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Banks M.L.,Virginia Commonwealth University | Blough B.E.,Research Triangle Institute International | Negus S.S.,Virginia Commonwealth University
Drug and Alcohol Dependence | Year: 2013

Background: The clinical utility of monoamine releasers such as phenmetrazine or d-amphetamine as candidate agonist medications for cocaine dependence is hindered by their high abuse liability. Phendimetrazine is a clinically available schedule III anorectic that functions as a prodrug for phenmetrazine and thus may have lower abuse liability. This study determined the effects of continuous 14-day treatment with phendimetrazine on cocaine vs. food choice in rhesus monkeys (N= 4). Methods: Responding was maintained under a concurrent schedule of food delivery (1-g pellets, fixed-ratio 100 schedule) and cocaine injections (0-0.1. mg/kg/injection, fixed-ratio 10 schedule). Cocaine choice dose-effect curves were determined daily before and during 14-day periods of continuous intravenous treatment with saline or (+)-phendimetrazine (0.32-1.0. mg/kg/h). Effects of 14-day treatment with (+)-phenmetrazine (0.1-0.32. mg/kg/h; N= 5) and d-amphetamine (0.032-0.1. mg/kg/h; N= 6) were also examined for comparison. Results: During saline treatment, food was primarily chosen during availability of low cocaine doses (0, 0.0032, and 0.01. mg/kg/injection), and cocaine was primarily chosen during availability of higher cocaine doses (0.032 and 0.1. mg/kg/injection). Phendimetrazine initially decreased overall responding without significantly altering cocaine choice. Over the course of 14 days, tolerance developed to rate decreasing effects, and phendimetrazine dose-dependently decreased cocaine choice (significant at 0.032. mg/kg/injection cocaine). Phenmetrazine and d-amphetamine produced qualitatively similar effects. Conclusions: These results demonstrate that phendimetrazine can produce significant, though modest, reductions in cocaine choice in rhesus monkeys. Phendimetrazine may be especially suitable as a candidate medication for human studies because of its schedule III clinical availability. © 2013 Elsevier Ireland Ltd.

Cleary K.L.,Columbia University | Roney K.,Research Triangle Institute International | Costantine M.,University of Texas Medical Branch
Seminars in Perinatology | Year: 2014

Statins (3-hydroxy-3 methyl-glutaryl coenzyme-A reductase inhibitors) are the most commonly prescribed cholesterol-lowering medications due to their efficacy in reducing cardiovascular mortality and morbidities, tolerability, and safety profiles. Based on pathophysiologic similarities between cardiovascular disease and preeclampsia, a common and dangerous complication of pregnancy, there is an increasing interest in studying this class of medications during pregnancy to prevent and/or treat preeclampsia. Undergoing such a study, which entails the use of a pregnancy class X medication for an off-label indication in pregnancy, requires intensive multidisciplinary involvement of a group of experts in basic and clinical pharmacology, research methods, pregnancy physiology and maternal-fetal medicine, as well as U.S. Food and Drug Administration (FDA) regulatory guidelines and practice. Issues of potential fetal risk, altered maternal-fetal pharmacokinetics and pharmacodynamics, and regulatory challenges are real, and must be carefully considered in the process of research in this arena. © 2014.

Jonas D.E.,University of North Carolina at Chapel Hill | Amick H.R.,University of North Carolina at Chapel Hill | Feltner C.,University of North Carolina at Chapel Hill | Bobashev G.,Research Triangle Institute International | And 8 more authors.
JAMA - Journal of the American Medical Association | Year: 2014

IMPORTANCE: Alcohol use disorders cause substantial morbidity and early mortality yet remain greatly undertreated. Medications are considerably underused. OBJECTIVE: To conduct a systematic review and meta-analysis of the benefits and harms of medications (US FDA-approved and others) for adults with alcohol use disorders. DATA SOURCES: PubMed, Cochrane Library, PsycINFO, CINAHL, EMBASE, FDA website, and clinical trials registries (January 1, 1970, to March 1, 2014). STUDY SELECTION: Two reviewers selected randomized clinical trials (RCTs) with at least 12 weeks' duration that reported eligible outcomes and head-to-head prospective cohort studies reporting health outcomes or harms. DATA EXTRACTION AND SYNTHESIS: We conducted meta-analyses using random-effects models and calculated numbers needed to treat for benefit (NNTs) or harm (NNHs). MAIN OUTCOMES AND MEASURES: Alcohol consumption, motor vehicle crashes, injuries, quality of life, function, mortality, and harms. RESULTS: We included 122 RCTs and 1 cohort study (total 22 803 participants). Most assessed acamprosate (27 studies, n = 7519), naltrexone (53 studies, n = 9140), or both. The NNT to prevent return to any drinking for acamprosate was 12 (95%CI, 8 to 26; risk difference [RD], -0.09; 95%CI, -0.14 to -0.04) and was 20 (95%CI, 11 to 500; RD, -0.05; 95%CI, -0.10 to -0.002) for oral naltrexone (50 mg/d). The NNT to prevent return to heavy drinking was 12 (95%CI, 8 to 26; RD -0.09; 95%CI, -0.13 to -0.04) for oral naltrexone (50 mg/d). Meta-analyses of trials comparing acamprosate to naltrexone found no statistically significant difference between them for return to any drinking (RD, 0.02; 95%CI, -0.03 to 0.08) or heavy drinking (RD, 0.01; 95%CI, -0.05 to 0.06). For injectable naltrexone,meta- analyses found no association with return to any drinking (RD, -0.04; 95%CI, -0.10 to 0.03) or heavy drinking (RD, -0.01; 95%CI, -0.14 to 0.13) but found an association with reduction in heavy drinking days (weighted mean difference [WMD], -4.6%; 95%CI, -8.5%to -0.56%). Among medications used off-label, moderate evidence supports an association with improvement in some consumption outcomes for nalmefene (heavy drinking days per month:WMD, -2.0; 95%CI, -3.0 to -1.0; drinks per drinking day:WMD, -1.02; 95%CI, -1.77 to -0.28) and topiramate (% heavy drinking days:WMD, -9.0%; 95%CI, -15.3%to -2.7%; drinks per drinking day:WMD, -1.0; 95%CI, -1.6 to -0.48). For naltrexone and nalmefene, NNHs for withdrawal from trials due to adverse events were 48 (95%CI, 30 to 112) and 12 (95%CI, 7 to 50), respectively; risk was not significantly increased for acamprosate or topiramate. CONCLUSIONS AND RELEVANCE: Both acamprosate and oral naltrexone were associated with reduction in return to drinking. When directly compared with one another, no significant differences were found between acamprosate and naltrexone for controlling alcohol consumption. Factors such as dosing frequency, potential adverse events, and availability of treatments may guide medication choice. Copyright 2014 American Medical Association. All rights reserved.

Witt K.,University of Oxford | van Dorn R.,Research Triangle Institute International | Fazel S.,University of Oxford
PLoS ONE | Year: 2013

Background: Previous reviews on risk and protective factors for violence in psychosis have produced contrasting findings. There is therefore a need to clarify the direction and strength of association of risk and protective factors for violent outcomes in individuals with psychosis. Method: We conducted a systematic review and meta-analysis using 6 electronic databases (CINAHL, EBSCO, EMBASE, Global Health, PsycINFO, PUBMED) and Google Scholar. Studies were identified that reported factors associated with violence in adults diagnosed, using DSM or ICD criteria, with schizophrenia and other psychoses. We considered non-English language studies and dissertations. Risk and protective factors were meta-analysed if reported in three or more primary studies. Meta-regression examined sources of heterogeneity. A novel meta-epidemiological approach was used to group similar risk factors into one of 10 domains. Sub-group analyses were then used to investigate whether risk domains differed for studies reporting severe violence (rather than aggression or hostility) and studies based in inpatient (rather than outpatient) settings. Findings: There were 110 eligible studies reporting on 45,533 individuals, 8,439 (18.5%) of whom were violent. A total of 39,995 (87.8%) were diagnosed with schizophrenia, 209 (0.4%) were diagnosed with bipolar disorder, and 5,329 (11.8%) were diagnosed with other psychoses. Dynamic (or modifiable) risk factors included hostile behaviour, recent drug misuse, non-adherence with psychological therapies (p values<0.001), higher poor impulse control scores, recent substance misuse, recent alcohol misuse (p values<0.01), and non-adherence with medication (p value <0.05). We also examined a number of static factors, the strongest of which were criminal history factors. When restricting outcomes to severe violence, these associations did not change materially. In studies investigating inpatient violence, associations differed in strength but not direction. Conclusion: Certain dynamic risk factors are strongly associated with increased violence risk in individuals with psychosis and their role in risk assessment and management warrants further examination. © 2013 Witt et al.

Singh J.P.,Molde University College | Desmarais S.L.,North Carolina State University | Van Dorn R.A.,Research Triangle Institute International
Behavioral Sciences and the Law | Year: 2013

The objective of the present review was to examine how predictive validity is analyzed and reported in studies of instruments used to assess violence risk. We reviewed 47 predictive validity studies published between 1990 and 2011 of 25 instruments that were included in two recent systematic reviews. Although all studies reported receiver operating characteristic curve analyses and the area under the curve (AUC) performance indicator, this methodology was defined inconsistently and findings often were misinterpreted. In addition, there was between-study variation in benchmarks used to determine whether AUCs were small, moderate, or large in magnitude. Though virtually all of the included instruments were designed to produce categorical estimates of risk - through the use of either actuarial risk bins or structured professional judgments - only a minority of studies calculated performance indicators for these categorical estimates. In addition to AUCs, other performance indicators, such as correlation coefficients, were reported in 60% of studies, but were infrequently defined or interpreted. An investigation of sources of heterogeneity did not reveal significant variation in reporting practices as a function of risk assessment approach (actuarial vs. structured professional judgment), study authorship, geographic location, type of journal (general vs. specialized audience), sample size, or year of publication. Findings suggest a need for standardization of predictive validity reporting to improve comparison across studies and instruments. © 2013 John Wiley & Sons, Ltd.

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