, and providers; about half included an interprofessional team. The studies primarily focused on the structure/process and physical aspects of quality palliative care, there was a paucity of insights on the spiritual, cultural, end of life, and ethical/legal aspects of care. Two-thirds (12/18) of the studies employed a descriptive design. Risk for selection, performance, detection, and reporting biases emerged for all the studies; for example, only four of the studies included control groups and less than 20% (3/18) reported on attrition of study participants. Additional limitations include the rapid review methodology which relied heavily on the lead author’s decisions and the restriction of studies published only in the English language. Conclusion: More rigorous research is required to confirm the viability of clinical care delivery and establish best practices for quality, virtual palliative care to remote/rural areas.

Purpose To assess the recruitment preferences of directors of postgraduate year 2 (PGY2) pharmacy residency programs and postgraduate year 1 (PGY1) pharmacy residents seeking PGY2 residency positions, as well as key drivers of preference. Methods Two Web-based questionnaires were administered to residency program directors (RPDs) of PGY2 programs and PGY1 residents, respectively. Participants were recruited via email, and responses were collected from November 27 through December 14, 2018. RPDs and PGY1 residents were surveyed about their preferences regarding participation in the ASHP Resident Matching Program (ASHP Match) and participation in the early commitment process (ECP). Respondents were also asked to rank the importance of prespecified factors in decisions about whether to participate in either the Match or the ECP. Results The RPD questionnaire was completed by 295 participants in 43 states. The majority of RPDs (70.2%) stated that their PGY2 program generally preferred the ECP to the ASHP Match. Regardless of program preference, the most important driver of preference was the current PGY1 resident’s personality and fit. There were 243 completed resident questionnaires from 41 states. The majority of respondents (83.5%) indicated a preference to participate in the ECP vs the ASHP Match. Of those preferring the ECP, the highest-ranked consideration was the opportunity for further development at their PGY1 site. Conclusion Overall, the survey results indicated that both PGY2 programs and PGY1 residents interested in PGY2 training generally prefer the ECP to the ASHP Match. The survey results should be considered by stakeholders (students, residents, and RPDs) in deciding whether to participate in the Match or the ECP process.

The misuse of alcohol in the United States continues to take a large toll on society, resulting in the deaths of about 88,000 Americans per year. Moreover, it is estimated that nearly 14.6 million Americans currently meet diagnostic criteria for current alcohol use disorder (AUD). However, very few individuals receive treatment, with an even smaller portion receiving medications approved by the U.S. Food and Drug Administration (FDA) for the treatment of AUD, despite scientifically rigorous evidence showing the benefits of combining medication approved for treating AUD with evidence-based behavioral therapy. These benefits include higher rates of abstinence and less risk of relapse to heavy drinking, with associated improvements in medical and mental health and in quality of life. This review provides an overview of FDA-approved medications and "off-label" drugs for the treatment of AUD. The article emphasizes that AUD medical advice and prescription recommendations should come from professionals with training in the treatment of AUD and that treatment plans should consider medication in conjunction with evidence-based behavioral therapy. Finally, this review notes the limited number of medications available and the continued need for the development of new pharmacotherapies to optimize AUD recovery goals.

Treatment options for Alcohol Use Disorders (AUD) have minimally advanced since 2004, while the annual deaths and economic toll have become alarmingly high. Bringing potential therapeutics beyond the bench and into the clinic for AUD requires rigorous pharmacological screening across molecular, behavioral, pre-clinical, and clinical studies in neuroscience. The repurposing of FDA approved compounds is an effective and expedited means of screening pharmacotherapies for AUD. Here, we demonstrate that apremilast, a phosphodiesterase type 4 inhibitor that is FDA approved for psoriasis and psoriatic arthritis, reduces binge-like alcohol intake and behavioral measures of motivation in unique, preclinical genetic risk models for drinking to intoxication and reduces excessive alcohol drinking in models of stress facilitated drinking and alcohol dependence. In a double blind, placebo-controlled human laboratory study in non-treatment seeking individuals with AUD, apremilast significantly reduced the number of drinks per day. Lastly, using site-directed drug infusions and electrophysiology we determined that apremilast may act by increasing neural activity in the nucleus accumbens, an important alcohol-related brain region, to reduce alcohol intake in mice. These results demonstrate that apremilast reduces excessive alcohol drinking across a spectrum of AUD severity and support its importance as a potential therapeutic for AUD.

OBJECTIVE: Alcohol use disorder (AUD) is a leading cause of global disease burden. Chronic, heavy use increases the likelihood of alcohol withdrawal symptoms and associated secondary outcomes of alcohol craving and mood, anxiety, and sleep disturbances, which are predictive of poor treatment outcomes. The authors examined whether alcohol withdrawal symptoms moderate the efficacy of prazosin in reducing alcohol intake and associated secondary outcomes. METHODS: A 12-week, double-blind, randomized, controlled proof-of-concept trial of prazosin (16 mg/day, with a 2-week titration) was conducted in community-recruited adults with current alcohol dependence (N=100) with varying levels of alcohol withdrawal symptoms assessed at treatment entry. Primary outcomes were daily self-reported drinking days and heavy drinking days, and secondary outcomes were average drinks/day and mood, anxiety, craving, and sleep quality ratings. RESULTS: Modified intent-to-treat analyses indicated a significant interaction of alcohol withdrawal symptom score by treatment by full-dose treatment period (weeks 3–12) for drinking days, heavy drinking days, and average drinks/day. By week 12, participants with high alcohol withdrawal symptoms on prazosin reported 7.07% heavy drinking days and 27.46% drinking days, while those on placebo had 35.58% heavy drinking days and 58.47% drinking days (heavy drinking days: odds ratio=0.14, 95% CI=0.058, 0.333; drinking days: odds ratio=0.265, 95% CI=0.146, 0.481). No such benefit of prazosin was observed in those reporting low or no alcohol withdrawal symptoms. Individuals with high alcohol withdrawal symptoms on prazosin compared with placebo also showed significantly improved anxiety, depression, and alcohol craving over the course of the trial. CONCLUSIONS: The findings indicate that alcohol withdrawal symptoms are a significant moderator of prazosin treatment response for alcohol use outcomes and for associated symptoms of alcohol craving, anxiety, and mood symptoms. These data support further evaluation of alcohol withdrawal symptoms as a prognostic indicator of prazosin’s efficacy in the treatment of AUD.

Alcohol use disorder (AUD) is associated with the dysregulation of brain stress and reward systems, including glucocorticoid receptors (GRs). The mixed glucocorticoid/progesterone receptor antagonist mifepristone and selective GR antagonist CORT113176 have been shown to selectively reduce alcohol consumption in alcohol-dependent rats. Mifepristone has also been shown to decrease alcohol consumption and craving for alcohol in humans with AUD. The present study tested the effects of the GR modulators CORT118335, CORT122928, CORT108297, and CORT125134 on alcohol self-administration in nondependent (air-exposed) and alcohol-dependent (alcohol vapor-exposed) adult male rats. Different GR modulators recruit different GR-associated transcriptional cofactors. Thus, we hypothesized that these GR modulators would vary in their effects on alcohol drinking. CORT118335, CORT122928, and CORT125134 significantly reduced alcohol self-administration in both alcohol-dependent and nondependent rats. CORT108297 had no effect on alcohol self-administration in either group. The present results support the potential of GR modulators for the development of treatments for AUD. Future studies that characterize genomic and nongenomic effects of these GR modulators will elucidate potential molecular mechanisms that underlie alcohol drinking in alcohol-dependent and nondependent states.

In March 2019, a scientific meeting was held at the University of California, Los Angeles (UCLA) Luskin Center to discuss approaches to expedite the translation of neurobiological insights to advances in the treatment of alcohol use disorder (AUD). A guiding theme that emerged was that while translational research in AUD is clearly a challenge, it is also a field ripe with opportunities. Herein, we seek to summarize and disseminate the recommendations for the future of translational AUD research using four sections. First, we briefly review the current landscape of AUD treatment including the available evidence-based treatments and their uptake in clinical settings. Second, we discuss AUD treatment development efforts from a translational science viewpoint. We review current hurdles to treatment development as well as opportunities for mechanism-informed treatment. Third, we consider models of translational science and public health impact. Together, these critical insights serve as the bases for a series of recommendations and future directions. Towards the goal of improving clinical care and population health for AUD, scientists are tasked with bolstering the clinical applicability of their research findings so as to expedite the translation of knowledge into patient care.

There is considerable variability in the use of outcome measures in clinical trials for cannabis use disorder (CUD), and a lack of consensus regarding optimal outcomes may have hindered development and approval of new pharmacotherapies. The goal of this paper is to summarize an evaluation of assessment measures and clinical endpoints for CUD clinical trials, and propose a research agenda and priorities to improve CUD clinical outcome assessments. The primary recommendation is that sustained abstinence from cannabis should not be considered the primary outcome for all CUD clinical trials as it has multiple limitations. However, there are multiple challenges to the development of a reliable and valid indicator of cannabis reduction, including the lack of a standard unit of measure for the various forms of cannabis and products and the limitations of currently available biological and self-report assessments. Development of a core toolkit of assessments is needed to both allow flexibility for study design, while facilitating interpretation of outcomes across trials. Four primary agenda items for future research are identified to expedite development of improved clinical outcome assessments for this toolkit: (1) determine whether minimally invasive biologic assays could identify an acute level of cannabis use associated with psychomotor impairment or other cannabis-related harms; (2) create an indicator of quantity of cannabis use that is consistent across product types; (3) examine the presence of cannabis-specific functional outcomes; and (4) identify an optimal duration to assess changes in CUD diagnostic criteria.

The identification of different stages within the alcohol use disorder (AUD) cycle that are linked to neurocircuitry changes in pathophysiology associated with the negative emotional states of abstinence has provided a view of medication development for AUD that emphasizes changes in the brain reward and stress systems. Alcohol use disorder can be defined as a chronic relapsing disorder that involves compulsive alcohol seeking and taking, loss of control over alcohol intake, and emergence of a negative emotional state during abstinence. The focus of early medications development was to block the motivation to seek alcohol in the binge/intoxication stage. More recent work has focused on reversing the motivational dysregulations associated with the withdrawal/negative affect and preoccupation/anticipation stages during protracted abstinence. Advances in our understanding of the neurocircuitry and neuropharmacological mechanisms that are involved in the development and maintenance of the withdrawal/negative affect stage using validated animal models have provided viable targets for future medications. Another major advance has been proof-of-concept testing of potential therapeutics and clinical validation of relevant pharmacological targets using human laboratory models of protracted abstinence. This review focuses on future targets for medication development associated with reversal of the loss of reward function and gain in brain stress function that drive negative reinforcement in the withdrawal/negative affect stage of addiction. Basic research has identified novel neurobiological targets associated with the withdrawal/negative affect stage and preoccupation/anticipation stage, with a focus on neuroadaptive changes within the extended amygdala that account for the transition to dependence and vulnerability to relapse. This article is part of the Special Issue entitled "Alcoholism".

BACKGROUND: Several single-site alcohol treatment clinical trials have demonstrated efficacy for immediate-release (IR) gabapentin in reducing drinking outcomes among individuals with alcohol dependence. The purpose of this study was to conduct a large, multisite clinical trial of gabapentin enacarbil extended-release (GE-XR) (HORIZANT(®)), a gabapentin prodrug formulation, to determine its safety and efficacy in treating alcohol use disorder (AUD). METHODS: Men and women (n= 346) who met DSM–5 criteria for at least moderate AUD were recruited across 10 US clinical sites. Participants received double-blind GE-XR (600 mg twice a day [BID]) or placebo and a computerized behavioral intervention (Take Control) for 6 months. Efficacy analyses were pre-specified for the last 4 weeks of the treatment period. RESULTS: The GE-XR and placebo groups did not differ significantly on the primary outcome measure, percentage of subjects with no heavy drinking days (28.3 vs 21.5, respectively, p=0.157). Similarly, no clinical benefit was found for other drinking measures (percent subjects abstinent, percent days abstinent, percent heavy drinking days, drinks per week, drinks per drinking day), alcohol craving, alcohol-related consequences, sleep problems, smoking, and depression/anxiety symptoms. Common side-effects were fatigue, dizziness, and somnolence. A population pharmacokinetics analysis revealed that patients had lower gabapentin exposure levels compared with those in other studies using a similar dose but for other indications. CONCLUSION: Overall, GE-XR at 600 mg BID did not reduce alcohol consumption or craving in individuals with AUD. It is possible that, unlike the IR formulation of gabapentin, which showed efficacy in smaller Phase 2 trials at a higher dose, GE-XR is not effective in treating AUD, at least not at doses approved by the FDA for treating other medical conditions.

The purpose of this chapter is to review the evidence for the efficacy and safety of anticonvulsants for reducing cannabis use and withdrawal symptoms, compared to placebo. A comprehensive literature search of PubMed and related databases and reference lists of obtained publications was performed. The search yielded four completed prospective pilot studies evaluating divalproex sodium (Depakote), gabapentin (Neurontin), and topiramate (Topamax) for therapeutic potential in cannabis use disorder. For three studies the average age was 30.1 years; one study targeted youth. About 78% of study participants were male. Studies were double-blind, placebo-controlled with random assignment to treatments. Cannabis use was measured by both urine toxicology and self-report. Medication adherence was verified by drug plasma level. Divalproex and topiramate generally did not show efficacy for reducing cannabis use and were poorly tolerated. Both drugs were associated with adverse drug reactions involving neurocognitive impairment and symptoms of negative affect such as depression, anxiety, and irritability. Gabapentin showed benefits over placebo in decreasing cannabis use and withdrawal symptoms, including cannabis craving, negative affect, and sleep disturbance, and was well-tolerated. Findings support further evaluation of gabapentin as a treatment for cannabis use disorder.

The identification of a heuristic framework for the stages of the addiction cycle that are linked to neurocircuitry changes in pathophysiology includes the binge/intoxication stage, the withdrawal/negative affect stage, and the preoccupation/anticipation (craving) stage, which represent neuroadaptations in three neurocircuits (basal ganglia, extended amygdala, and frontal cortex, respectively). The identification of excellent and validated animal models, the development of human laboratory models, and an enormous surge in our understanding of neurocircuitry and neuropharmacological mechanisms have provided a revisionist view of addiction that emphasizes the loss of brain reward function and gain of stress function that drive negative reinforcement (the dark side of addiction) as a key to compulsive drug seeking. Reversing the dark side of addiction not only explains much of the existing successful pharmacotherapies for addiction but also points to vast new opportunities for future medications to alleviate this major source of human suffering.

High Drinking in the Dark (HDID-1) mice represent a unique genetic risk model of binge-like drinking and a novel means of screening potential pharmacotherapies to treat alcohol use disorders (AUDs). We tested the effects of tacrolimus (0, 0.5, 1, and 2 mg/kg), sirolimus (0, 5, 10, and 20 mg/kg), palmitoylethanolamide (PEA; 0, 75, 150, and 225 mg/kg), and secukinumab (0, 5, 20, and 60 mg/kg) on binge-like ethanol intake (2-day, “Drinking in the Dark” [DID]) and blood alcohol levels (BALs) in HDID-1 mice. Tacrolimus reduced ethanol intake and BALs. Tacrolimus had no effect on water intake, but reduced saccharin intake. There was no effect of sirolimus, PEA, or secukinumab on ethanol intake or BALs. These results compare and contrast with previous work addressing these compounds or their targeted mechanisms of action on ethanol drinking, highlighting the importance of screening a wide range of models and genotypes to inform the role of neuroimmune signaling in AUDs.

Alcohol misuse is the fifth leading risk factor for premature death and disability worldwide. Fewer than 10% of afflicted Americans receive pharmacological treatment for alcohol use disorder. Gabapentin is a calcium channel GABAergic modulator that is widely used for pain. Studies showing reduced drinking and decreased craving and alcohol-related disturbances in sleep and affect in the months following alcohol cessation suggest therapeutic potential for alcohol use disorder. Areas covered: Human laboratory and clinical studies assessing gabapentin for alcohol use disorder are reviewed. Data were obtained by searching for English peer-reviewed articles on PubMed, reference lists of identified articles, and trials registered on clinicaltrials.gov. Additionally, the mechanism of action of gabapentin specific to alcohol use disorder, and studies of gabapentin for alcohol withdrawal and non-alcohol substance use disorders are summarized. Expert opinion: Alcohol use disorder represents a challenge and large, unmet medical need. Evidence from single-site studies lend support to the safety and efficacy of gabapentin as a novel treatment for alcohol use disorder, with unique benefits for alcohol-related insomnia and negative affect, relative to available treatments. Proprietary gabapentin delivery systems may open a path to pivotal trials and registration of gabapentin as a novel treatment for alcohol use disorder.

Alcoholism, or alcohol use disorder, is a major public health concern that is a considerable risk factor for morbidity and disability; therefore, effective treatments are urgently needed. Here, we demonstrated that the glucocorticoid receptor (GR) antagonist mifepristone reduces alcohol intake in alcohol-dependent rats but not in nondependent animals. Both systemic delivery and direct administration into the central nucleus of the amygdala, a critical stress-related brain region, were sufficient to reduce alcohol consumption in dependent animals. We also tested the use of mifepristone in 56 alcohol-dependent human subjects as part of a double-blind clinical and laboratory-based study. Relative to placebo, individuals who received mifepristone (600 mg daily taken orally for 1 week) exhibited a substantial reduction in alcohol-cued craving in the laboratory, and naturalistic measures revealed reduced alcohol consumption during the 1-week treatment phase and 1-week post-treatment phase in mifepristone-treated individuals. Mifepristone was well tolerated and improved liver-function markers. Together, these results support further exploration of GR antagonism via mifepristone as a therapeutic strategy for alcoholism.

The treatment for cocaine use constitutes a clinical challenge because of the lack of appropriate therapies and the high rate of relapse. Recent evidence indicates that the immune system might be involved in the pathogenesis of cocaine addiction and its co-morbid psychiatric disorders. This work examined the plasma pro-inflammatory cytokine and chemokine profile in abstinent cocaine users (n = 82) who sought outpatient cocaine treatment and age/sex/body mass-matched controls (n = 65). Participants were assessed with the diagnostic interview Psychiatric Research Interview for Substance and Mental Diseases according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). Tumor necrosis factor-alpha, chemokine (C-C motif) ligand 2/monocyte chemotactic protein-1 and chemokine (C-X-C motif) ligand 12 (CXCL12)/stromal cell-derived factor-1 (SDF-1) were decreased in cocaine users, although all cytokines were identified as predictors of a lifetime pathological use of cocaine. Interleukin-1 beta (IL-1β), chemokine (C-X3-C motif) ligand 1 (CX3CL1)/fractalkine and CXCL12/SDF-1 positively correlated with the cocaine symptom severity when using the DSM-IV-TR criteria for cocaine abuse/dependence. These cytokines allowed the categorization of the outpatients into subgroups according to severity, identifying a subgroup of severe cocaine users (9-11 criteria) with increased prevalence of co-morbid psychiatric disorders [mood (54%), anxiety (32%), psychotic (30%) and personality (60%) disorders]. IL-1β was observed to be increased in users with such psychiatric disorders relative to those users with no diagnosis. In addition to these clinical data, studies in mice demonstrated that plasma IL-1β, CX3CL1 and CXCL12 were also affected after acute and chronic cocaine administration, providing a preclinical model for further research. In conclusion, cocaine exposure modifies the circulating levels of pro-inflammatory mediators. Plasma cytokine/chemokine monitoring could improve the stratification of cocaine consumers seeking treatment and thus facilitate the application of appropriate interventions, including management of heightened risk of psychiatric co-morbidity. Further research is necessary to elucidate the role of the immune system in the etiology of cocaine addiction.

Five years after completion of a randomised placebo-controlled trial of calcium supplements, there was no effect of calcium on total fracture incidence, a significant reduction in vertebral and forearm fractures and, in a subset, no effect on bone density. There was no increased risk of cardiovascular events after discontinuation of calcium.The Auckland calcium study was a 5-year randomised controlled trial of 1 g/day calcium citrate in 1,471 postmenopausal women. Calcium did not reduce total, vertebral or forearm fracture incidence, increased hip fracture incidence and had beneficial effects on bone mineral density (BMD). A secondary analysis raised concerns about the cardiovascular safety of calcium. The purpose of this study was to determine whether the effects of calcium on fracture incidence, BMD and cardiovascular endpoints persisted after supplement discontinuation.Approximately 5-years post-trial, we collected information on the 1,408 participants alive at trial completion from the national databases of hospital admissions and deaths. We contacted 1,174 women by phone, and from these we obtained information on medical events and post-trial calcium use. We undertook BMD measurements at 10 years in a selected subset of 194 women who took study medication for 5 years in the original trial, and did not take bone-active medications post-trial.Over the 10-year period, there was no effect on total fracture (HR 0.90, 95% CI 0.75-1.07) or hip fracture incidence (1.40, 0.89-2.21), but significant reductions in forearm (0.62, 0.43-0.89) and vertebral fractures (0.52, 0.32-0.85) in those assigned to calcium. There were no between-group differences in BMD at 10 years at any site. The adverse cardiovascular outcomes observed in the 5-year trial did not persist post-trial.Calcium supplementation for 5 years had no effect on total fracture incidence at 10 years. The positive benefits on BMD and the adverse cardiovascular effects did not persist once supplements were stopped.

Background: It is unknown whether women derive comparable benefits and have a similar safety and tolerability profile as men from acamprosate, a widely prescribed drug for the maintenance of abstinence in alcohol dependence. The objective of this study was to assess sex-specific differences in the efficacy, safety, and tolerability of acamprosate in the treatment of women and men with alcohol dependence. Methods: A sex-specific meta-analysis was conducted based on individual patient data (IPD). Data were obtained from double-blind, randomized controlled trials with quantitative drinking measures in patients with alcohol dependence receiving oral acamprosate or placebo. Sources included PubMed, PsychInfo, and Cochrane electronic databases; reference lists from retrieved articles and presentations at professional meetings; and direct access to authors and companies who provided IPD. Results: Individual records were obtained from 1,317 women and 4,794 men who participated in 22 eligible studies conducted in 18 countries. IPD meta-analyses found a significant beneficial effect of acamprosate relative to placebo across all 4 efficacy end points: an incremental gain of 10.4% (95% CI 7.1 to 13.7, p

Recent observational studies have highlighted the beneficial role of dairy ingestion in gout prevention. The aims of this study were to determine the acute effects of milk ingestion on serum urate concentrations and examine the mechanisms of these effects.This was a short-term randomised controlled crossover trial of milk in 16 healthy male volunteers. The following products were tested (each 80 g protein): soy control, early season skim milk, late season skim milk (containing high concentrations of orotic acid, a naturally occurring uricosuric agent) and ultrafiltrated MPC 85 skim milk. Each participant received a single dose of each product in random order. Serum and urine were obtained immediately before and then hourly over a 3 h period after ingestion of each study product.Ingestion of the soy control led to an increase in serum urate concentrations by approximately 10%. In contrast, ingestion of all milks led to a decrease in serum urate concentrations by approximately 10% (p0.0001). All products (including soy) rapidly increased the fractional excretion of uric acid (FEUA). Late season milk led to a greater increase in FEUA than MPC 85 (p=0.02) and early season milk (p=0.052). There were no differences over time in serum oxypurines or purine-containing nucleosides. However, all products increased the fractional excretion of xanthine.Intact milk has an acute urate-lowering effect. These data provide further rationale for long-term intervention studies to determine whether such dietary interventions have an adjunctive role in the management of individuals with hyperuricaemia and gout.

This secondary analysis of the first U.S. acamprosate trial (N = 601) for alcohol dependence examines the effects of subsyndromal psychiatric symptoms or history of severe psychopathology on alcoholism treatment outcomes and any mitigating effects of acamprosate. Psychiatric antecedents were documented using a protocol-specific interview. Current psychiatric symptoms were assessed using Hamilton Anxiety and Depression (HAM-A, HAM-D) rating scales. Predictors of good response, defined as abstinence foror =90% of trial duration, were identified using logistic regression. Subsyndromal anxiety (as determined by HAM-A "Anxious Mood" item) and the presence ofor =1 psychiatric antecedent were significant negative predictors of good response. Lower pretreatment drinking intensity, baseline motivation to have abstinence as a goal, and treatment with acamprosate were significant positive predictors of good response. No significant interactions among predictors were detected, indicating that they are independent, additive factors. Thus, the beneficial effects of acamprosate treatment in combination with motivational therapy may offset the liabilities for alcoholism recovery that are associated with current anxiety symptoms and/or a significant past psychiatric history. (Am J Addict 2010;00:1-8).

Acamprosate, marketed under the brand name Campral, (Forest Pharmaceuticals, Inc., Saint Louis, MO, USA; Merck Sante s.a.s., Lyon, France) is an orally administered drug approved in the US and throughout much of the world for treating alcohol dependence. Its safety and efficacy have been demonstrated in a number of clinical trials worldwide and as with all pharmacotherapies for alcoholism, it is used in conjunction with psychosocial interventions.This article reviews the mechanism of action, clinical efficacy and safety of acamprosate in Phase I, II and III randomized controlled trials involving healthy and alcohol-dependent populations using published reports from 1984 to 2009.This review provides an update of the mechanism of action and the safety and efficacy profile of acamprosate.Acamprosate appears to act centrally to restore the normal activity of glutamatergic neurotransmission altered by chronic alcohol exposure. Acamprosate's excellent safety profile along with several pharmacokinetic and pharmacodynamic characteristics make it well suited for treating a broad population of alcohol-dependent patients.

To evaluate the effect of current smoking and lifetime illicit drug use on alcoholism treatment outcomes and to assess whether these factors influence acamprosate efficacy.: This is a secondary analysis of data from the intention-to-treat population (N = 601) in a 6-month, randomized, placebo-controlled US trial of acamprosate (2 or 3 g/d). Patients met Diagnostic and Statistical Manual of Mental Disorders, 4th Edition criteria for alcohol dependence and no other dependence disorders other than nicotine or cannabis, although patients with recent substance use were included. Baseline severities of current nicotine dependence and lifetime drug use were determined using the Fagerström test of nicotine dependence and the illicit drug use inventory, respectively. The primary endpoint was rate of good response (abstinence from alcohol for ≥90% of trial). Secondary endpoints were rate of controlled drinking (≤5 drinks/d for ≥90% of trial), percent days abstinent, and percent days controlled drinking. The effect of smoking, drug use, treatment, and any interactions on study endpoints was assessed by a backward selection process to eliminate nonsignificant variables.: In the intention-to-treat population, 44.9% of patients were current smokers and 78.7% reported lifetime illicit drug use. Current nicotine dependence and lifetime illicit drug use were significant negative predictors of rates of good response (nicotine: odds ratio [OR] = 0.56, 95% confidence interval [CI] = 0.35-0.88, P = 0.01; illicit drugs: OR = 0.47, 95% CI = 0.31-0.71, P0.01) and all other secondary outcomes. Acamprosate had a significant positive effect on rate of good response (OR = 1.65, 95% CI = 1.08-2.52, P = 0.020) and all other secondary outcomes.: Current nicotine dependence and lifetime illicit drug use were found to have a significant negative impact on alcoholism treatment outcomes, but no impact on the significant positive effects of acamprosate. The effect sizes of smoking, drug use, and acamprosate are equivalent and thus, treatment with acamprosate may offset some of the negative effects of smoking or drug use on alcoholism treatment outcomes.

Current pharmacotherapies for addiction represent opportunities for facilitating treatment and are forming a foundation for evaluating new medications. Furthermore, validated animal models of addiction and a surge in understanding of neurocircuitry and neuropharmacological mechanisms involved in the development and maintenance of addiction — such as the neuroadaptive changes that account for the transition to dependence and the vulnerability to relapse — have provided numerous potential therapeutic targets. Here, we emphasize a ‘Rosetta Stone approach’, whereby existing pharmacotherapies for addiction are used to validate and improve animal and human laboratory models to identify viable new treatment candidates. This approach will promote translational research and provide a heuristic framework for developing efficient and effective pharmacotherapies for addiction.

Laboratory paradigms are useful for investigating mechanisms of human alcohol cue reactivity in a highly controlled environment. A number of studies have examined the effects of beverage exposure or negative affective stimuli on cue reactivity independently, but only a few have reported on interaction effects between beverage cue and affective stimuli, and none have evaluated the effects of positive stimuli on beverage cue reactivity.To assess independent and interactive effects of both positive and negative affective stimuli and beverage cue on psychophysiological and subjective measures of reactivity in alcohol dependence.A total of 47 non-treatment-seeking paid volunteers with current alcohol dependence participated in a within-subjects trial where each was exposed to a standardized set of pleasant, neutral, or unpleasant visual stimuli followed by alcohol or water cues. Psychophysiological cue-reactivity measures were obtained during beverage presentation, and subjective reactivity measures were taken directly following beverage presentation.Mixed-effect models revealed a significant main effect of beverage and positive (but not negative) affective stimuli on subjective strength of craving and significant main effects of both positive and negative affective stimuli on ratings of emotionality. Despite the power to detect relatively small interaction effects, no significant interactions were observed between affect and beverage conditions on any reactivity measure.A key finding of this study is that positive affective stimuli commonly associated with drinking situations can induce craving in the absence of alcohol cues. Main effects of beverage cue replicated results from previous studies. Beverage and affective cues showed no interaction effects.

OBJECTIVES: Sleep disturbance constitutes a major risk factor for drinking relapse after alcohol withdrawal and necessitates regular follow-up. We reported previously that the sum-score of the 4 sleep items of the Hamilton Anxiety and Depression Scales (the Short Sleep Index [SSI]) constitutes a valid and simple sleep measurement tool. The objective of this study was to evaluate the psychometric features of the SSI relative to the lengthier Pittsburgh Sleep Quality Index (PSQI), which is widely used for measuring sleep disturbance in patients with alcohol use disorders during and after alcohol withdrawal. METHODS: In this French, multicenter, cross-sectional survey, alcoholic patients were recruited in 2 academic hospitals and 1 community treatment center. Demographic data, alcohol history, and current consumption of alcohol and other abused substances were documented. The SSI and the PSQI questionnaires were completed in face-to-face interviews by a trained clinical research associate. RESULTS: A total of 257 patients were studied (88 females), with a mean age of 49 years (range: 24-80 years). The prevalence of sleep disturbance as measured by the PSQI and the SSI was 73.5% and 74.3%, respectively. The correlation between the 2 indices was strong (r = 0.764; 95% CI: 0.709-0.811), with negative and positive predictive values for the SSI (score > 1) of 71.2% and 89%, respectively, and an area under the receiver operating characteristic curve of 0.91 (95% CI: 0.85-0.92). The discriminant and convergent validity of the SSI was found to be noninferior to the PSQI. CONCLUSIONS: Compared to the PSQI, the SSI represents a quick, quantifiable, and reliable method that could help clinicians assess and manage sleep disturbance in alcoholic patients. Language: en

Alcohol dependence is a chronic, relapsing disorder affecting more than 8 million Americans who are at increased risk for negative interpersonal and health consequences from pathological drinking. Successful treatment would potentially decrease these risks and lessen the tremendous personal and societal burdens attributed to this disorder. Psychosocial interventions without pharmacotherapy have long been the traditional treatment approach, but relapse is common. Advances in the identification of neurotransmitter systems involved in the addiction cycle have led to the development of new medications that, used in combination with counseling, further improve treatment outcome over that with counseling alone. Acamprosate is one of the medications that have shown success in promoting abstinence in alcohol-dependent individuals. For some patients, integrating acamprosate therapy into clinical practice as a complement to psychosocial interventions would enhance therapeutic options to assist in recovery. This art...

Purpose Calcium has been shown to have positive effects on bone mineral density in postmenopausal women. However, these effects are small, it is unknown whether they are sustained with long-term use, they have not been shown with intention-to-treat analyses, and the evidence for fracture prevention with calcium monotherapy is inconsistent. Methods A randomized controlled trial of calcium (1 g/day as the citrate) in 1471 healthy postmenopausal women (aged 74±4 years) was performed to assess the effects on bone density and fracture incidence over 5 years. Results Follow-up was complete in 90% of subjects, and average medication compliance was 55% to 58%. Calcium had a significant beneficial effect on bone density (intention-to-treat analysis), with between-groups differences at 5 years of 1.8% (spine), 1.6% (total hip), and 1.2% (total body). Effects were greater in a per-protocol analysis (5-year differences of 2.3%, 2.8%, and 1.8%, respectively). A total of 425 fractures occurred in 281 women. Hazard ratios, based on time to first fracture, were 0.90 (95% confidence interval [CI], 0.71-1.16) for any symptomatic fracture, 0.72 (95% CI, 0.44-1.18) for vertebral, 3.55 (95% CI, 1.31-9.63) for hip, and 0.65 (95% CI, 0.41-1.04) for forearm fracture. Per-protocol analysis found respective hazard ratios of 0.86 (95% CI, 0.64-1.17), 0.62 (95% CI, 0.33-1.16), 3.24 (95% CI, 0.65-16.1), and 0.45 (95% CI, 0.24-0.87). Height loss was reduced by calcium in the per-protocol population ( P =.03). Serum alkaline phosphatase and procollagen type-I N-terminal propeptide were lower in the calcium group at 5 years, but constipation was more common. Conclusions Calcium results in a sustained reduction in bone loss and turnover, but its effect on fracture remains uncertain. Poor long-term compliance limits its effectiveness.

This article represents the proceedings of a symposium presented at the 158th Annual Meeting of the American Psychiatric Association held in Atlanta, Georgia, on May 24, 2005. The organizer/chairman was Bankole A. Johnson, DSc, MD, PhD. The presentations included the following: (1) Neuropharmacological Basis of Alcohol Dependence, by George F. Koob, PhD; (2) Recent Developments in the Genetics of Alcohol Dependence, by Marc A. Schuckit, MD; (3) New Pharmacological Strategies for Treating Alcohol Dependence, by Barbara J. Mason, PhD; (4) New Medications: The Use of Anticonvulsants, Both Alone and in Combination, with Various Forms of Psychotherapy, by Bankole A. Johnson, DSc, MD, PhD; and (5) Differential Effects of Pharmacological Agents on Craving, by Nassima Ait-Daoud, MD.

This article provides an evidence-based review of acamprosate and naltrexone, used alone and in combination. Both medications are gaining increasing availability worldwide by prescription for the treatment of alcohol dependence. There is scientific and clinical interest in examining these drugs in combination, given their high tolerability, moderate effect sizes, different pharmacological profiles and potentially different effects on drinking outcomes.This article includes a review of the key similarities and differences between acamprosate and naltrexone in the treatment of alcohol dependence; the published double-blind, placebo-controlled trials of acamprosate and naltrexone across a uniform range of outcome criteria to elucidate the differences and similarities in the behavioral effects of these drugs; the two published pharmacokinetic and pharmacodynamic drug interaction studies of acamprosate and naltrexone; and the single-site clinical trial of acamprosate and naltrexone used alone and in combination relative to placebo.Pharmacokinetic and pharmacodynamic studies report an increase in acamprosate plasma levels with no clinically significant elevation in adverse events when the two drugs are used in combination. Data from dose-response studies for acamprosate alone suggest that the augmentation of acamprosate plasma levels by co-administration of naltrexone may have clinical benefits.These factors support investigating the efficacy and safety of combining acamprosate and naltrexone for the treatment of alcohol dependence in a large-scale multisite trial, with evaluation of potential predictors of response to each drug alone and in combination relative to placebo.

A rapid gas chromatography-mass spectrometric method for the determination of nalmefene in human plasma is described. The procedure involves protein precipitation, extraction with ethanol-chloroform mixture and derivatization with pentafluropropionic anhydride. The deuterated analog of nalmefene, 6beta-naltrexol-d(7), was used as the internal standard. Quantitation was achieved on a HP-1 column (12 mx0.2 mm I.D.) with negative chemical ionization (NCI) using methane:ammonia (95:5) as the reagent gas. The standard curves were fitted using a quadratic equation with the curve encompassing a range of 0.5 to 200 ng/ml, and the intra- and inter-assay variations for three different nalmefene levels were less than 10% throughout. The limit of quantitation was found to be 0.5 ng/ml. The method described is highly specific and reproducible, and could also be applied for the determination of naltrexone and 6beta-naltrexol. Application of the method to actual human plasma samples is demonstrated.

This article represents the proceedings of a symposium at the 2001 RSA Meeting in Montreal, Canada. The organizers were Barbara J. Mason and George F. Koob. Anita M. Goodman served as chair. The presentations were (1) Acamprosate inhibits alcohol withdrawal-induced neurotoxicity in organotypic hippocampal cultures, by John Littleton; (2) Acamprosate alteration of NMDA receptor-dependent synaptic transmission and synaptic plasticity, by George R. Siggins; (3) Acamprosate and glutamate during ethanol withdrawal, by Philippe De Witte; (4) Clinical evidence of protective CNS effects of acamprosate in alcohol-dependent individuals, by Barbara J. Mason.

Purpose To determine the effect of supplementation with calcium citrate on circulating lipid concentrations in normal older women. Subjects and methods As part of a study of the effects of calcium supplementation on fractures, we randomly assigned 223 postmenopausal women (mean [± SD] age, 72 ± 4 years), who were not receiving therapy for hyperlipidemia or osteoporosis, to receive calcium (1 g/d, n=111) or placebo (n = 112) for 1 year. Fasting serum lipid concentrations, including high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol, were obtained at baseline, and at 2, 6, and 12 months. Results After 12 months, HDL cholesterol levels and the HDL cholesterol to LDL cholesterol ratio had increased more in the calcium group than in the placebo group (mean between-group differences in change from baseline: for HDL cholesterol, 0.09 mmol/L (95% confidence interval [CI]: 0.02 to 0.17; P = 0.01); for HDL/LDL cholesterol ratio, 0.05 (95% CI: 0.02 to 0.08; P = 0.001). This was largely due to a 7% increase in HDL cholesterol levels in the calcium group, with a nonsignificant 6% decline in LDL cholesterol levels. There was no significant treatment effect on triglyceride level ( P = 0.48). Conclusion Calcium citrate supplementation causes beneficial changes in circulating lipids in postmenopausal women. This suggests that a reappraisal of the indications for calcium supplementation is necessary, and that its cost effectiveness may have been underestimated.

Bone density has been followed up for 20 months following completion of a trial which compared calcium 1,200 mg/day with placebo, in normal older men. Following cessation of calcium supplements, there is a small residual benefit in total body bone density, but not at the hip or spine. Calcium supplements, or supplements of calcium-rich foods, have a positive effect on bone mineral density (BMD). However, it is uncertain whether there are any residual benefits of calcium on BMD following cessation of supplementation. In a previously published study, 323 healthy men were randomized to receive elemental calcium 600 mg/day (n = 108), calcium 1,200 mg/day (n = 108), or placebo (n = 107) over 2 years. Consenting men from the placebo and calcium 1,200 mg/day groups (85 and 87, respectively) were followed over the next 1–2 years (mean 20 months), off trial medication. In the core trial, BMD increased at all sites by 1.0–1.5 % at 2 years in the group receiving calcium 1,200 mg/day, compared to the group receiving placebo. In post-trial follow-up, the calcium group has some residual benefit at the total body (0.41 % above placebo; P = 0.04) but there was no significant between-group differences at other sites. Following cessation of calcium supplements in healthy men, there is a small residual benefit in total body BMD, but not at the hip or spine. This is unlikely to confer a clinically significant dividend in terms of ongoing fracture prevention.

Francisco Aboitiz*, F. Xavier Castellanos and Ximena Carrasco Departamento de Psiquiatria, Facultad de Medicina, and Centro Interdisciplinario de Neurociencia, Pontificia Universidad Catolica de Chile, Santiago, Chile New York University Child Study Center, Nathan Kline Institute for Psychiatric Research, New York, NY, USA Servicio de Neurologia y Psiquiatria infantil, Hospital Luis Calvo Mackenna Facultad de Medicina, Universidad de Chile, Santiago, Chile

The relationships between drug therapy and health-related quality of life in 1054 patients who received care from Department of Veterans Affairs medical centers (VAMCs) were assessed. Patients at high risk for drug-related problems were enrolled into a pharmaceutical care study at nine VAMCs. On enrollment, the short form (SF)-36 was completed and medical records were examined for evidence of coexisting illness. Drug therapy in the year before enrollment was analyzed in relation to SF-36 scores. Mean +/- SD SF-36 scores ranged from 37.99+/-41.70 for role physical to 70.78+/-18.97 for mental health domains, with all domain scores significantly below age-adjusted national norms (p0.05). Patients taking a drug that required therapeutic monitoring had significantly lower SF-36 scores (p=0.0001 to p=0.0033) across all domains except for bodily pain and mental health, compared with patients not taking these agents.

We examined the impact of ambulatory care clinical pharmacist interventions on clinical and economic outcomes of 208 patients with dyslipidemia and 229 controls treated at nine Veterans Affairs medical centers. This was a randomized, controlled trial involving patients at high risk of drug-related problems. Only those with dyslipidemia are reported here. In addition to usual medical care, clinical pharmacists were responsible for providing pharmaceutical care for patients in the intervention group. The control group did not receive pharmaceutical care. Seventy-two percent of the intervention group and 70% of controls required secondary prevention according to the National Cholesterol Education Program guidelines. Significantly more patients in the intervention group had a fasting lipid profile compared with controls (p=0.021). The absolute change in total cholesterol (17.7 vs 7.4 mg/dl, p=0.028) and low-density lipoprotein (23.4 vs 12.8 mg/dl, p=0.042) was greater in the intervention than in the control group. There were no differences in patients achieving goal lipid values or in overall costs despite increased visits to pharmacists. Ambulatory care clinical pharmacists can significantly improve dyslipidemia in a practice setting designed to manage many medical and drug-related problems.

Study Objective. To determine if clinical pharmacists could affect economic resource use and humanistic outcomes in an ambulatory, high-risk population. Design. Prospective, randomized, controlled study. Setting. Nine Veterans Affairs medical centers. Patients. Patients who were at high risk for medication-related problems. Intervention. Patients were randomized to usual medical care with input from a clinical pharmacist (intervention group) or just usual medical care (control group). Measurements and Main Results. Of 1054 patients enrolled, 523 were randomized to the intervention group and 531 to the control group. The number of clinic visits increased in the intervention group (p=0.003), but there was no difference in clinic costs. Mean increases in total health care costs were $1020 for the intervention group and $1313 for the control group (p=0.06). Conclusion. Including the cost of pharmacist interventions, overall health care expenditures were similar for patients randomized to see a clinical pharmacist versus usual medical care.