bluuebunny/crossref_metadata_2025_split huggingface dataset:
104 Valproate-Induced Hyperammonemic Encephalopathy: Case Studies
Authors: Matthews Dan , Matthews Glenda 
Published: June 2018

AbstractBACKGROUNDHyperammonemia and carnitine deficiency with concomitant encephalopathy have been reported to result from valproic acid administration (Coulter DL, J Child Neurol 1991Jan; 6(1); 7-14 and Mock, CM, et al, Am J Health Syst Pharm, 2012 Jan; 69(1):35-9). Although there have been numerous publications regarding this adverse event in the neurology literature, there have been very few reports published in the psychiatric literature. The reported incidence of hyperammonemia in children treated with valproate is 19%. It is important that prescribers be aware of the risk of valproic acid induced hyperammonemic encephalopathy, as well as its diagnosis and management.OBJECTIVEThe current study explores the feasibility of reversing Valproate Induced Hyperammonemic Encephalopathy (VHE) by discontinuing valproic acid and normalizing the carnitine level via L-carnitine supplementation.METHODSThree males (ages 10-16 years), are reported with 12 - 24 month histories of cognitive decline during treatment for “Bipolar Disorder of Childhood” with valproate. All were referred with multi-year histories of explosive/impulsive aggression and multiple unsuccessful psychopharmacological regimes. The one consistent medication throughout treatment was sodium valproate. The subjects received serial neuropsychological testing, complex EEG, MRI, valproic acid, carnitine, and ammonia blood levels. Oxcarbazepine titrated to 30-50 mg/kg/day was substituted for valproate after initial testing was completed. Normative reference laboratory levels were as follows: (1) ammonia (reference interval 15-45 mcg/dl), (2) total carnitine (reference interval 34-77 nmol/ml), and (3) valproic acid (reference interval 50-125 mcg/ml).RESULTSCase Study 1: Male, 10 years old, ammonia 78 mcg/dl; carnitine 17 nmol/ml; valproic acid 92 mcg/ml. IQ 79 (compared to 105 one year earlier); MRI cerebral atrophy; EEG - left temporal aberrancies.Case Study 2: Male, 12 years old, ammonia 76 mcg/dL; carnitine 14 nmol/ml; valproic acid 104 mcg/ml. IQ 89 (compared to 109); MRI normal; EEG - left temporal aberrancies.Case Study 3: Male, 16 years old, ammonia 72 mcg/dl; carnitine 24 nmol/ml; valproic acid 125 mcg/ml. IQ 45 (compared to 65); MRI normal; EEG - left temporal aberrancies.In all three subjects, after valproate was removed (oxcarbazepine substituted) and supplemental L-carnitine added, ammonia and total carnitine levels normalized. At one year follow up, IQ’s returned to previous baselines, and MRI atrophy (Case 1) normalized. EEG aberrancies were unchanged. Patients were mood and behaviorally stable on oxcarbazepine.CONCLUSIONEvidence of cognitive decline while on valproate warrants ammonia and carnitine level testing. If these levels are abnormal, VHE should be diagnosed and valproate should be removed as rapidly as feasible; L-carnitine supplementation (the lesser of 100 mg/kg/day or 2 grams/day) should be implemented to normalize the carnitine level.Funding AcknowledgementsNo funding.
127 Cardiovascular Safety Assessment of Deutetrabenazine in Healthy Volunteers and Implications for Patients With Huntington Disease or Tardive Dyskinesia
Authors: Cox Donna S. , Levi Micha , Rabinovich-Guilatt Laura , Truong David , Stamler David 
Published: June 2018

AbstractIntroductionDeutetrabenazine is approved for treating Huntington disease (HD) chorea and is being evaluated for tardive dyskinesia (TD).ObjectiveTo assess the effect of deutetrabenazine on cardiac repolarization.MethodsA QT interval study was performed to evaluate effects of deutetrabenazine 12 and 24 mg on cardiac repolarization, as assessed by time-matched change from baseline, placebo-adjusted, in Fridericia-corrected QT interval (ΔΔQTcF). Moxifloxacin (400 mg) and tetrabenazine (50 mg) were the positive control and comparator, respectively. An exposure–response analysis was developed from this study to predict maximal effects on QTcF at maximum recommended dosing based on CYP2D6 status, an approach consistent with regulatory guidance at predicting QT interval effects.ResultsMaximal ΔΔQTcF between the least-squares mean (90% two-sided confidence interval) of deutetrabenazine 12 and 24 mg (n=45 in each group) were 2.8 (0.7–4.8) ms and 4.5 (2.4–6.5) ms, respectively. The ΔΔQTcF increase with tetrabenazine (n=45) was 7.6 (5.6–9.5) ms. Assay sensitivity was verified with moxifloxacin (n=47), which produced a maximal effect on ΔΔQTcF of 14.0 (11.9–16.0) ms. A linear model was developed that described a correlation between plasma concentrations from pivotal HD andTD trials (n=101) and QT interval prolongation. Using that model and the individual predicted Cmax for HD and TD patients, the placebo-adjusted change from baseline inQTcF for deutetrabenazine at maximal recommended daily doses was found to be 5.4 (2.5–9.5) ms.ConclusionsPatients receiving the maximal recommended doses of deutetrabenazine are predicted to have a QTcF increase below the level of regulatory concern.Presented at: Psych Congress; September 16–19, 2017; New Orleans, Louisiana, USA.Funding AcknowledgementsThis study was funded by Teva Pharmaceutical Industries, Petach Tikva, Israel
129 Effect of DR/ER-MPH on Caregiver-Reported ADHD Symptom Improvement in Children With ADHD and Caregiver Strain: Results From a Phase 3 Trial
Authors: Pliszka Steven R. , Arnold Valerie K. , Marraffino Andrea , DeSousa Norberto J. , Incledon Bev , Sallee F. Randy , Wilens Timothy E. , Newcorn Jeffrey H. 
Published: June 2018

AbstractObjectiveEvening-dosed DR/ER-MPH (formerly HLD200), a delayed-release and extended-release methylphenidate, was designed to provide efficacy upon awakening and through the evening. The objective was to evaluate whether treatment with DR/ER-MPH in children with attention-deficit/hyperactivity disorder (ADHD): (1) improves caregiver-rated ADHD symptoms, and (2) reduces caregiver strain, versus placebo.MethodCaregiver-rated ADHD symptoms (Conners’ Global Index–Parent [CGI-P]) and caregiver strain (Caregiver Strain Questionnaire [CGSQ]) were assessed as secondary endpoints following 3 weeks of treatment in a randomized, double-blind, multicenter, placebo-controlled, parallel-group, phase 3 trial of DR/ER-MPH in children (6-12 years) with ADHD (NCT02520388). Using the 10-item CGI-P, parents rated their child’s ADHD symptoms on a 4-point scale (0=never/seldom; 3=very often/frequently). Caregivers also rated the impact of caring for a child with emotional and behavioral challenges on the 21-item CGSQ (5-point scale: 1=not at all; 5=very much). A reduction on individual item and total scores for both measures indicated an improvement.ResultsOf 163 children enrolled across 22 sites, 161 were included in the intent-to-treat population (DR/ER-MPH, n=81; placebo, n=80) and 138 completed the study. The mean DR/ER-MPH dose after 3 weeks of treatment was 68.1 mg. Mean CGI-P scores at baseline and CGSQ scores at screening (ie, before washout of prior ADHD therapy) were comparable for both DR/ER-MPH (CGI-P: 22.8, CGSQ: 54.5) and placebo (CGI-P: 21.8; CGSQ: 54.9) groups. After 3 weeks of treatment, caregivers of children onDR/ER-MPH reported significant reductions in CGI-P scores versus those on placebo (least-squares [LS] mean: 12.3 vs 17.4; P<0.001). Additionally, there was a significant reduction in CGSQ scores after 3 weeks of treatment with DR/ER-MPH versus placebo (LS mean: 41.2 vs 49.1; P<0.001). Post hoc analyses on the effect of DR/ER-MPHversus placebo on individual items of CGI-P and CGSQ, and the two subscales of CGI-P will be presented. No serious TEAEs were reported and all TEAEs were consistent with those of MPH.ConclusionsCaregivers reported significant improvements in their child’s ADHD symptoms and these improvements coincided with reductions in caregiver strain after 3 weeks of treatment on evening-dosed DR/ER-MPH versus placebo.Funding AcknowledgementsIronshore Pharmaceuticals & Development, Inc.
130 Consistent Efficacy of DR/ER-MPH on Early Morning Functioning in Children With ADHD: Analysis of BSFQ Item Ratings From a Pivotal Phase 3 Trial
Authors: Wilens Timothy E. , Pliszka Steven R. , Arnold Valerie K. , Marraffino Andrea , DeSousa Norberto J. , Incledon Bev , Sallee F. Randy , Newcorn Jeffrey H. 
Published: June 2018

AbstractObjectiveIn a phase 3 trial of children with attention-deficit/hyperactivity disorder (ADHD), DR/ER-MPH (formerly HLD200), a delayed-release and extended-release methylphenidate, improved ADHD symptoms and reduced at-home early morning and late afternoon/evening functional impairment versus placebo. The validated Before School Functioning Questionnaire (BSFQ), a key secondary endpoint, was used to measure early morning functional (EMF) impairment. This post hoc analysis evaluated the effect of DR/ER-MPH versus placebo on individual BSFQ item scores from baseline.MethodData were analyzed from a pivotal, randomized, double-blind, multicenter, placebo-controlled, parallel-group, phase 3 trial of DR/ER-MPH in children (6-12 years) withADHD (NCT02520388). Using the 20-item BSFQ, investigators evaluated EMF impairment by scoring each item on a severity scale of 0 to 3, with 0 denoting “no impairment” and 3 denoting “severe impairment”. For post hoc analyses, treatment comparisons between DR/ER-MPH and placebo at endpoint were determined by using least squares mean changes from baseline on individual BSFQ items score derived from an analysis of covariance (ANCOVA) model with treatment as the main effect, and study center and baseline score as covariates.ResultsOf 163 children enrolled across 22 sites, 161 were included in the intent-to-treat population (DR/ER-MPH, n=81; placebo, n=80) and 138 completed the study. The mean DR/ER-MPH dose achieved after 3 weeks of treatment was 68.1 mg. Following 3 weeks of treatment, DR/ER-MPH significantly reduced mean BSFQ item scores frombaseline on 18 out of 20 items versus placebo (P<0.001 in 8 items [listening, following directions, attention, forgetfulness, talkativeness, silliness, time awareness, getting to school]; P<0.01 in 7 items [overall organization, being quiet, distraction, interrupt/blurt out, breakfast, hygiene, independence]; P<0.05 in 3 items [procrastination, hyperactivity, awaiting turn]). Only “dressing” and “misplacing/losing items” showed no significant between-group differences (P=0.171 and P=0.175, respectively). Distributions of the severity ratings for each item will be presented. No serious TEAEs were reported; TEAEs were consistent with methylphenidate.ConclusionsPost hoc analyses revealed that DR/ER-MPH significantly reduced 18 out of 20 individual BSFQ item scores versus placebo in children with ADHD. These findings are worth further exploration.Funding AcknowledgementsIronshore Pharmaceuticals & Development, Inc.
132 Effects of Valbenazine on Depression and Suicidality in Adults With Tardive Dyskinesia: Pooled Results of 3 Double-Blind, Placebo-Controlled Trials
Authors: Remington Gary , Thai-Cuarto Dao , Burke Joshua , Siegert Scott , Liang Grace S. 
Published: June 2018

AbstractStudy ObjectivesValbenazine (INGREZZA; VBZ) is a novel and highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor that is approved for the treatment of tardive dyskinesia (TD) in adults. The randomized, double-blind, placebo (PBO)-controlled trials of VBZ evaluated the treatment of TD in patients with a primary psychiatric diagnosis (schizophrenia/schizoaffective disorder or mood disorder) while on concomitant psychiatric medications to manage these disorders. Since treatment-emergent depression and suicidal ideation/behavior are important clinical concerns in psychiatric patient populations, data from these trials were analyzed to assess the effectsof once-daily VBZ on depression and suicidality.MethodsData were pooled from three 6-week trials: KINECT (NCT01688037), KINECT 2 (NCT01733121), KINECT 3 (NCT02274558). Outcome data were analyzed in the safety population by pooled VBZ doses (40 mg, 80 mg) and PBO. Outcomes of interest included: treatment-emergent adverse events (TEAEs) related to depression or suicidality; mean score change from baseline to Week 6 in the Calgary Depression Scale for Schizophrenia (CDSS, for participants with schizophrenia/schizoaffective disorder) or the Montgomery-Åsberg Depression Rating Scale (MADRS, for participants with mood disorder); and, worsening from baseline in Columbia-Suicide Severity Rating Scale (C-SSRS) suicidal ideation scores. All outcomes were analyzed descriptively.ResultsThere were 400 total participants in the pooled safety population; 286 participants had schizophrenia/schizoaffective disorder (40 mg, n=82; 80 mg, n=70; PBO, n=134) and 114 had a mood disorder (40 mg, n=28; 80 mg, n=42; PBO, n=44). Over one-third of participants had a lifetime history of suicidal ideation or behavior (40 mg, 45%; 80 mg, 39%; PBO, 37%). Few participants had a depression- or suicide-related TEAE, with no apparent differences between VBZ and PBO: suicidal ideation (40 mg, 3.6%; 80 mg, 0.9%; PBO, 2.2%); depression (40 mg, 0%; 80 mg, 1.8%; PBO, 1.1%); depressive symptom (40 mg, 0.9%; 80 mg, 0%; PBO, 0.6%); suicide attempt (40 mg, 0%; 80 mg, 0.9%; PBO, 0%). Mean changes from baseline to Week 6 in depression scale scores were generally small and similar across treatment groups: CDSS total score (40 mg, -0.5; 80 mg, -0.6; PBO, -0.3); MADRS total score (40 mg, -0.2; 80 mg, -1.7; PBO, 0.6). Few participants had a shift from no suicidal ideation at baseline (C-SSRS score=0) to any suicidal ideation during treatment (C-SSRS score=1-5): 40 mg, 3.9% (4/103); 80 mg, 0.9% (1/111); PBO, 2.9% (5/174).ConclusionData from 3 double-blind, placebo-controlled trials indicate that once-daily VBZ treatment was not associated with a worsening in depression-related symptoms or an increased risk of suicidal ideation or behavior.Funding AcknowledgementsThis study was funded by Neurocrine Biosciences, Inc.
158 Long-Term Safety of Deutetrabenazine for the Treatment of Tardive Dyskinesia: Results From an Open-Label, Long-Term Study
Authors: Anderson Karen E. , Davis Mat D. , Factor Stewart A. , Hauser Robert A. , Jarskog L. Fredrik , Jimenez-Shahed Joohi , Kumar Rajeev , Ochudlo Stanislaw , Ondo William G. , Fernandez Hubert H. 
Published: June 2018

AbstractIntroductionIn the 12-week ARM-TD and AIM-TD studies, deutetrabenazine showed clinically significant improvements in Abnormal Involuntary Movement Scale (AIMS) scores at Week 12 compared with placebo, and was generally well tolerated.ObjectiveTo evaluate the long-term safety/tolerability and efficacy of deutetrabenazine in patients with TD. Week 54 open-labelresults are reported in this interim analysis.MethodsPatients with TD who completed ARM-TD or AIM-TD were included in this open-label, single-arm extension study, in which all patients restarted/started deutetrabenazine 12 mg/day, titrating up to a maximum total daily dose of 48 mg/day based on dyskinesia control and tolerability. The study comprised a 6-week titration period and a long-term maintenance phase. Safetymeasures included incidence of adverse events (AEs), serious AEs (SAEs), drug-related AEs, and AEs leading to withdrawal, dose reduction, or dose suspension. This analysis reports results up to Week 54.Results304 patients enrolled in the extension study. There were 215 patient-years of exposure in this analysis, and exposure-adjusted incidence rates (EAIRs) of AEs (incidence/patient-years) were comparable to or lower than those observed with short-term deutetrabenazine treatment and placebo. The frequency of SAEs (EAIR 0.14) was similar to rates observed with short-termplacebo (EAIR 0.33) and deutetrabenazine (EAIR range 0.06–0.33) treatment. AEs leading to study discontinuation (EAIR 0.08), dose reduction (EAIR 0.17), and dose suspension (EAIR 0.09) were uncommon.ConclusionsLong-term treatment with deutetrabenazine was generally safe and well tolerated in patients with TD, and did not result in cumulative toxicity.Presented at: The American Psychiatric Association 2017 Annual Meeting; May 20–24, 2017; San Diego, California, USA.Funding AcknowledgementsThis study was funded by Teva Pharmaceutical Industries, Petach Tikva, Israel.
199 Cardiac Safety and QTc Intervals With DM/Q Treatment for Pseudobulbar Affect: A Review of Clinical Trial Data
Authors: Mason Jay W. , Hugentobler Emmanuelle , Formella Andrea E. , Pope Laura E. 
Published: June 2018

AbstractOBJECTIVEDextromethorphan hydrobromide and quinidine sulfate (DM/Q) 20mg/10mg is FDA approved to treat pseudobulbar affect (PBA), a neurological condition characterized by sudden, frequent, involuntary crying or laughing. Although the total dose of quinidine (20 mg) from twice daily DM/Q for PBA is well below the antiarrhythmic dose (600-1600 mg/day), clinicians may be reticent to use DM/Q due to concerns for cardiac safety.METHODDM/Q cardiac safety was evaluated in two thorough QTc (TQT) studies and by ECG monitoring in DM/Q phase 3 clinical trials. In the TQT studies, twice daily DM/Q 30mg/10mg (Study 08-AVR-126; N=50 enrolled) and supratherapeutic doses 30mg/30mg and 60mg/60mg (Study 05-AVR-119; N=36 enrolled) were studied in healthy volunteers. In phase 3 controlled clinical trials, the effects of DM/Q on Fridericia’s corrected QT intervals (QTcF) were assessed, as was the incidence of ECG outliers. Adverse events (AEs) were monitored in all clinical trials.RESULTSOverall, 47/50 participants completed TQT study 08-AVR-126 and 36/36 completed TQT study 05-AVR-119. Time-matched, placebo-corrected mean maximal changes in QTcF for DM/Q 30mg/10mg and 30mg/30mg occurred 3h post-dose (10.3 and 10.1ms, respectively) vs moxifloxacin (12.2 and 14.4ms at 1.5 and 1.0h). For the supratherapeutic DM/Q 60/60 mg dose, mean maximal QTcF change was 18.8ms. No participant had a QTcF >480 ms or QTc increase >60 ms. In PBA phase 3 controlled trials, mean changes in QTcF were similar for DM/Q containing Q 10 mg (0.4 to 3.5 ms; n=217) andplacebo (0.4 to 3.1 ms; n=183), but greater for DM/Q with Q 30 mg (2.9 to 7.6 ms; n=146). In an outlier analysis, a similar percentage of DM/Q-treated participants (3.9%) had a QTcF shift from <450 ms at baseline to ≥450 ms during treatment vs placebo (2.9%). No participant with PBA had a QTc change from baseline >60 ms or an absolute QTc interval >480 ms. No dose- or time-related trends in cardiac arrhythmias or other cardiac-related AEs were observed.Of 2552 DM/Q-treated patients and healthy participants across all controlled and open-label trials for any indication, 11 deaths due to any cardiovascular AE have been reported; none were attributable to DM/Q treatment and none occurred in placebo-controlled PBA clinical trials in any treatment group. Overall 16 patients had a QTcF that exceeded 500 ms at any ECG measurement.CONCLUSIONSThe TQT studies demonstrated that DM/Q has the potential to prolong the QT interval in a dose-dependent manner, but that the risk for QTc prolongation and arrhythmias with Q 10 mg formulations is low. In clinical trials with PBA patients, the cardiac safety profile of DM/Q 20mg/10mg or 30/10 mg was indistinguishable from placebo.Funding AcknowledgementsAvanir Pharmaceuticals, Inc.
Decentralised clinical training in optometry: a developmental strategy for eye health in KwaZulu Natal?
Authors: van Staden Diane 
Published: June 2018

AbstractBackgroundDecentralised clinical training (DCT) in optometry is an emerging concept in South Africa. In 2016, the University of KwaZulu Natal (UKZN) implemented this adaptive model of clinical training for undergraduate health professions. The initiative, which emanated through an agreement between UKZN’s College of Health Sciences and the KwaZulu Natal Department of Health, centres on the placement of undergraduate optometry students within public health facilities for clinical training purposes. Optometry services in South Africa have, however, had a historical bias towards a private sector model of training and a curative practice approach resulting in access barriers for the rural poor and high levels of unmet need. It has further contributed to a general state of underdevelopment of eye health services within the public sector.DiscussionDCT challenges historical undergraduate programme structures and modes of teaching and learning in optometry. It is largely underpinned by a need to strengthen health service delivery through a primary health care-centred, community-based training approach and produce ‘fit-for-purpose’ graduates who have contextually appropriate competencies for effective, local health service delivery. The historical absence of optometry services within the public sector has, however, contributed to limited planning for, and development of eye health services in this sector. This has inadvertently contributed to the burden of avoidable vision impairment in the country. The public health system in South Africa, therefore, faces various developmental challenges which impact eye health services and student clinical training.ConclusionWhile the model is still in a developmental state and resourcing challenges potentially affecting DCT are noted, early experiences of the Discipline of Optometry at the UKZN are that DCT shows promise in terms of its potential contribution towards the development of eye health services within the public health sector from graduate readiness, resource strengthening, access improvement and health service development perspectives.
Cover crop nitrogen contribution to organic broccoli production
Authors: Luna John M. , Sullivan Dan , Garrett Amy M. , Xue Lan 
Published: June 2018

AbstractNitrogen (N) is a difficult nutrient to manage in organic farming systems, and yield reductions related to N deficiency have been reported in organic systems. Legume-based cover crops offer opportunities for biologically fixed N; however, improved quantification of N contribution is needed for cost-effective N management. A 2-yr experiment was conducted near Corvallis, OR, USA, in 2007 and 2008 to (1) evaluate biomass production and N accumulation from selected cover crop treatments, (2) compare the effects of fall-planted cover crops on broccoli [(Brassica oleraceaeL. (Italica group)] yield, (3) estimate the quantity of feather meal-N replaced by cover crops. Cover crop treatments included common vetch (Vicia sativaL.), phacelia (Phacelia tanacetifoliaBenth), oats (Avena sativaL.) and the mixtures phacelia plus vetch, oats plus vetch and a no-cover crop (fallow) treatment as the control. Using feather meal as an N source, four rates of N fertilizer (0, 100, 200 and 300 kg N ha−1) were randomized within each cover crop treatment in a randomized, split-plot design. Cover crop biomass and N accumulation differed between the 2 yr of the study. In 2007, total biomass accumulation ranged from 5000 to 10,000 kg ha−1, whereas in 2008, cover crop accumulation was 1500 to 5000 kg ha−1. Biomass of both phacelia and vetch (in mixtures or as sole crops) was reduced by 80% from 2007 to 2008, whereas oat biomass and weed biomass in the fallow plots was reduced by only 40% between the 2 yr. The accumulation of N was also reduced in 2008, with vetch (either as a sole crop or in mixtures) contributing less than a third of total N produced in 2007. In 2007, vetch and vetch-based cover crop mixtures increased broccoli yield compared with the fallow, providing 100–135 kg fertilizer equivalent N ha−1. But due to decreased cover crop biomass and N accumulation in 2008, vetch and vetch-based mixtures failed to increase broccoli yield, providing <20 kg N ha−1fertilizer equivalence. In 2007, oats grown as a sole cover crop reduced broccoli yield when no supplemental N was applied. In 2008, both phacelia and oats reduced broccoli yield at all N levels, with estimated N fertilizer equivalence values of −80 to −95 kg N ha−1. Although legume and legume mixtures increased broccoli yield in only 1 yr of the experiment, addition of vetch to the mixtures reduced yield loss in both years compared with oats and phacelia grown as sole crops.