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Cheng J.,Virginia Commonwealth University | Joyce A.,Venebio Group LLC | Aouizerat B.,University of California at San Francisco | Sanyal A.J.,Virginia Commonwealth University
PLoS ONE | Year: 2012

Vitamin E was recently shown to improve hepatic histology in a randomized controlled trial of pioglitazone or vitamin E for nonalcoholic steatohepatitis (PIVENS). The current study utilized samples collected in the PIVENS trial to identify: (1) baseline metabolomic profiles that could identify who would respond to vitamin E treatment and (2) end of treatment metabolomic profiles reflective of histologic improvement. A comprehensive analysis of metabolomics profiles (n = 547) quantified by mass spectrometry was performed in vitamin E responders (n = 16), vitamin E non-responders (n = 15), and placebo responders (n = 15). At baseline, phenyl-propionic acid (Odds ratio: 29.4, p<0.01), indole-propionic acid levels (Odds ratio: 16.2, p<0.01) were directly associated with a subsequent histologic response to vitamin E treatment whereas γ-carboxyethylhydroxychroman (CEHC) levels were inversely related to histologic response. Adjusting for baseline values by analysis of covariance, the end of treatment levels of gamma-glutamyl leucine (Fold change: 0.82, p<0.02) and gamma-glutamyl valine (Fold change: 0.8, p<0.03) were significantly lower in vitamin E responders compared to non-responders. The levels of gamma-glutamyl transpeptidase were not significantly different across the two groups. Subjects receiving placebo who demonstrated a histologic improvement also demonstrated lower levels of gamma-glutamylated amino acids (leucine, valine and isoleucine) compared to vitamin E non-responders. These data provide exploratory proof that there are measurable differences in the metabolic profile of subjects who are likely (vs unlikely) to respond to vitamin E treatment for NASH and in those experiencing histologic improvement (vs no improvement) on treatment and support further studies to validate these biomarkers. © 2012 Cheng et al.


Lavonas E.J.,Denver Health and Hospital Authority | Lavonas E.J.,Aurora University | Banner W.,University of Oklahoma | Banner W.,Pediatric Intensive Care Unit | And 8 more authors.
Journal of Pediatrics | Year: 2013

Objective To characterize the rates, root causes, and clinical effects of unintentional exposures to buprenorphine sublingual formulations among young children and to determine whether exposure characteristics differ between formulations. Study design Unintentional exposures to buprenorphine-containing products among children 28 days to less than 6 years old were collected from the Researched Abuse, Diversion, and Addiction-Related Surveillance System Poison Center Program and Reckitt Benckiser Pharmaceuticals' pharmacovigilance system from October 2009-March 2012. After adjustment for drug availability, negative binomial regression was used to estimate average exposure rates. Root cause assessment was conducted, and an expert clinician panel adjudicated causality and severity of moderate to severe adverse events (AEs). Results A total of 2380 cases were reviewed, including 4 deaths. Exposures to buprenorphine-naloxone combination film were significantly less frequent than exposures to buprenorphine tablets (rate ratio 3.5 [95% CI, 2.7-4.5]) and buprenorphine-naloxone combination tablets (rate ratio 8.8 [7.2-10.6]). The most commonly identified root causes were medication stored in sight, accessed from a bag or purse, and not stored in the original packaging. Among 536 panel review cases, the most common AEs reported for all formulations were lethargy, respiratory depression, miosis, and vomiting. The highest level AE severity did not differ significantly by formulation. Conclusions Unintentional exposure to buprenorphine can cause central nervous system depression, respiratory depression, and death in young children. Exposure rates to film formulations are significantly less than to tablet formulations. Package and storage deficiencies contribute to unintentional exposures in young children. © 2013 Mosby Inc. All rights reserved.


PubMed | University of Minnesota, Virginia Commonwealth University, University of Colorado at Boulder, Karolinska Institutet and 7 more.
Type: | Journal: Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco | Year: 2016

Previous studies in adolescents were not adequately powered to accurately disentangle genetic and environmental influences on smoking initiation across adolescence.Mega-analysis of pooled genetically informative data on smoking initiation was performed, with structural equation modeling, to test equality of prevalence and correlations across cultural backgrounds, and to estimate the significance and effect size of genetic and environmental effects according to the classical twin study, in adolescent male and female twins from same-sex and opposite-sex twin pairs (N=19 313 pairs) between age 10 and 19, with 76 358 longitudinal assessments between 1983 and 2007, from 11 population-based twin samples from the US, Europe and Australia RESULTS: Although prevalences differed between samples, twin correlations did not, suggesting similar etiology of smoking initiation across developed countries. The estimate of additive genetic contributions to liability of smoking initiation increased from approximately 15% to 45% from age 13 to 19. Correspondingly, shared environmental factors accounted for a substantial proportion of variance in liability to smoking initiation at age 13 (70%) and gradually less by age 19 (40%).Both additive genetic and shared environmental factors significantly contribute to variance in smoking initiation throughout adolescence. The present study, the largest genetic epidemiological study on smoking initiation to date, found consistent results across 11 studies for the etiology of smoking initiation. Environmental factors, especially those shared by siblings in a family, primarily influence smoking initiation variance in early adolescence, while an increasing role of genetic factors is seen at later ages, which has important implications for prevention strategies.This is the first study to find evidence of genetic factors in liability to smoking initiation at ages as young as 12. It also shows the strongest evidence to date for decay of effects of the shared environment from early adolescence to young adulthood. We found remarkable consistency of twin correlations across studies reflecting similar etiology of liability to initiate smoking across different cultures and time periods. Thus familial factors strongly contribute to individual differences in who starts to smoke with a gradual increase in the impact of genetic factors and a corresponding decrease in that of the shared environment.


Zedler B.,Venebio Group LLC | Xie L.,STATinMED Research | Wang L.,STATinMED Research | Joyce A.,Venebio Group LLC | And 6 more authors.
Pain Medicine (United States) | Year: 2015

Objective: Develop a risk index to estimate the likelihood of life-threatening respiratory depression or overdose among medical users of prescription opioids. Subjects, Design, and Methods: A case-control analysis of administrative health care data from the Veterans' Health Administration identified 1,877,841 patients with a pharmacy record for an opioid prescription between October 1, 2010 and September 30, 2012. Overdose or serious opioid-induced respiratory depression (OSORD) occurred in 817. Ten controls were selected per case (n=8,170). Items for an OSORD risk index (RIOSORD) were selected through logistic regression modeling, with point values assigned to each predictor. Modeling of risk index scores produced predicted probabilities of OSORD; risk classes were defined by the predicted probability distribution. Results: Fifteen variables most highly associated with OSORD were retained as items, including mental health disorders and pharmacotherapy; impaired drug metabolism or excretion; pulmonary disorders; specific opioid characteristics; and recent hospital visits. The average predicted probability of experiencing OSORD ranged from 3% in the lowest risk decile to 94% in the highest, with excellent agreement between predicted and observed incidence across risk classes. The model's C-statistic was 0.88 and Hosmer-Lemeshow goodness-of-fit statistic 10.8 (P>0.05). Conclusion: RIOSORD performed well in identifying medical users of prescription opioids within the Veterans' Health Administration at elevated risk of overdose or life-threatening respiratory depression, those most likely to benefit from preventive interventions. This novel, clinically practical, risk index is intended to provide clinical decision support for safer pain management. It should be assessed, and refined as necessary, in a more generalizable population, and prospectively evaluated. © 2015 American Academy of Pain Medicine.


PubMed | Venebio Group LLC and STATinMED Research
Type: Journal Article | Journal: Pain medicine (Malden, Mass.) | Year: 2015

Develop a risk index to estimate the likelihood of life-threatening respiratory depression or overdose among medical users of prescription opioids.A case-control analysis of administrative health care data from the Veterans Health Administration identified 1,877,841 patients with a pharmacy record for an opioid prescription between October 1, 2010 and September 30, 2012. Overdose or serious opioid-induced respiratory depression (OSORD) occurred in 817. Ten controls were selected per case (n=8,170). Items for an OSORD risk index (RIOSORD) were selected through logistic regression modeling, with point values assigned to each predictor. Modeling of risk index scores produced predicted probabilities of OSORD; risk classes were defined by the predicted probability distribution.Fifteen variables most highly associated with OSORD were retained as items, including mental health disorders and pharmacotherapy; impaired drug metabolism or excretion; pulmonary disorders; specific opioid characteristics; and recent hospital visits. The average predicted probability of experiencing OSORD ranged from 3% in the lowest risk decile to 94% in the highest, with excellent agreement between predicted and observed incidence across risk classes. The models C-statistic was 0.88 and Hosmer-Lemeshow goodness-of-fit statistic 10.8 (P>0.05).RIOSORD performed well in identifying medical users of prescription opioids within the Veterans Health Administration at elevated risk of overdose or life-threatening respiratory depression, those most likely to benefit from preventive interventions. This novel, clinically practical, risk index is intended to provide clinical decision support for safer pain management. It should be assessed, and refined as necessary, in a more generalizable population, and prospectively evaluated.


Zedler B.K.,Venebio Group LLC | Joyce A.,Venebio Group LLC | Murrelle L.,Venebio Group LLC | Kakad P.,Virginia Commonwealth University | Harpe S.E.,Virginia Commonwealth University
Clinical Therapeutics | Year: 2011

Background: Calendar blister packaging (CBP) that incorporates a day or date feature is a simple medication packaging technology that is designed to improve medication adherence and persistence. Objective: This study was conducted to assess the effect of a new calendar packaging technology on prescription refill adherence and persistence for daily, self-administered, long-term medication use. Methods: Anonymized pharmacy dispensing data from a large US mass merchandiser were analyzed. This retrospective cohort study included people aged 18 to 75 years who filled prescriptions for oral lisinopril or enalapril (control group) at a study pharmacy during 1 year before and after the switch of lisinopril packaging from vials to CBP. Cohorts were stratified into new and prevalent medication users. We used linear and logistic regression modeling and propensity score matching to assess the impact of CBP on refill adherence, using medication possession ratio (MPR) and proportion of days covered (PDC), and persistence using length of therapy (LOT). Results: Our sample comprised 76,321 new users and 249,040 prevalent users. Across all user, medication, and packaging groups, the mean unadjusted LOT decreased in the follow-up year, possibly due to economic recession. The LOT decline was attenuated in the CBP cohort. After adjustment for covariates, CBP use in new and prevalent medication users was associated with significantly higher LOT and PDC but not MPR. The odds of achieving PDC ≥80% were higher by 15% in new users (odds ratio [OR] = 1.15; 95% CI, 1.09-1.21) and 12% in prevalent users (OR = 1.12; 95% CI, 1.09-1.15) who switched to CBP, compared with continued vial use. Conclusions: CBP of medication prescribed for daily, self-administered, long-term use was associated with modest improvement in prescription refill adherence and persistence. An adherence strategy of even small effect size that is broadly implemented on a population level could significantly leverage therapeutic effect and provide substantial cumulative public health benefit. Clinical benefit, or harm, associated with use of CBP should be investigated. Usability assessments of CBP in patient subgroups may provide insight about differential impact on adherence and persistence. © 2011 Elsevier HS Journals, Inc.


Lavonas E.J.,Denver Health and Hospital Authority | Severtson S.G.,Denver Health and Hospital Authority | Martinez E.M.,Denver Health and Hospital Authority | Bucher-Bartelson B.,Denver Health and Hospital Authority | And 8 more authors.
Journal of Substance Abuse Treatment | Year: 2014

Buprenorphine abuse is common worldwide. Rates of abuse and diversion of three sublingual buprenorphine formulations (single ingredient tablets; naloxone combination tablets and film) were compared. Data were obtained from the Researched Abuse, Diversion, and Addiction-Related Surveillance (RADARS®) System Poison Center, Drug Diversion, Opioid Treatment (OTP), Survey of Key Informants' Patients (SKIP), and College Survey Programs through December 2012. To control for drug availability, event ratios (rates) were calculated quarterly, based on the number of patients filling prescriptions for each formulation ("unique recipients of a dispensed drug," URDD) and averaged and compared using negative binomial regression. Abuse rates in the OTP, SKIP, and College Survey Programs were greatest for single ingredient tablets, and abuse rates in the Poison Center Program and illicit diversion rates were greatest for the combination tablets. Combination film rates were significantly less than rates for either tablet formulation in all programs. No geographic pattern could be discerned. © 2014 The Authors.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 607.59K | Year: 2016

Problem Over the last two decades unintentional opioid related overdose has emerged as a major public health threat in the United States This increasingly common yet preventable cause of morbidity and death among users of prescription opioids is partially due to a substantial expansion in the prescription of opioid analgesics to manage acute and chronic pain conditions Within any given year during the past five of the U S population filled at least one opioid prescription In million opioid prescriptions were written in the U S enough for every American adult to have one bottle of opioid painkillers in their home medicine cabinet In nearly two million Americans aged or older either abused or were dependent on opioid painkillers Opioid poisoning or overdose deaths have more than quadrupled from in to in Total prescription opioid overdose costs in the U S were more than $ billion in This is a significant and rapidly growing problem Solution Venebio Opioid Advisor VOA is a clinical decision support system CDSS based on VG s existing patent pending risk index algorithm that accurately identifies individuals at risk for overdose or serious opioid induced respiratory depression OIRD by utilizing evidence based clinical data gathered from patient electronic medical records EMRs as opioids are being prescribed VOA will be delivered via a stand alone computer application embedded in an EMR system or alternatively located on a remote server accessible through a secure Internet connection VOA will extract a patient s relevant clinical data automatically from the EMR assess the patient s risk for opioid overdose and present the patient s risk score directly to the health care provider enabling evidence based guidance and education that is personalized to the individual patientandapos s specific risk factor profile The ability to identify individuals at elevated risk of experiencing prescription opioid related toxicity or opioid overdose will provide awareness of the individual risk level to both the health care provider and the patient Methods The overarching objective of our proposed Phase II research is first to refine and validate the clinical content used to create the existing Venebio Opioid Advisor algorithm then to incorporate this refined information along with the additional evidence based guidance and educational content into a clinical decision support system and finally to validate this CDSS during a prospective pilot study of VOA in the real world clinical pain management setting Over the last two decades unintentional prescription opioid related overdose has emerged as a major public health threat in the United States Our innovative Venebio Opioid Adviser VOA technology has the potential to become an essential clinical decision support system to reduce opioid related overdose events thereby significantly decreasing associated morbidity mortality and overall healthcare economic burden


PubMed | Venebio Group LLC, Duke University and University of North Carolina at Chapel Hill
Type: Review | Journal: Addiction (Abingdon, England) | Year: 2016

To assess the safety of buprenorphine compared with methadone to treat pregnant women with opioid use disorder.We searched PubMed, Embase and the Cochrane Library from inception to February 2015 for randomized controlled trials (RCT) and observational cohort studies (OBS) that compared buprenorphine with methadone for treating opioid-dependent pregnant women. Two reviewers assessed independently the titles and abstracts of all search results and full texts of potentially eligible studies reporting original data for maternal/fetal/infant death, preterm birth, fetal growth outcomes, fetal/congenital anomalies, fetal/child neurodevelopment and/or maternal adverse events. We ascertained each studys risk of bias using validated instruments and assessed the strength of evidence for each outcome using established methods. We computed effect sizes using random-effects models for each outcome with two or more studies.Three RCTs (n=223) and 15 cohort OBSs (n=1923) met inclusion criteria. In meta-analyses using unadjusted data and methadone as comparator, buprenorphine was associated with lower risk of preterm birth [RCT risk ratio (RR)=0.40, 95% confidence interval (CI)=0.18, 0.91; OBS RR=0.67, 95% CI=0.50, 0.90], greater birth weight [RCT weighted mean difference (WMD)=277g, 95% CI=104, 450; OBS WMD=265g, 95% CI=196, 335] and larger head circumference [RCT WMD=0.90cm, 95% CI=0.14, 1.66; OBS WMD=0.68cm, 95% CI=0.41, 0.94]. No treatment differences were observed for spontaneous fetal death, fetal/congenital anomalies and other fetal growth measures, although the power to detect such differences may be inadequate due to small sample sizes.Moderately strong evidence indicates lower risk of preterm birth, greater birth weight and larger head circumference with buprenorphine treatment of maternal opioid use disorder during pregnancy compared with methadone treatment, and no greater harms.


PubMed | Venebio Group LLC
Type: | Journal: Substance abuse : research and treatment | Year: 2016

Untreated opioid dependence in pregnant women is associated with adverse birth outcomes. Buprenorphine and methadone are options for opioid agonist medication-assisted treatment during pregnancy.The aim of this study was to describe adverse birth outcomes observed with buprenorphine or methadone treatment compared to the general population in Sweden.Pregnant women and their corresponding births during 2005-2011 were identified in the Swedish Medical Birth Register. Data on stillbirth, neonatal/infant death, mode of delivery, gestational age at birth, Apgar score, growth outcomes, neonatal abstinence syndrome, and congenital malformations were examined. Frequencies were compared using two-sided Fishers exact tests. Unadjusted estimates of birth outcomes for women treated with buprenorphine or methadone were compared to the registered general population.A total of 746,257 pregnancies among 538,178 unique women resulted in 746,485 live births. Among the 194 women treated with buprenorphine (N = 176) or methadone (N = 52), no stillbirths or neonatal/infant deaths occurred. Neonatal abstinence syndrome developed in 23.3% and 38.5% of infants born to mothers treated with buprenorphine and methadone, respectively. The frequency of the selected adverse birth outcomes assessed in women treated with buprenorphine as compared to the general population was not significantly different. However, a significantly higher frequency of preterm birth and congenital malformations was observed in women treated with methadone as compared to the general population. Compared with the general population, methadone-treated women were significantly older than buprenorphine-treated women, and both treatment groups began prenatal care later, were more likely to smoke cigarettes, and did not cohabitate with the babys father.An increased frequency of the selected adverse birth outcomes was not observed with buprenorphine treatment during pregnancy. Twofold increased frequency of preterm birth [2.21 (1.11, 4,41)] and congenital malformations [2.05 (1.08, 3.87)] was observed in the methadone group, which may be partly explained by older average maternal age and differences in other measured and unmeasured confounders.

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