Research Triangle Institute International

Lake Park, NC, United States

Research Triangle Institute International

Lake Park, NC, United States
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Goldfinger J.Z.,Mount Sinai School of Medicine | Preiss L.R.,Research Triangle Institute International | Hendershot T.P.,Research Triangle Institute International | Kroner B.L.,Research Triangle Institute International | And 3 more authors.
Journal of the American College of Cardiology | Year: 2017

Background Previous small studies suggested reduced quality of life (QOL) for people with Marfan syndrome (MFS) compared with those without MFS. The national registry of GenTAC (Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions) is a longitudinal observational cohort study of patients with conditions that predispose to thoracic aortic aneurysms and dissections, including MFS. At the time of registry enrollment, GenTAC study participants are asked to complete questionnaires about demographics, medical history, health habits, and QOL. Objectives This study assessed QOL in GenTAC participants with MFS and identify associated factors using self-reported data. Methods QOL was assessed using the 4 subscales of the Physical Component Summary (PCS) of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36): physical functioning; role limitations due to physical health; bodily pain; and general health. We studied the association of QOL with self-reported demographics, health behaviors, physical impairments, surgeries, comorbid medical conditions, medications, and MFS severity. Results In the GenTAC registry, 389 adults with MFS completed the SF-36. Mean age was 41 years, 51% were men, 92% were white, and 65% were college graduates. The mean PCS composite score was 42.3. In bivariate analysis, predictors of better QOL included college education, marital status, higher household income, private health insurance, full-time employment, moderate alcohol use, fewer prior surgeries, fewer comorbid conditions, absence of depression, and less severe MFS manifestations. In a multivariable analysis, insurance status and employment remained significant predictors of QOL. Conclusions In a large cohort of patients with MFS in the GenTAC registry, health-related QOL was below the population norm. Better QOL was independently associated with socioeconomic factors, not factors related to general health or MFS severity. © 2017 American College of Cardiology Foundation

Wiley J.L.,Research Triangle Institute International | Marusich J.A.,Research Triangle Institute International | Lefever T.W.,Research Triangle Institute International | Grabenauer M.,Research Triangle Institute International | And 2 more authors.
Neuropharmacology | Year: 2013

Synthetic indole-derived cannabinoids have become commonly used recreational drugs and continue to be abused despite their adverse consequences. As compounds that were identified early in the epidemic (e.g., naphthoylindoles) have become legally banned, new compounds have appeared on the drug market. Two tetramethylcyclopropyl ketone indoles, UR-144 [(1-pentyl-1H-indol-3-yl)-(2,2,3,3-tetramethylcyclopropyl)methanone] and XLR-11 [(1-(5-fluoropentyl)-1H-indol-3-yl)-(2,2,3,3-tetramethylcyclopropyl)methanone], recently have been identified in confiscated products. These compounds are structurally related to a series of CB2-selective compounds explored by Abbott Labs. The purpose of the present study was to evaluate the extent to which UR-144 and XLR-11 shared cannabinoid effects with Δ9- tetrahydrocannabinol (Δ9-THC). Indices of in vitro and in vivo activity at cannabinoid receptors were assessed. Similar to other psychoactive cannabinoid agonists, XLR-11 and UR-144 showed low nanomolar (<30) affinity for CB1 and CB2 receptors, activated these receptors as full agonists, and produced dose-dependent effects that were blocked by rimonabant in mice, including antinociception, hypothermia, catalepsy and suppression of locomotor activity. The potency of both compounds was several-fold greater than Δ9-THC. XLR-11 and UR-144 also substituted for Δ9-THC in a Δ9-THC discrimination procedure in mice, effects that were attenuated by rimonabant. Analysis of urine from mice treated with the compounds revealed that both were extensively metabolized, with predominant urinary excretion as glucuronide conjugates. Together, these results demonstrate that UR-144 and XLR-11 share a pharmacological profile of in vitro and in vivo effects with Δ9-THC and other abused indole-derived cannabinoids and would be predicted to produce Δ9-THC-like subjective effects in humans. © 2013 Elsevier Ltd. All rights reserved.

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.

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.

Banks M.L.,Virginia Commonwealth University | Blough B.E.,Research Triangle Institute International | Fennell T.R.,Research Triangle Institute International | Snyder R.W.,Research Triangle Institute International | Negus S.S.,Virginia Commonwealth University
Neuropsychopharmacology | Year: 2013

There is currently no Food and Drug Administration-approved pharmacotherapy for cocaine addiction. Monoamine releasers such as d-amphetamine constitute one class of candidate medications, but clinical use and acceptance are hindered by their own high-abuse liability. Phendimetrazine (PDM) is a schedule III anorectic agent that functions as both a low-potency monoamine-uptake inhibitor and as a prodrug for the monoamine-releaser phenmetrazine (PM), and it may serve as a clinically available, effective, and safer alternative to d-amphetamine. This study determined efficacy of chronic PDM to reduce cocaine self-administration by rhesus monkeys (N=4) using a novel procedure that featured both daily assessments of cocaine vs food choice (to assess medication efficacy to reallocate behavior away from cocaine choice and toward choice of an alternative reinforcer) and 20 h/day cocaine access (to allow high-cocaine intake). Continuous 21-day treatment with ramping PDM doses (days 1-7: 0.32 mg/kg/h; days 8-21: 1.0 mg/kg/h) reduced cocaine choices, increased food choices, and nearly eliminated extended-access cocaine self-administration without affecting body weight. There was a trend for plasma PDM and PM levels to correlate with efficacy to decrease cocaine choice such that the monkey with the highest plasma PDM and PM levels also demonstrated the greatest reductions in cocaine choice. These results support further consideration of PDM as a candidate anti-cocaine addiction pharmacotherapy. Moreover, PDM may represent a novel pharmacotherapeutic approach for cocaine addiction because it may simultaneously function as both a monoamine-uptake inhibitor (via the parent drug PDM) and as a monoamine releaser (via the active metabolite PM). © 2013 American College of Neuropsychopharmacology. All rights reserved.

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.

Hersey J.C.,Research Triangle Institute International | Nonnemaker J.M.,Research Triangle Institute International | Homsi G.,Research Triangle Institute International
Nicotine and Tobacco Research | Year: 2010

Introduction: Menthol cigarettes are a common choice of cigarettes among young smokers that contribute to the addictive potential of cigarette smoking. Methods: We reviewed prior research and analyzed the 2006 National Youth Tobacco Survey (NYTS), using logistic regression to assess the relationship between menthol cigarette use and needing a cigarette within 1 hr after smoking. Results: In the 2006 NYTS, 51.7% (95% CI: 45.8-57.5) of middle school smokers and 43.1% (95% C.I.: 37.0, 49.1) of high school smokers reported that they usually smoked a menthol brand of cigarettes, using a menthol smoking status definition based on consistency between smokers' report of the brand and the menthol status of the cigarettes they usually smoked. A logistic regression model of dependence, controlling for background (i.e., school level, gender, and race/ethnicity) and smoking level (i.e., years, frequency, and level of smoking) found that smoking menthol cigarettes was significantly associated with reduced time to needing a cigarette among smokers with a regular brand (odds ratio [OR]: 1.86, p = .003) and among established smokers (OR: 2.06, p = .001). This is consistent with other studies that found that youth who smoked menthol cigarettes were significantly more likely than those who smoked nonmenthol cigarettes to report signs of nicotine dependency. Conclusions: Menthol cigarettes contribute to the appeal of youth smoking and to the addictive potential of smoking cigarettes among youth. It is important to control the use of menthol cigarettes and to implement cessation strategies that are effective with youth smokers. © The Author 2010. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved.

Jonas D.E.,University of North Carolina at Chapel Hill | Feltner C.,University of North Carolina at Chapel Hill | Amick H.R.,University of North Carolina at Chapel Hill | Sheridan S.,University of North Carolina at Chapel Hill | And 5 more authors.
Annals of Internal Medicine | Year: 2014

Background: Approximately 10% of ischemic strokes are caused by carotid artery stenosis (CAS). Estimated prevalence of asymptomatic CAS is 1%. Purpose: To evaluate evidence on screening and treating asymptomatic adults for CAS. Data Sources: MEDLINE, the Cochrane Library, EMBASE, and trial registries through September 2013; MEDLINE through March 2014 for trials. Study Selection: Good- or fair-quality trials of screening, carotid endarterectomy (CEA), or stenting compared with medical therapy or of intensification of medical therapy; systematic reviews; multi-institution studies reporting harms; and externally validated risk-stratification tools. Data Extraction: Dual extraction and quality assessment. Data Synthesis: No trials compared screening with no screening or stenting with medical therapy or assessed intensification of medical therapy, and no externally validated, reliable risk-stratification tools were found. Given the specificity of ultrasonography (range, 88% to 94% for CAS ≥50% to ≥70%), its use in low-prevalence populations would yield many false-positive results. Absolute reduction of nonperioperative strokes was 5.5% (95% CI, 3.9% to 7.0%; 3 trials; 5223 participants) over approximately 5 years for CEA compared with medical therapy. The 30-day rates of stroke or death after CEA in trials and cohort studies were 2.4% (CI, 1.7% to 3.1%; 6 trials; 3435 participants) and 3.3% (CI, 2.7% to 3.9%; 7 studies; 17 474 participants), respectively. Other harms of interventions included myocardial infarction, nerve injury, and hematoma. Limitations: Trials may have overestimated benefits and used highly selected surgeons. Medical therapy used in trials was out-dated, and stroke rates have declined in recent decades. Harms may have been underreported. Conclusion: Current evidence does not establish incremental over-all benefit of CEA, stenting, or intensification of medical therapy. Potential for overall benefit is limited by low prevalence and harms.

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